A Neoadjuvant Phase II Study of Chemo-Radiotherapy in Patients With Resectable and Borderline Resectable Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreas Neoplasm Malignant Resectable
Sponsor: Henry Ford Health System

 
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HFHS- 13-03:  A NEOADJUVANT PHASE II STUDY OF CHEMO-RADIOTHERAPY 
IN PATIENTS WITH RESECTABLE AND BORDERLINE RESECTABLE 
PANCREATIC CANCER 
 
 
Study Team 
Principal Investigator/Hematology Oncology 
Gazala Khan, MD 
Henry Ford Hospital 
2799 West Grand Blvd 
Detroit, MI  
 
Participating Sites 
Henry Ford Hospital, Detroit, MI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol version 2.0 03/11/2013 
 
Eligible patients with resectable and borderline resectable pancreatic cancer will be accrued onto protocol 
therapy, which would include a neo-adjuvant phase followed by surgical resection.  
                   
 
SCHEMA 
 
                              Resectable and Borderline Resectable Pancreatic Cancer 
Pre-study: Determine eligibility, baseline CT scan, surgical evaluation, Ca19-9 
Sign Informed Consent  
 
2 cycles – FOLFOX6 (1 month) 
 
Gemcitabine/RT (5-6 weeks) 
 
Rest period 2 weeks 
 
Re-staging evaluation (CT scan to be done during the 2 weeks of rest)                          
 
Surgery (To be performed no later than 6 weeks after completion of chemo-radiation) 
 
*Note: If patient has evidence of distant disease progression at any restaging CT they will 
be removed from protocol treatment 

 
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TABLE OF CONTENTS                                                                                                      Page 
 
SCHEMA ............................................................................................................................... 2 
 
1. INTRODUCTION............................................................................................................ 4 
 
2. OBJECTIVES .................................................................................................................. 6 
 
3. PATIENT SELECTION .................................................................................................. 6 
 
3.1 
Conditions for Patient Eligibility  ............................................................................ 6 
3.2 
Conditions for Patient Ineligibility ........................................................................... 7 
3.3 
Inclusion of Women and Minorities ......................................................................... 8 
 
4. REGISTRATION PROCEDURES .................................................................................. 8 
 
5. TREATMENT PLAN....................................................................................................... 8 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ............................................................. 14 
 
 
7. ADVERSE EVENT REPORTING ................................................................................ 18 
 
8. PHARMACEUTICAL INFORMATION ...................................................................... 19 
 
8.1   5FU.......................................................................................................................... 19 
8.2   Oxaliplatin ............................................................................................................... 19 
8.3   Leucovorin .............................................................................................................. .20 
8.4   Gemcitabine…………………………………………………………………………….21                               
 
9. STUDY CALENDAR ..................................................................................................... 22 
 
10. MEASUREMENT OF EFFECT .................................................................................... 23 
 
11. STATISTICAL CONSIDERATIONS............................................................................ 25 
 
REFERENCES .................................................................................................................... 25 
 
APPENDIX…………………………………………………………….…………...………..28 
 
 
 
 
 
 
 
 
 

 
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1. INTRODUCTION 
 
Pancreatic Cancer 
 
There were an estimated 37,680 new cases of pancreatic cancer in the US in 2008 making it 
the 10th most common cancer. The estimated number of deaths, however, was 34,290 
which places pancreatic cancer 4th among deaths caused by cancer1.  A practical staging 
system for pancreatic cancer based on the approach to treatment separates patients into four 
categories: 1) resectable, 2) locally advanced unresectable, 3) metastatic disease, and 4) 
borderline resectable. 
 
Resectable Disease 
 
A small minority of patients fall into the category of resectable disease. Surgical treatment 
is most often the initial treatment and is offered with curative intent.  However, median 
survival with surgery alone is only 13-20 months.  Following resection, patients benefit 
from the addition of adjuvant radiation and/or chemotherapy2-4.  Even in this most 
favorable group of patients, however, the 5 year survival is less than 30% in single 
institution series5, 6.  A large majority of patients treated with surgery, with or without 
adjuvant therapy, progress with hepatic metastases. 
 
