A Phase II Trial of Gemcitabine and Erlotinib (GE) Plus Proton-chemotherapy (PCT) and Capox for Locally Advanced Pancreatic Cancer (LAPC)
Phase: NA
Conditions: Pancreatic Cancer
Sponsor: Loma Linda University

 
 
A Phase II Trial of Gemcitabine and Erlotinib (GE) plus Proton-chemotherapy (PCT) and 
CapOx for Locally Advanced Pancreatic Cancer (LAPC) 
 
IRB# 5110324 
PI   Gary Yang, MD 
 
**NCT# 01683422 
 
 
Results reporting:  ClinicalTrials.Gov 
 
 
Protocol 
 
Version dated September 27, 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
 
 
 
 
IRB# 5110324 
 
 
 
 
 
RMPT 1201 
 
A Phase II Trial of Gemcitabine and Erlotinib (GE) plus Proton-chemotherapy (PCT) and 
CapOx for Locally Advanced Pancreatic Cancer (LAPC) 
 
 
 
 
 
 
 
Principal Investigator 
Gary Y Yang, MD 
 
Proton Therapy Principal Investigator 
Jerry D Slater, MD 
 
Co-Investigators 
Chung-Tsen Hsueh, MD, PhD 
S Mirshahidi, PhD 
Jun Wang, MD 
Carlos Garberoglio, MD 
Mark Reeves, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
3 
 
 
Current Edition: September 27, 2014; January 12, 2012 
 
INDEX 
Schema 
Eligibility Check 
1.0 Introduction 
2.0 Objectives 
3.0 Patient Selection 
4.0 Pretreatment Evaluations 
5.0 Registration Procedures 
6.0 Radiation Therapy 
7.0 Drug Therapy 
8.0Tissue/Specimen  
9.0 Toxicity Related Therapy Adjustment 
10.0 Patient Assessments 
11.0 Statistics 
References 
Appendix I - Staging System 
Appendix II - FACIT Fatigue Scale Questionnaire 
 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Proton-chemotherapy (PCT) 
Patients will receive a combination of the agents (Gemcitabine plus Erlotinib) for 8 weeks prior to PCT 
Gemcitabine 1000 mg/m2 IV, days 1, 8, 15, 29, 36 and 43 
Erlotinib 100 mg po qd days 1-43 
 
PCT 
To be started in 4 to 8 weeks after completion of Pre-PCT 
Proton therapy: 50.4 Gy/28 fractions (1.8 Gy per fraction) once a day for 5 ½ weeks. 
Chemotherapy: Capecitabine 825mg/m2 po bid M-F, starting on day 1 of proton therapy until proton therapy 
completed 
 
Post-PCT 
To be started in 4 to 6 weeks after completion of PCT 
Oxaliplatin 130 mg/m2, day 1  
Capecitabine 1000 mg/m2 po bid on days 2 to 15 for 14 days 
The CapOx regimen (Capecitabine plus Oxaliplatin) is repeated every 3 weeks for 4 cycles 
 
 
 
Gemcitabine  
+ Erlotinib 
Proton 
therapy +  
Capcitabine 
R 
E 
G 
I 
S 
T 
E 
R 
Patients with 
Unresectable 
Pancreatic 
Adenocarcinoma 
 
Evaluate to Confirm  
No Metastasis 
Oxaliplatin  
+ Capcitabine 
(CaPox) 
 
 
 

 
4 
ELIGIBILITY: (See Section 3.0 for details) 
- Pathologically-confirmed unresectable non-metastatic adenocarcinoma of the pancreas 
- Radiographically assessable. 
- No prior irradiation to the planned field. 
- WBC ≥ 2,000 cells/mm3 
- ANC ≥1,500 cells/mm3 
- Platelets ≥ 100,000 cells/mm3 
- Serum bilirubin ≤ 2.5 mg/dL 
- Serum creatinine ≤ 2 x upper limit of normal (ULN), or creatinine clearance (Ccr) ≥ 30ml/min  
- ALT ≤ 3 x ULN 
- AST ≤ 3 x ULN 
- Signed study-specific consent form 
 
Required Sample Size: 43 
 
ELIGIBILITY CHECK  
(Y) 1. Does the patient have a pathologically-confirmed adenocarcinoma of the pancreas? 
(Y) 2. Does the patient have unresectable disease? 
(N) 3. Is there evidence of metastatic disease in the major viscera or peritoneal seeding? 
(Y/N) 4. Does the patient have biliary or gastroduodual obstruction? 
(Y) If yes, does/will the patient have drainage prior to beginning PCT? 
(Y) 5. Does the patient have radiographically measurable disease? 
(N) 6. Has the patient had prior radiation to the planned field? 
(N) 7. Has the patient had prior chemotherapy? 
 
 
1.0    INTRODUCTION 
 
1.1     Background 
Pancreatic cancer remains a highly lethal malignancy despite advances in treatment.  At present, 
complete surgical resection offers the best chance of cure. However, because of the invasion of 
major vessels or the presence of metastasis, at initial diagnosis, 50% of patients already present 
with metastatic disease, 30% present with a locally advanced (unresectable) tumor and only 20% 
are resectable. The prognosis for locally advanced pancreatic cancer (LAPC), 6-10 months, lies 
between those for metastatic and resected disease1. 
 
1.2     The Role of Combined Therapy for Locally Advanced Pancreatic Cancer 
The role of combined therapy for LAPC continues to evolve. The goals of radiotherapy in LAPC 
include improvement in local control and palliation of pain and/or obstructive symptoms. Trials of 
chemoradiotherapy (CRT) versus chemotherapy alone in LAPC have reported mixed findings 
regarding survival 2-6.  In a trial conducted by the Gastrointestinal Tumor Study Group5 the effect 
of concurrent CRT versus chemotherapy alone in LAPC was evaluated and a benefit in survival 
from combined modality therapy was noted. The CRT arm consisted of radiation combined with 
5-fluorouracil to a total dose of 54 Gy in 1.8 Gy fractions followed by maintenance streptozocin, 
mitomycin and 5-fluorouracil (SMF). The chemotherapy-only arm was SMF combination 
chemotherapy for two years or until progression. In this trial, the one-year OS was 41% in the 
CRT arm compared to 19% in the chemotherapyalone arm (p<0.02). 
 
Modern chemotherapy and radiation techniques have been tested in two recent phase III trials 
evaluating the efficacy of CRT. In the trial by the Eastern Cooperative Oncology Group (E4201), 
patients with LAPC were randomly assigned to CRT (50.4 Gy in 28 fractions) with concurrent 
gemcitabine (600 mg/m2 weekly x 6) followed by 5 cycles of gemcitabine alone (1,000 mg/m2 
weekly x 3 every 4 wks) versus gemcitabine alone (1,000 mg/m2 weekly x 3 every 4 wks) for 7 
cycles. This trial showed that CRTwas associated with a slightly improved survival (11 versus 9.2 
months, p=0.044) 2. 
 

 
5 
In a second recent study by Chauffert et al. reported in 2008, 10 CRT was delivered to a total dose 
of 60 Gy concurrently with cisplatin (20 mg/m2/day, days 1–5during weeks 1 and 5) and 5-
fluorouracil (300 mg/m2/day, days 1–5 for 6 weeks). Thechemotherapy-alone arm consisted of 
gemcitabine (1000 mg/m2 weekly for 7 weeks).Maintenance gemcitabine (1000 mg/m2 weekly, 
3/4 weeks) was given in both arms until disease progression or toxicity. Overall survival in this 
trial was shorter in the CRT arm (13.0 vs. 8.6 months, p=0.044) and these patients experienced a 
higher rate of grade 3-4 toxicity compared with the chemotherapy arm (66% vs. 40% respectively; 
p=0.0008). A potential explanation for increased toxicity is the combination of aggressive 
chemotherapy delivered with concurrent radiation (60 Gy followed by high-dose weekly 
maintenance Gemcitabine). Due to inferior survival in the CRT arm, this study was stopped prior 
to planned enrollment. However, it adds to the growing body of opinion that the benefit of CRT 
for LAPC is likely confined to a carefully selected group of patients. 
 
1.3      Erlotinib and Gemcitabine in Pancreatic Cancer 
The epidermal growth factor receptor (EGFR) is a cell surface receptor for EGF and transforming 
growth factor-alpha which is over expressed by a number of human tumors. Erlotinib is an oral 
selective EGFR tyrosine kinase inhibitor, the only drug of its class approved for the treatment for 
first-line treatment of advanced pancreatic cancer with Gemcitabine. 
 
The FDA approved Erlotinib in combination with Gemcitabine for the treatment of patients with 
locally advanced, unresectable or metastatic pancreatic carcinoma in 2005. This approval was on 
the basis of the results of the large, double-blind, randomized, multicenter Phase III trial 7.  This 
study randomized 569 patients with locally advanced or metastatic pancreatic adenocarcinoma in 
a1:1 ratio to Gemcitabine with Erlotinib versus Gemcitabine and placebo. The primary end point 
was overall survival, and secondary end points were progression-free survival, tumor response rate 
and duration of response, role of EGFR status and survival, and quality of life. Patients in the 
Gemcitabine and Erlotinib arm had a prolonged median survival of 6.24 months versus 5.91 
months in the Gemcitabine and placebo arm, which was statisticallysignificant (p = 0.038). One-
year survival was 23% in the Erlotinib arm versus 17% in the placebo arm, and progression free 
survival was also significantly longer in the Erlotinib with Gemcitabine arm than the placebo with 
Gemcitabine arm (3.75 vs 3.55 months; p = 0.004). There was no significant difference between 
the two arms in global qualityof life scores, and EGFR status did not correlate to response, disease 
stability or survival. 
 
1.4     Proton Beam Therapy 
The beneficial feature of the proton beam is that it produces excellent dose localization to a target 
compared with photons.  The proton beam allows reduction of the irradiated volume and dose 
given to the normal liver, kidneys and digestive tract, while increasing the dose conformality to 
the tumor.  Several dosimetric and phase I studies have shown that it is effective and feasible in 
treating pancreatic cancer regardless of the degree of tumor size, and presence or absence of 
combined therapies8-12. 
 
For localized pancreatic cancer, dose distribution patterns achievable with proton beam could 
potentially offer important clinical advantages relative to those achievable with x-rays.  Based on 
this, we believe that this study should be conducted with the modality that offers the best 
dosimetry achievable at our institution. 
 
1.5     Capecitabine and Oxaliplatin, CapOx 
There is no established second-line chemotherapy for patients with pancreatic cancer who have 
received Gemcitabine-based therapy. A multicenter randomized phase II trial was performed to 
compare the efficacy and safety of three different chemotherapy doublets in the treatment of 
advanced pancreatic cancer (PC) 13.At total of 190 patients were randomly assigned to receive 
Capecitabine plus Oxaliplatin (CapOx), Capecitabine plus Gemcitabine (CapGem) or Gemcitabine 
plus Oxaliplatin (mGemOx). Treatment cycles were repeated every three weeks. The result of the 
study showed CapOx, CapGem and mGemOx have similar clinical efficacy. Each regimen has a 
distinct but manageable tolerability profile. A phase II study from MD Anderson showed the 

 
6 
combination of capecitabine and oxaliplatin is active in Gemcitabine-pretreated patients with 
LAPC, especially in patients with a good PS and those who have responded to first-line 
chemotherapy 14.Of the 39 evaluable patients, 1 patient had a partial response and 10 patients 
demonstrated stable disease.The most common grade 3-4 nonhematologic toxicity was fatigue. 
 
1.6     Correlative Studies 
Appropriate identification and validation of biomarkers as well as pharmacogenetics are important 
in formulating patient-oriented, individualized chemoradiotherapy or biological therapy in cancer 
patients. These markers can be especially valuable in pancreatic cancer, where high mortality and 
complex disease biology are frequently encountered.  
 
Recently, several advances have been made to further our knowledge in this specific area of 
pancreatic cancer.  Researchers have identified several potential biomarkers:  shorter EGFR intron 
1 CA repeat length is associated with worse pancreatic cancer clinical prognosis and in vitro 
response to Erlotinib. EGFR intron 1 length can be reliably measured in peripheral blood and may 
translate into a quantitative predictive marker of both pancreatic cancer aggressiveness and 
Erlotinib sensitivity15; the increased level of 14-3-3s protein likely contributes to the poor clinical 
outcome of pancreatic cancer by causing resistance to radiation and anticancer drugs 16; 
methylenetetrahydrofolatereductase (MTHFR) single nucleotide polymorphisms predicted serum 
folate and plasma homocysteine levels, and, combined, these factors may be important predictors 
of Capecitabine induced toxicity 17.  Additional markers affect clinical prognosis of patients and 
treatment toxicities will also be investigated18 (see Section 10). 
 