       Advanced Metastatic Disease 
 
Patients presenting with evidence of distant metastasis at diagnosis are offered treatment 
with palliative chemotherapy.  Gemcitabine has dominated systemic therapy for pancreatic 
cancer for most of the past decade. A pivotal study randomized 126 patients with advanced, 
symptomatic pancreatic cancer to either weekly gemcitabine 1000 mg/m2 over 30 minutes 
or weekly bolus 5FU 600 mg/m2 using clinical benefit response (CBR) as the primary 
endpoint9. The study found CBR more commonly in the gemcitabine treated patients 
(23.8% vs 4.8%, P=0.002).  Gemcitabine also led to improved median survival (5.6 vs. 4.4 
months) and 1 year survival (18% vs. 2%) as compared to 5FU. Tumor response was 
infrequent in both arms (5.4% gemcitabine vs. 0% 5FU).  While gemcitabine as a single 
agent in advanced pancreatic cancer has utility, enthusiasm is muted considering the 
limited benefit it provides.  The recent ACCORD trial evaluated gemcitabine vs. 
FOLFIRINOX (5FU, oxaliplatin and irinotecan) and determined that FOLFIRINOX was 
superior to gemcitabine in the treatment of metastatic disease, both in terms of overall 
survival (OS) and progression free survival (PFS). This pivotal trial has led to the 
acceptance of FOLFIRINOX as a standard in the first line treatment of metastatic 
pancreatic cancer28. It is noteworthy, however, that the toxicity caused by FOLFIRINOX 
was three times greater than gemcitabine. The role of irinotecan in the treatment of 
metastatic pancreatic cancer is unclear. A Phase II series suggests that the survival benefit 
with FOLFOX alone is very similar to that seen with FOLFIRINOX in the ACCORD 
trial29. Hence it is also reasonable to consider treatment with FOLFOX alone in the 
metastatic setting. Several trials addressing this important question are ongoing. 
 
 

 
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Borderline Resectable Disease 
 
Patients with disease that falls somewhere between the first two categories, resectable and 
localized but unresectable, are designated as having borderline resectable disease.  While 
not clearly unresectable, if surgery is the initial treatment, there is a high likelihood of an 
R1 or R2 resection with subsequent local recurrence10-12.  Consequently, it is reasonable to 
provide chemotherapy and/or radiation with the intent of increasing the likelihood of a 
subsequent margin negative resection.   
 
Historically, the rate of successful resection in borderline resectable pancreatic cancer 
following neoadjuvant treatment is in the range of 30%13-15.  The variable reported rates of 
successful resection can be attributed to the variable definition of borderline resectable 
disease, different approaches to combining chemotherapy with radiation, and the surgeon’s 
willingness and ability to perform vascular resection +/- reconstruction.  As compared to 
R0 resection rates in resectable disease with up front surgery (60-80%),  in recent studies 
investigating neoadjuvant therapies in resectable and borderline resectable disease, R0 
resection rates have generally  been reported  in the range of 90%, suggesting an 
improvement in successful R0 resection rates following preoperative treatment 13, 14, 16, 17. 
Additionally, in locally advanced borderline or unresectable disease, down staging with 
chemotherapy and radiation permitting resection yields post-surgery survival similar to that 
achieved in upfront resectable disease17.  This suggests a significant benefit of neoadjuvant 
therapy, which aides in obtaining an R0 resection in borderline resectable disease.   
 
There is currently no standard therapy approach for borderline resectable pancreatic cancer. 
The purpose of this study is to improve outcomes in patients with borderline resectable and 
resectable disease utilizing a planned course of neoadjuvant therapy, consisting of 
chemoradiation, in order to optimize successful R0 resection rates and local disease 
control, and combination chemotherapy to optimize control of distant disease . 
 