1.7     Quality of Life/Patient-Reported Outcomes 
1.7.1  
               Importance of Patient-reported Outcomes in Pancreas Cancer 
Patient-reported outcomes, in addition to overall survival, are now accepted by oncologists as an 
important clinical endpoint in clinical trial design for patients with advanced pancreatic cancer. 
This is largely based on the landmark randomized trial of Burris et.al, which reported, for patients 
with advanced pancreatic cancer, a significant increase using Gemcitabine (rather than 
Fluorouracil) in the “clinical benefit response” that included nontraditional measures related to 
symptoms, including pain, performance status and weight 19. To date, there has been limited 
available literature using formal patient reported measures for patients with pancreatic cancer 20. 
This is unfortunate, because the majority of patients with this cancer have incurable disease and 
palliation and quality of their remaining life become the major goals. 
1.7.2 
Patient-Reported Fatigue Using FACIT-Fatigue May Predict for Overall Survival in Patients with 
Pancreatic Cancer 
Fatigue has been described as the most frequent and distressing symptom related to cancer and its 
treatment 21. The FACIT-Fatigue, version 4, is a 13-item questionnaire that assesses self-reported 
tiredness, weakness, and difficulty conducting usual activities due to fatigue. This questionnaire 
can be completed by patients in approximately 5 minutes.  The FACIT-Fatigue is a 
psychometrically sound instrument and has been widely used to measure fatigue for patients with 
various chronic illnesses including cancer 22. Data has suggested a high baseline FACIT–Fatigue 
score (> 30), indicating low fatigue, was the best predictor of longer overall survival in a stepwise, 
Cox proportional hazards multiple-regression analysis (HR, 0.47; CI: 0.30–0.74) 23. We 
hypothesize that patients reporting low baseline fatigue, as measured by the FACIT-Fatigue13 
item questionnaire, will experience longer overall survival. 
 
1.8     Study Rationale and Potential Significance 
The current trend toward using the biology of the disease as it becomes evident over a period of 
chemotherapy to better select patients who will benefit from CRT seems to be the most pragmatic 
way to proceed, until we have a better means of predicting tumor behavior and more active 
systemic agents.This has led to increased interest in treatment regimens incorporating induction 
chemotherapy with target agent followed by CRT and additional chemotherapy for diseases that 
carry a high risk for systemic relapse. 
 

 
7 
The PA.3 trial was the first phase III trial in advanced pancreatic cancer to show a survival 
advantage with the addition of a second drug, in this case the oral EGFR inhibitor Erlotinib to 
gemcitabine. The approval provides an important proof of concept regarding the use ofnewer 
"targeted" therapies in pancreatic cancer 7.  Proton beam therapy may result in lower toxicity, 
enhanced efficacy and could contribute to improved local control of patients with LAPC. The 
CAPOX regimen utilized in this trial has been proven to be active in gemcitabine-pretreated 
patients with advanced pancreatic cancer 14. 
 
The current trial will provide important data on the recurrence rates and patterns of failure using 
state of the art target agent, chemotherapy and proton beam technology for patients with LPAC. A 
median survival of 10 months or greater would be considered evidence of a regimen potentially 
worthy of further study as a new treatment paradigm in one arm in a future phase III trial. 
 
 
2.0     OBJECTIVES 
 
2.1     Primary Objective 
To determine the one-year survival rate 
 
2.2     Secondary Objectives 
2.2.1 
To evaluate the frequency of serious adverse events (section 9.1.1) 
2.2.2 
 
To evaluate disease control rate and progression-free survival 
2.2.3 
 
To determine the predictive value of CA 19-9 for prognosis 
2.2.4 
 
To evaluate quality of life and clinical benefit response 
 
 
3.0      PATIENT SELECTION 
 
3.1      Eligibility Criteria 
3.1.1 
 
Histologically or cytologically confirmed unresectable non-metastatic adenocarcinoma of the  
pancreas 
3.1.2 
AJCC stage I-III with unresectable or borderline unresectable disease as defined by NCCN 
guidelines 
3.1.2.1   
Radiological resectability is defined by the following criteria on abdominal imaging: 
a) No evidence of tumor extension to the celiac axis, hepatic artery or superior mesenteric artery. 
b) No evidence of tumor encasement or occlusion of the superior mesenteric vein (SMV) or the 
SMV/portal vein confluence 
c) No evidence of visceral or peritoneal metastases 
3.1.2.2 
Borderline and Unresectable cases would be defined as those that do not meet the criteria in 
section and also show no evidence of distant metastatic or intraperitoneal disease.  
3.1.3 
 
Eastern Cooperative Oncology Group performance status of ≤ 2 
3.1.4 
 
Age > 18 years 
3.1.5 
 
Adequate hematologic reserve, hepatic reserve and renal function 
3.1.5.1  
WBC > 2,000 cells/mm3 
3.1.5.2  
ANC > 1,500 cells/mm3 
3.1.5.3  
Platelets > 100,000 cells/mm3 
3.1.5.4  
Serum bilirubin ≤ 2.5 mg/dL 
3.1.5.6  
Serum creatinine ≤ 2 x upper limit of normal (ULN), or creatinine clearance (Ccr) ≥ 30ml/min  
3.1.5.6  
ALT < 3 times ULN 
3.1.5.7  
AST < 3 times ULN 
3.1.5.8  
Albumin > 3.2 g/dl 
3.1.5.9  
Patient must sign study-specific informed consent 
 
 
4.0     PRETREATMENT EVALUATION 
 

 
8 
4.1     Required Evaluations 
4.1.1 
 
History and physical examination 
4.1.2 
 
CT scan of chest, abdomen, and pelvis 
4.1.3 
 
CBC, serum chemistries, liver function tests, amylase/lipase, CA 19-9 
4.1.4 
 
Histologic confirmation of malignancy  
4.1.5 
 
Female Participant Evaluation: 
Non-pregnant and non-breast-feeding female participants of child-bearing potential must have a 
negative urine or serum pregnancy test prior to registration. Perimenopausal participants must be 
amenorrheic> 12 months to be considered not of childbearing potential. All patients of 
reproductive potential must agree to use an effective method of birth-control while receiving study 
therapy. 
 
5.0    REGISTRATION 
Patient registration as per LLUMC institutional standards for participation in clinical trials. 
 
6.0     RADIATION THERAPY 
 
6.1     Immobilization and Treatment Planning CT Scan 
6.1.1 
 
All patients will be immobilized in a full body immobilization device in the supine position. 
6.1.2 
 
A CT scan from T5 to L5/S1 with intravenous and oral contrast will be performed. 
 
6.2     Treatment Planning 
6.2.1 
 
The GTV will be the primary tumor and involved regional nodes. There will be no prophylactic  
elective nodal irradiation 
6.2.2 
 
The CTV will be GTV + 1 cm margin 
6.2.3 
 
A margin will be created around the CTV to account for proton beam penumbra and setup error. 
6.2.4 
A multi-field conformal proton beam treatment plan with the 90% isodose covering the CTV will 
be created.  
6.2.5 
Critical normal structures to be outlined are: small bowel with duodenum as a distinct volume, 
spinal cord, kidneys, and liver.  DVH data will be generated for these structures and standard 
normal tissue constraints will be upheld with the exception of the duodenum.   
 