Optimization of Local Disease Control Using Chemoradiation 
 
In order to optimize local control of disease in borderline pancreatic cancer, 
chemoradiation can be given neoadjuvantly.  Chemoradiation for pancreatic cancer has 
historically incorporated 5-fluorouracil.  Gemcitabine has greater systemic efficacy than 5-
fluorouracil in pancreatic cancer and is a potent radiosensitizer.  Therefore, gemcitabine 
has been evaluated in combination with radiation therapy using conformal radiation 
techniques.  Early studies using gemcitabine with radiation were hampered by limitations 
in radiation and or gemcitabine dose based on regional toxicity and poor distant disease 
control due to suboptimal doses of gemcitabine24, 25.  However recent trials have 
demonstrated gemcitabine as a more potent radio-sensitizer with a more acceptable toxicity 
profile.  Locoregional toxicity has been addressed by limiting the radiation field to the 
primary tumor alone and titrating the radiation dose 26,27.   
 
Neoadjuvant Therapy 
 
In resectable and borderline resectable pancreatic cancer, surgery is most often the initial 

 
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treatment.  The adequacy of that resection is questionable, however, in that a significant 
minority of patients have positive margins and some patients have incomplete resection (R2 
resections)18, 19.  Median survivals in patients with R1 or R2 resections are no different than 
that observed with non-operative therapy.  Patients deemed to have borderline resectable 
disease are at even higher risk for a margin positive resection if treated initially with 
surgery.  A reasonable strategy to address this problem is neoadjuvant therapy to try to 
increase successful resectability12.  Compared with adjuvant therapy, neoadjuvant therapy 
has the potential advantage of an improved tolerance of combined modality treatment 
preoperatively, and a greater proportion of patients receiving all components of 
multimodality therapy completed over a shorter time interval.  As many as 30% of resected 
patients fail to receive post-operative adjuvant therapy because of inadequate recovery 
from surgery or patient refusal.  Treatment delays following surgery may impact efficacy 
of adjuvant treatment.  In the ESPAC adjuvant trial, the median time to initiation of post 
operative chemotherapy was 46 days and for combined modality treatment 61 days4.  
Neoadjuvant treatment provides a more timely systemic therapy.  Finally, patients that 
progress during neoadjuvant therapy have biologically aggressive disease and are spared a 
major operation which provides little benefit.   
 
One of the potential downsides of neo-adjuvant treatment is: theoretical concerns of disease 
progression during treatment. However this has not been proved in clinical trials. 
 
Summary and Rationale for This Study:  
 
Considering the aggressive biology of pancreatic cancer, and the relatively limited survival 
with the current standard, which is surgery followed by adjuvant chemotherapy, we hereby 
propose this clinical trial to evaluate the safety and effectiveness of a novel neoadjuvant 
treatment strategy incorporating FOLFOX chemotherapy in combination with chemo-radiation 
with gemcitabine. 
2. OBJECTIVES 
Primary Objective: 
1a. To evaluate frequency of achieving R0 resection in patients with resectable and borderline   
resectable pancreatic cancer treated with a neoadjuvant regimen of FOLFOX followed by 
RT concurrent with gemcitabine chemotherapy at standard dosing.  
 Secondary Objectives: 
 
 
 
2a. To determine overall survival and progression-free survival as a function of time from 
study enrollment.  
2b. To evaluate tolerability and toxicity of the protocol treatment. 
 
2c.  To evaluate radiographic primary tumor response rate using modified RECIST criteria 
 
3. PATIENT SELECTION: 
 
3.1  
Conditions for Patient Eligibility: 

 
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3.1.1 Patients must have histologically or cytologically confirmed pancreatic 
adenocarcinoma of the pancreatic head or body 
 
                  3.1.2 Patients must have radiographically-confirmed surgically resectable (or) 
borderline resectable disease at study entry staged at T1-3, N0-1 and M0 
(see Appendix B for NCCN criteria for determining resectability status,  
borderline is at the discretion of the surgeon). Surgical resectability will be 
assessed by a surgeon experienced in pancreatic surgery in conjunction with 
a radiologist specializing in radiographic pancreatic imaging. 
                