6.3     Dose and Fractionation 
 
 
Standard fractionation of 1.8 Gy per day will be used for all patients to a total dose of 50.4 Gy. 
 
6.4     Radiation Toxicity 
 
All patients will be seen and examined on a weekly basis during treatment.  All acute toxicities 
will be scored according to the NCI Common Toxicity Criteria v 4.0.  Late toxicity will be scored 
per RTOG guidelines. 
 
6.5     Toxicity Related Radiation Treatment Modification 
 
 
Radiation is held if chemotherapy is held due to hematologic toxicities. (Section 9) 
 
6.0    DRUG THERAPY 
 
7.1     Gemcitabine 
7.1.1 
 
Drug Administration 
Gemcitabine is to be administered intravenously over 30 minutes weekly at a dose of 1000mg/m2.   
7.1.2 
 
Formulation 
Gemcitabine is an antineoplastic agent that is structurally related to Cytarabine. It is a pyrimidine 
analogue that is cell-cycle specific. Gemcitabine is available commercially as a lyophilized 
powder in sterile vials containing 200 mg or 1 gram of Gemcitabine as the hydrochloric salt 
(expressed as the free base) formulated with mannitol and sodium acetate.  
7.1.3 
 
Mechanism of Action  
Gemcitabine is cytotoxic to cells undergoing DNA synthesis (S-phase) and also blocks the 
progression of cells through the G1/S- phase boundary. Gemcitabine is converted intracellularly to 

 
9 
gemcitabine-5'-triphosphate, its active form. Steady-state plasma levels of Gemcitabine occur 
within 15 minutes after starting the infusion. The elimination half-life of gemcitabine ranges from 
32 to 638 minutes, depending on the age and gender of the patient and the rate of administration of 
Gemcitabine.  
7.1.4 
 
Toxicities  
The major side effects observed with Gemcitabine include leukopenia, thrombocytopenia, anemia, 
and a collection of signs and symptoms referred to collectively as a flu-like syndrome with fever, 
headache, rigors, nausea, diarrhea, itchy skin rash, myalgia, and anorexia. Other side effects have 
included fatigue, peripheral edema, and proteinuria. Less likely side effects include abnormal renal 
and liver function tests, vomiting, constipation, malaise, and anorexia. Rare side effects include 
Stevens-Johnson syndrome (severe skin reaction) and shortness of breath, cough, inflammation or 
scarring of the lung. Rare side effects have included hemolytic uremic syndrome/renal failure and 
liver failure have occurred following therapeutic gemcitabine therapy. Cardiac dysfunction 
(myocardial infarction, congestive heart failure, and atrial fibrillation) have been infrequently 
reported.  
7.1.5 
 
Supply  
Gemcitabine is commercially available. 
 
7.2     Erlotinib 
7.2.1 
 
Drug Administration 
Erlotinib should be taken once daily by mouth one hour before or two hours after a meal. 
Administration through G-tube or J-tube: The tablets required for the dose should be dissolved in 
100 mL of sterile water. The dissolved tablets should be shaken vigorously to form a uniform 
suspension. The suspension should be drawn up into a syringe and administered through the G-
tube or J-tube port. Repeat the syringe transfer until the entire volume has been administered. A 
small volume (40 mL) of sterile water should be added to the container used to dissolve the tablets 
and the residual suspension should be shaken, aspirated into syringe, and administered. This last 
step should be repeated to ensure the entire dose is administered. The total volume of 
delivery/rinse is ~180 mL. 
7.2.2 
 
Formulation 
Erlotinib is supplied as 25 mg, 100 mg, and 150 mg white filmcoated immediate-release tablets. 
7.2.3 
 
Mechanism of Action  
Direct inhibition of EGFR tyrosine kinase. 
7.2.4 
 
Toxicities  
In clinical trials, rash (dermatosis), diarrhea, nausea, fatigue, stomatitis, vomiting, and headache 
were the most frequently observed undesirable effects following exposure to single-agent 
Erlotinib. Patients receiving Erlotinib in combination with various chemotherapy agents have 
generally experienced the same type of adverse events as with either agent alone. Adverse events 
considered study drug related that appear to occur more frequently when Erlotinib is administered 
with chemotherapy, regardless of regimen, include fatigue, nausea, vomiting, stomatitis, and 
anemia. The skin rash commonly occurs on the face, upper chest and back, but may be more 
generalized with desquamation and may be accompanied by itching and tenderness and/or 
burning. Additional expected events include dry skin, nail changes, paronychia, painful fissures or 
cracking of skin on the hands and feet, hair growth abnormalities (alopecia, thinning hair, 
eyelash/eyebrow changes, and hirsutism), dehydration, hypotension, electrolyte changes, renal 
failure, dry mouth, glossodynia, mucositis/stomatitis, constipation, gastrointestinal bleeding, 
pneumonia, interstitial lung disease, cough, dyspnea including respiratory impairment, infection, 
sepsis, cellulitis, hemorrhage, subdural hematoma, cerebral hemorrhage, hematuria, hemoptysis, 
epistaxis, conjunctivitis, keratitis with associated facial rash, corneal ulceration/perforation, 
uveitis, orbital cellulites, anemia, thrombocytopenia, neutropenia with or without fever, 
neutropenic sepsis, elevations of PT or INR, stroke, myocardial infarction, liver function 
abnormalities, hepatic failure, acute renal failure/renal insufficiency, chest pain, bone pain, 
insomnia, syncope, ileus, hand-foot skin reaction and erythema multiforme (e.g., Stevens-Johnson 
syndrome, toxic epidermal necrolysis). 
7.2.5 
 
Supply  
Erlotinib is commercially available. 

 
10
 
7.3     Capecitabine 
7.3.1 
 
Drug Administration 
The Capecitabine daily dose is given orally in two divided doses (approximately 12 hours apart) at 
the end of a meal. The tablets should be taken with water. Administration of Capecitabine 
dissolved in water or through a feeding tube was allowed for patients unable to swallow tablets. 
7.3.2 
 
Formulation 
Capecitabine is supplied as a biconvex, oblong film-coated tablet for oral administration. Only the 
500 mg tablets will be utilized in this study.  
7.3.3 
 
Mechanism of Action  
Capecitabine is an oral prodrug of 5-Fluorouracil. Metabolized in the liver to 5'-
deoxyfluorocytidine, subsequently converted to 5'-deoxy-5-Fluorouridine which is then 
hydrolyzed to 5-Fluorouracil (active).  
7.3.4 
 
Toxicities  
Common side effects from Capecitabine include diarrhea (which may be severe), dermatologic 
effects (hand-and-foot syndrome referred to as palmar-plantar erythodysesethesia), hematologic 
effects (neutropenia, thrombocytopenia, anemia and lymphopenia), weight gain, gastrointestinal 
effects (diarrhea, nausea, vomiting stomatitis, abdominal pain and constipation). Uncommon side 
effects include hepatotoxicitiy (hyperbilirubinemia). Rare side effects may include cardiovascular 
effects (myocardial infarction, dysrhythmias, cardiomyopathy). 
7.3.5 
 
Supply  
Capecitabine is commercially available. 
 
7.4     Oxaliplatin 
7.4.1 
 
Drug Administration 
Oxaliplatin is infused either by peripheral vein or central venous line over 2 hours. 
7.4.2 
 
Formulation 
Oxaliplatin for injection is presented in the form of a sterile, preservative-free, 
lyophilized powder contained in clear glass vials, sealed with an elastomeric stopper and flip-off 
cover. Oxaliplatin is available as 50 mg or 100 mg vials. The lyophilized powder is reconstituted 
by adding 10 mL (for the 50-mg vial) or 20 mL (for the 100-mg vial) of water for Injection, USP, 
or dextrose 5% in water for injection (D5W). The reconstituted solution must be further diluted in 
an infusion solution of 250 mL to 500 mL of D5W.  
7.4.3 
 
Mechanism of Action  
Oxaliplatin is a platinum derivative in which the platinum atom is complexed with 
1,2diaminocyclohexane and with an oxalate ligand as a leaving group. The mechanism of action of 
Oxaliplatin is similar to that of Cisplatin as well as other platinum (Pt) compounds. Studies 
conducted to date indicate that the types and percentages of Pt-DNA adducts formed by 
Oxaliplatin are qualitatively similar to those formed by Cisplatin, but preclinical data suggest 
several unique attributes of the cytotoxic/antitumor activity of Oxaliplatin. Oxaliplatin 
demonstrates a broad spectrum of in vitro cytotoxic and in vivo antitumor activity that differs from 
that of either Cisplatin or Carboplatin. Oxaliplatin is active against several Cisplatin-resistant cell 
lines, colon carcinoma, and other solid tumors that are not responsive to Cisplatin.  
   7.4.4  
Toxicities  
Neurotoxicity: The occurrence of acute reversible sensory symptoms, described as dysesthesias, is 
predominantly associated with oxaliplatin administration. This toxicity is generally of mild to 
moderate intensity and is associated with early onset and brief duration, following Oxaliplatin 
administration. It is mainly located in the upper extremities, peri-oral and pharyngo-laryngeal 
areas, and can be exacerbated by cold exposure. The incidence to mild to moderate distal 
paresthesias is also commonly observed. Hematologic: Oxaliplatin myelotoxicity is modest.  
Gastrointestinal: Nausea, vomiting, constipation, diarrhea, and stomatitis can occur. Rash: Hand-
foot skin reaction and injection site reactions have been seen. Fever: Fever during infusion of 
Oxaliplatin has been reported. Fever has been associated with the use of Oxaliplatin. Infection: 
May occur with normal ANC or unknown ANC. Hepatic: Alkaline phosphatase, bilirubin, 
gamma-glutamyltranspeptidase(GGT), SGOT, ALT, SGPT have all been reported to be elevated. 
Venoocclusive disease of the liver is a rare event. Renal: Patients may experience some degree of 

 
11
elevation of serum creatinine. The incidence of grade 3/4 elevations is about 1% in previously 
treated patients. Pulmonary: Dyspnea and cough have been reported. Oxaliplatin has also been 
associated with pulmonary fibrosis in < 1% of patients. Anaphylactic reaction: Allergic reaction 
including fever has been reported. Cardiovascular: There has been reported incidence of 
thromboembolism. 
7.4.5 
 
Supply  
Oxaliplatin is commercially available.  
 
 
8.0     TISSUE/SPECIMEN 
 
8.1     Tumor Tissue 
8.1.1 
Paraffin embedded tissue sections or cytologic material from patient’s initial diagnostic or surgical 
procedure will be collected for correlative studies of the following molecular markers in relation to 
treatment response and outcome with methods such as immunohistochemistry 24-30. 
8.1.1.1  
Equilibrative nucleoside transporter (ENT1)  
8.1.1.2  
DPC4/Smad4 
8.1.1.3  
Vimentin 
8.1.1.4  
E-cadherin 
8.1.1.5  
BAX 
8.1.1.6  
Survivin 
8.1.1.7  
COX-2 
8.1.1.8  
S100A2 
8.1.1.9  
p16(INK4A) 
8.1.1.10  
14-3-3σ 
 
8.2     Peripheral Blood 
8.2.1 
Ten-ml peripheral blood will be collected before and during treatment. Each ten-ml peripheral 
blood will be divided equally into two purple-top vacutainer containing EDTA anticoagulant, and 
the tubes are inverted five times to ensure adequate mixing of the anticoagulant. DNA will be 
extracted from leukocytes for pharmacgenomic study to analyze polymorphisms in genes (as 
below) which encoded proteins are involved in chemotherapy drug metabolism. The results of 
genetic study will be compared to treatment efficacy and toxicity 31-39. 
8.2.1.1  
EGFR intron 1  
8.2.1.2  
Cytidinedeaminase 
8.2.1.3  
ENT1 
8.2.1.4  
RRM1  
8.2.1.5  
ERCC1 
8.2.1.6  
MTHFR 
8.2.1.7  
Thymidylate synthase  
8.2.1.8  
XRCC1 
8.2.1.9  
RecQ1 
8.2.1.10  
RAD54L  
8.2.1.12  
ATM  
8.2.1.12  
xCT 
 
9.0     TOXICITY RELATED THERAPY ADJUSTMENT 
 
9.1     Dosing Delays/Modifications: 
9.1.1 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 

 
12
9.1.2 
Once a dose of chemotherapeutic agent has been reduced, it should not be increased at a later time. 
Reasons for dose modifications or delays, the supportive measures taken, and the outcome will be 
documented in progress notes. 
9.1.3 
No dose reductions or interruptions will be required for anemia as it can be satisfactorily managed 
by transfusions. 
9.1.4 
Standard medical supportive care for nausea/vomiting should be provided prior to considering 
dose modification. 
9.1.5 
For patients who have had dosing delays, all subsequent evaluations will be correspondingly 
delayed. 
 
9.2     Dose Levels for Gemcitabine and Erlotinib 
 
Dose level 
Gemcitabine 
Erlotinib 
0 
1000 mg/m2 
100 mg 
-1 
750 mg/m2 
75 mg 
-2* 
500 mg/m2 
50 mg 
* Two dose reductions are allowed for either Gemcitabine or Erlotinib. If a third reduction is required, treatment 
with that drug should be discontinued. 
 
9.3     Dosing Delays/Modifications for Gemcitabine 
 
Hematological toxicity 
ANC 
 
Platelets 
Gemcitabine dose level  
≥1000 
and 
≥50,000 
Maintain dose. 
500-999 
or 
25,000 – 49,999 
Reduce dose by 1 dose level. 
<500 
or 
<25,000 
Hold until ANC ≥1500 and platelets ≥75,000. Restart at 1 
dose level lower than previous.  
Febrile neutropenia* 
Hold until ANC ≥1500 and platelets ≥75,000. Restart at 1 
dose level lower than previous. 
Not recovered by 14 days  
Hold until ANC ≥1500 and platelets ≥75,000. Restart at 1 
dose level lower than previous. 
Not recovered by 28 days  
Discontinue Gemcitabine chemotherapy. May continue 
Erlotinib. 
*Febrile neutropenia: ANC <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than one hour. 
 
Non-hematologic toxicity 
Adverse event 
CTCAE toxicity grade 
Gemcitabine dose level 
Hepatic (AST, ALT,  bilirubin)  
0-2 
Maintain dose. 
3 
Reduce dose by 1 dose level. 
4 
Hold until resolved to grade 0-2 then 
restart at 1 dose level lower than 
previous. Discontinue if not resolved 
within 28 days. 
Edema  
0-2 
Maintain dose. 
3 
Reduce dose by 1 dose level. 
4 
Hold until resolved to grade 0-2 then 
restart at 1 dose level lower than 
previous. Discontinue if not resolved 
within 28 days. 
Other non-hematologic toxicity 
(except nausea/vomiting) 
0-2 
Maintain dose. 
3 
Reduce dose by 1 dose level. 
4 
Reduce dose by 1 dose level. 
Not improved from grade 3-
Hold until resolved to grade 0-2 then 

 
13
4 toxicity within 14 days 
restart at 1 dose level lower than 
previous. 
Not improved from grade 3-
4 toxicity within 28 days 
Discontinue Gemcitabine. May 
continue Erlotinib.. 
 
9.4     Dosing Delays/Modifications for Erlotinib 
 
Hematological toxicity 
Adverse event 
Erlotinib dose level 
ANC < 500 (grade 4), platelets < 
50,000 (grade 3 or 4), febrile 
neutropenia 
Hold until resolved to < grade 2 or febrile neutropenia is resolved. 
May reduce dose by 1 dose level if toxicity is felt to be possibly 
related to erlotinib.  
Non-hematologic toxicity 
Adverse event 
CTCAE toxicity grade 
Erlotinib dose level 
Rash  
3 
Hold until resolved to grade 2 or 
less then restart at 1 dose level 
lower than previous. Discontinue 
if not resolved within 14 days. 
4  
Discontinue erlotinib.  
Diarrhea 
0-2 
Maintain dose. 
3-4 
Hold until resolved to grade 1 or 
less then restart at 1 dose level 
lower than previous. Discontinue 
if not resolved within 14 days. 
Pulmonary toxicity 
any 
Hold temporarily pending 
diagnosis. Discontinue if 
pneumonitis or pulmonary 
infiltrate is confirmed and 
considered to be related to 
Erlotinib.  
Hepatic (AST, ALT,  bilirubin) 
0-2 
Maintain dose. 
3-4 
Hold until resolved to grade 2 or 
less then restart at 1 dose level 
lower than previous. Discontinue 
if not resolved within 14 days. 
Other non-hematologic toxicity  
0-2 
Maintain dose. 
3-4 
Hold until resolved to grade 2 or 
less then restart at 1 dose level 
lower than previous. Discontinue 
if not resolved within 14 days. 
 
9.5     Dosing Delays/Modifications for Capecitabine and Radiation 
 
Hematological toxicity 
Adverse event 
Capecitabine dose level 
ANC > 1000  
and platelets > 75,000 
No dose modification 
 
ANC 500-999  
and/or platelets 50,000-75,000 
Continue radiation. Hold capecitabine until ANC > 
1000 and platelets > 75,000, then resume at 
permanent 25% dose reduction 
ANC < 500  
and/or Platelets < 50,000 
Hold Capecitabine and radiation until ANC > 1000 
and platelets > 75,000 then resume radiation and 
restart Capecitabine at permanent 25% dose 
reduction. 
NOTE: Patients who have required three dose reductions and who experience a fourth episode of ANC < 

 
14
1000 and platelets < 75,000 will complete radiation and but will not receive additional Capecitabine.  
 
 
Non-hematologic toxicity 
Adverse event 
Capecitabine dose level 
Grade 2 palmar-plantar 
erythrodysesthesia (hand-foot) syndrome  
Hold Capecitabine until resolves to ≤ grade 1, then 
resume at permanent 25% dose reduction 
Grade 3 palmar-plantar 
erythrodysesthesia syndrome  
Hold Capecitabine until resolves to ≤ grade 1, then 
resume at permanent 50% dose reduction 
Grade 3 oral mucositis 
Hold Capecitabine until resolves to ≤ grade 2, then 
resume at permanent 25% dose reduction 
Grade 4 oral mucositis 
Hold Capecitabine until resolves to ≤ grade 2, then 
resume at permanent 50% dose reduction 
Other grade 3 or 4 AE, 1st occurrence 
Hold Capecitabine and radiation until toxicity has 
resolved to ≤ grade 2, then resume radiation and 
Capecitabine with a permanent 25% dose reduction 
Other grade 3 or 4 AE, 2nd occurrence 
Hold Capecitabine and radiation until toxicity has 
resolved to ≤ grade 2, then resume radiation and 
Capecitabine with a permanent 25% dose reduction 
Other grade 3 or 4 AE, 3rd occurrence 
Hold Capecitabine and radiation until toxicity has 
resolved to ≤ grade 2, then resume radiation and 
capecitabine with a permanent 25% dose reduction 
Other grade 3 or 4 AE, 4th occurrence or grade 3 or 
4 AE that persists for > 4weeks 
Discontinue Capecitabine and radiation 
permanently 
 
 
9.6     Dose levels, Dosing delays/Modifications for Oxaliplatin and Capecitabine 
Dose level 
Oxaliplatin   
Capecitabine 
0 
130 mg/m2 
1000 mg/m2 bid 
-1 
100 mg/m2 
Reduce original daily dose by one 
500-mg tablet 
-2 
75 mg/m2 
Reduce original daily dose by 
two 500-mg tablets 
 
Hematological toxicity 
ANC 
 
Platelets 
Oxaliplatin dose level 
Capecitabine dose level 
≥1000 
and 
≥50,000 
Maintain dose. 
Maintain dose. 
500-999 
or 
25,000 – 49,999 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 
1 dose level lower than 
previous. 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 1 
dose level lower than previous. 
<500 
or 
<25,000 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 
1 dose level lower than 
previous. 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 1 
dose level lower than previous. 
Febrile neutropenia 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 
1 dose level lower than 
previous 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 1 
dose level lower than previous 
Not recovered by 14 days  
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 
1 dose level lower than 
previous. 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 1 
dose level lower than previous. 
Not recovered by 28 days 
Discontinue Oxaliplatin. 
May continue Capecitabine. 
Hold until ANC ≥1500 and 
platelets ≥75,000. Restart at 1 

 
15
dose level lower than previous. 
 
Non-hematologic toxicity 
Adverse event  
Oxaliplatin dose level 
Capecitabine dose level 
Grade 2 palmar-plantar 
erythrodysesthesia (hand-foot) 
syndrome 
Maintain dose. 
Hold Capecitabine until resolves 
to ≤ grade 1, then resume at 1 
dose level lower than previous.  
Grade 3 palmar-plantar 
erythrodysesthesia (hand-foot) 
syndrome 
Hold Oxaliplatin until resolves to 
≤ grade 1, then resume at 1 dose 
level lower than previous.  
Hold Capecitabine until resolves 
to ≤ grade 1, then resume at 2 
dose levels lower than previous. 
Grade 3 oral mucositis 
Maintain dose. 
Hold Capecitabine until resolves 
to ≤ grade 2, then resume at 1 
dose levels lower than previous. 
Grade 4 oral mucositis 
Hold Oxaliplatin until resolves to 
≤ grade 2, then resume at 1 dose 
level lower than previous. 
Hold Capecitabine until resolves 
to ≤ grade 2, then resume at 2 
dose levels lower than previous. 
Grade 2 peripheral neuropathy 
Reduce 1 dose level than 
previous 
Maintain dose. 
Grade 3 peripheral neuropathy 
Hold Oxaliplatin until resolves to 
≤ grade 1, then resume at 2 dose 
levels lower than previous. 
Hold Capecitabine until resolves 
to ≤ grade 2, then resume at 1 
dose levels lower than previous. 
Grade 3 or 4 allergic reaction 
Discontinue permanently if due to 
Oxaliplatin 
Discontinue permanently if due to 
Capecitabine 
Other grade 3 or 4 AE 
Hold until resolves to ≤ grade 2, 
then resume at 1 dose level lower 
than previous. 
Hold until resolves to ≤ grade 2, 
then resume at 1 dose level lower 
than previous. 
 
 
10.0    PATIENTASSESSMENTS 
 
10.1    Patient Evaluation Timing 
10.1.1 
Pre-proton chemotherapy 
 
Pre-proton-chemotherapy (PCT) 
Required 
studies 
Pre-study 
(within 4 
weeks) 
Day  
1 
Day  
8 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Post-
chemotherapy/ 
pre-proton  
Evaluations 
H&P, vitals, 
weight & PS 
X 
X 
X 
X 
 
X 
X 
X 
X 
AE 
assessment 
X 
(baseline) 
X 
X 
X 
 
X 
X 
X 
X 
Quality of 
Life 
Assessments 
X 
(baseline) 
 
 
 
X 
 
Laboratory and imaging 
CBC/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CA 19-9 
X 
 
 
 
 
 
 
 
X 
PT-INR and 
PTT 
X 
 
 
 
 
 
 
 
 
Whole 
blood  for 
correlative 
study 
X 
 
 
 
 
X 
 
 
X 

 
16
X-rays & 
scans as 
needed for 
disease 
assessment  
X 
 
 
 
 
 
 
 
X 
Treatment 
Gemcitabine 
 
X 
X 
X 
 
X 
X 
X 
 
Erlotinib 
 
Daily from day 1 to day 43 
 
 
10.1.2 
PCT 
 
PCT 
Required 
studies 
Day 1 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Post-proton 
Evaluations 
H&P, vitals, 
weight & PS 
X 
X 
X 
X 
X 
X 
X 
AE 
assessment 
X 
X 
X 
X 
X 
X 
X 
Quality of 
Life 
Assessments 
 
 
X 
 
Laboratory and imaging 
CBC/diff 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
CA 19-9 
 
 
 
 
 
 
X 
Whole blood  
for 
correlative 
study 
 
 
 
 
X 
 
X 
X-rays & 
scans as 
needed for 
disease 
assessment 
 
 
 
 
 
 
X 
Treatment 
Capecitabine 
825mg/m2 po bid on days of radiation, starting on day 1 of proton therapy until 
proton therapy is completed. 
 
Proton 
50.4 Gy/28 fractions (1.8 Gy per fraction) once a day for 5 ½ weeks. 
 
 
10.1.3 
Post-PCT (begins 4-6 weeks after protontherapy) 
 
Post-proton 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
 
Required 
studies 
Day  
1 
Day  
8 
Day 
15 
Day  
1 
Day  
8 
Day  
15 
Day  
1 
Day   
8 
Day 
15 
Day  
1 
Day  
8 
Day  
15 
Post-
chemotherapy 
Evaluations 
H&P, vitals, 
weight & PS 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
AE 
assessment 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Quality of 
Life 
Assessments 
 
 
X 
 
Laboratory and imaging 
CBC/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
17
CMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CA 19-9 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Whole blood  
for 
correlative 
study 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X-rays & 
scans as 
needed for 
disease 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Treatment 
Oxaliplatin 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Capecitabine 
Day 1-14 
 
Day 1-14 
 
Day 1-14 
 
Day 1-14 
 
 
 
10.2     Toxicity Definitions 
 
Late toxicities defined per the CTCAE v. 4.0 will be defined as those occurring 3 months or greater after 
the completion of radiation treatment.  All toxicities occurring prior to that time period will be scored as 
acute.  If there is any fatal treatment morbidity, the event will be reported to the study chairs and the IRB 
for review.  
 
10.3     Assessment of Treatment Response 
The tumor response will be determined by comparison of the pre- and post-treatment CT scans and 
assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.  
 
10.4     Quality of Life Assessments 
Patients should complete the FACIT-Fatigue at baseline before therapy initiation, after completion of each 
phase of therapy, pre-PCT, PCT and post-proton chemotherapy, as well as at 9, 12, and 24 months from 
start of therapy. FACIT-Fatigue, version 4, is a 13-item questionnaire that assesses self-reported tiredness, 
weakness, and difficulty conducting usual activities due to fatigue. A 5-point intensity type of rating scale 
(from “not at all” to “very much”) is used.  This questionnaire can be completed by patients in 
approximately 5 minutes (Appendix) 
 
 
11.0     STATISTICS 
 
11.1     Study Endpoints  
11.1.1     Primary Endpoint  
One-year overall survival rate (failure: death due to any cause).  
11.1.2     Secondary Endpoints  
11.1.2.1  Frequency of patients developing serious adverse events (section 9.1.1) attributable to protocol treatment.  
11.1.2.2  Progression-free survival (failure: local, regional or distant progression or death due to any cause). 
 
11.2     Sample Size  
11.2.1     Sample Size Derivation  
The primary objective of this study is to estimate the one-year overall survival rate. In the previous RTOG 
protocol for unresectable pancreatic cancer (RTOG 98-12), a one-year survival rate of approximately 43% 
was observed40. There were 109 analyzable patients on RTOG 98-12 with 61 still at risk for death at one 
year. Using the method of Dixon and Simon41, a sample size of 39 analyzable patients followed over 12 
months will ensure at least 90% probability of detecting a minimum of 17% improvement in the one-year 
survival rate compared to RTOG 98-12 at the 0.10 significance level (with a one-sided test). Adjusting this 
figure by 10% to allow for patient ineligibility or loss, a total sample size of 43 patients will be required for 
this study.  

 
18
11.2.2     Patient Accrual  
Based upon an accrual rate of at least 1 patient per month, and allowing 6 months for institutional IRB 
review and approval, accrual should be completed in approximately 49 months. If the average monthly  
accrual is less than 1 case per month, the study will be re-evaluated with respect to feasibility.  
 
11.3     Analysis Plan  
11.3.1     Interim Reports  
Interim reports will be prepared every six months until the primary endpoint has been presented.  
In general, these reports include: 
11.3.1.1 The patient accrual rate with projected completion date  
11.3.1.2  Institutional accrual  
11.3.1.3  Pretreatment characteristics  
11.3.1.4  Compliance rates of treatment delivery with respect to the protocol prescription  
11.3.1.5  The frequency and severity of reported adverse events  
11.3.2     Analysis for Reporting the Initial Treatment Results 
The major analysis for reporting the initial results of treatment will be undertaken when each patient has    
 been potentially followed for a minimum of 12 months. The usual components of this analysis are:  
11.3.2.1  Tabulation of all cases entered, and any patients excluded from the analysis with reasons for exclusion  
11.3.2.2   Institutional accrual  
11.3.2.3   Patient accrual rate  
11.3.2.4   Distribution of important prognostic baseline other pretreatment variables  
11.3.2.5   Observed results with respect to the endpoints described in Section 11.1 
The estimated survival will be tested against the RTOG 98-12 trial with a one-sided log-rank test.  
Estimates of the median and one-year progression-free and overall survival rates will be estimated using the 
Kaplan-Meier method.  
 
 
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11. Bouchard M, et al, Dose escalation with proton or photon radiation treatment for pancreatic cancer, 
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27. Jamieson NB, et al. Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic 
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patients with pancreatic cancer. Br J Surg. 98:1041-55, 2011.  
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30. Li Z, et al. Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic 
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31. Tzeng CW, et al. Pancreatic cancer epidermal growth factor receptor (EGFR) intron 1 polymorphism 
influences postoperative patient survival and in vitro Erlotinib response.  Ann Surg Oncol. 14:2150-8, 
2007.  
32. Xu X, et al. Biomarkers and pharmacogenetics in pancreatic cancer. J Pancreas 12:325-329, 2011. 
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20
34. Sharma R, et al. Thymidylate synthase and methylenetetrahydrofolatereductase gene polymorphisms and 
toxicity to capecitabine in advanced colorectal cancer patients. Clin Cancer Res. 14:817-25, 2008.  
35. Paez D, et al. Pharmacogenetic study in rectal cancer patients treated with Preoperative chemoradiotherapy: 
polymorphisms in thymidylate synthase, epidermal growth factor receptor, GSTP1, and DNA repair genes. 
Int J Radiat Oncol Biol Phys. May 2011.  
36. Li D, et al. Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with 
reduced survival of pancreatic cancer. JCO 11:1720-1728, 2006. 
37. Huang TJ, et al. Prognostic significance of xCT gene single nucleotide polymorphisms in patients with 
advanced pancreatic cancer treated with Gemcitabine plus platinum analogues. Proc. ASCO Abs 4065, 
2010. 
38. Tanaka M, et al. Gemcitabine metabolic and transporter gene polymorphisms are associated with drug 
toxicity and efficacy in patients with locally advanced pancreatic cancer. Cancer 116:5325-35, 2010. 
39. Okazaki T, et al. Single nucleotide polymorphisms of Gemcitabine metabolic genes and pancreatic cancer 
survival and drug toxicity. Clin Cancer Res. 16:320-9, 2010.  
40. Rich T, et al: Phase II study of external irradiation and weekly Paclitaxel for nonmetastatic, unresectable 
pancreatic cancer: RTOG-9812. Am J Clin Oncol 27:51-56, 2004  
41. Dixon DO, et al: Sample size considerations for studies comparing curves using historical controls. Journal 
of Clinical Epidemiology 41: 1209-1213, 1988. 
 
 
 
 
 
 
 
Appendix I   Staging System 
 
 
 
 
 

 
21
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix II - FACIT Fatigue Scale Questionnaire 
 
 
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 
at all 
 
 A 
 little 
 bit 
 Some- 
 what 
 
Quite 
 a bit 
 
Very 
much 
 
 
I feel fatigued ............................................................................... 
0 
1    
2    
  3    
   4  
 
I feel weak all over ....................................................................... 
0    
1    
2    
  3 
   4 
  
I feel listless (“washed out”) ........................................................ 
0 
1  
2  
  3  
   4 
  
I feel tired...................................................................................... 
0  
1  
2  
  3  
   4 
  
I have trouble starting things because I am tired........................... 
0  
1  
2  
  3   
   4 
  

 
22
I have trouble finishing things because I am tired .......................  
0  
1  
2  
  3  
   4  
 
I have energy.................................................................................  
0  
1  
2  
  3  
   4 
  
I am able to do my usual activities................................................  0  
1  
2  
  3  
   4  
 
I need to sleep during the day ...................................................... 
0  
1  
2  
  3  
   4 
  
I am too tired to eat....................................................................... 
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I need help doing my usual activities .......................................... 
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I am frustrated by being too tired to do the things I want to do...      0  
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I have to limit my social activity because I am tired.................... 
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