                  3.1.3 Age >18 years 
 
3.1.4 Life expectancy of greater than 6 months in the opinion of the investigator, 
excluding the pancreatic cancer. 
 
3.1.5 ECOG performance status <1 (see Appendix A). 
 
3.1.6 Required laboratory data: 
 
- 
absolute neutrophil count 
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
< 2mg/dl 
- 
AST(SGOT)/ALT(SGPT)  
<5 X institutional upper limit of normal 
- 
Creatinine  
 
 
 
 
<2.0 mg/dl 
-    Negative β-HCG for females 
-    Mg                                            >LLN institutional lower limit of normal 
-   Calcium                                     > LLN institutional lower limit of normal 
-   Sodium                                      > LLN institutional lower limit of normal 
-   Potassium                                  > LLN institutional lower limit of normal 
-   CA 19-9 
 
 
 
 
 
3.1.7   Disease assessment by CT scan within 4 weeks of study entry 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Conditions for Patient Ineligibility: 
 
3.2.1 Patients may not be receiving any other investigational agents. 
 
3.2.2 Patients with metastatic disease are excluded from this clinical trial  
 
3.2.3 History of allergic reactions attributed to 5FU, oxaliplatin and gemcitabine 
 

 
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3.2.4 No prior chemotherapy or radiation therapy for pancreatic cancer. Previous 
chemotherapy or radiation therapy for other malignancies is permitted.  
 
3.2.5 Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, 
hypophosphatemia or hypokalemia defined as less than the lower limit of 
normal for the institution, despite adequate electrolyte supplementation are 
excluded from this study. 
 
3.2.6 Uncontrolled serious intercurrent illness including, but not limited to, 
ongoing or serious active infection requiring IV antibiotics for over 30 days, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia other than chronic, stable atrial fibrillation, or psychiatric 
illness/social situations that would limit compliance with study 
requirements. 
 
3.2.7 Pregnant or breastfeeding women are excluded from this study.  
 
3.2.8 Known HIV-positive patients are ineligible. 
 
                  3.2.9  Patients with unresectable disease are excluded from the protocol. (see 
Appendix  B for NCCN criteria for determining resectability status). 
Surgical resectability must be confirmed by a surgeon experienced in 
pancreatic surgery. 
       
               3.2.10 Patients with pancreatic tail lesions will be excluded 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for 
this trial.  
 
 
4.0 REGISTRATION PROCEDURES 
 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site has Institutional Review Board approval. Patients 
must have signed and dated all applicable consents and authorization forms. To register a 
patient to this study,   the signed and dated eligibility checklist, along with any necessary 
supporting documentation,  and the signed patient consent form will be forwarded to the 
responsible data manager.  To complete the registration process, the data manager will 
assign a patient study number, in sequential order of consent, register the patient to the 
study, and contact the treating investigator and responsible research nurse to confirm 
registration. 
 
5.0 TREATMENT PLAN 
 

 
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5.1  
Chemotherapeutic Agent Administration 
 
Treatment will be administered on an outpatient basis.  Appropriate dose 
modifications for 5FU, oxaliplatin and gemcitabine are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient's malignancy.   
 
5.2 
FOLFOX 
 
A cycle of treatment is 14 days. 2 cycles are intended prior to combined modality 
treatment, although this may be modified based on patient tolerance and toxicity 
experienced.  
 
Starting dose levels are as follows: 
  
Oxaliplatin 85mg/m2 infused intravenously over 120 minutes on day 1. 
Leucovorin 400mg/m2  infused intravenously over 90 minutes on day 1. 
5FU 400mg/m2 as a bolus intravenous injection following leucovorin on day 
1. 
5FU 2,400mg/m2 infused intravenously as a continuous infusion over 46 
hours following the bolus 5FU, beginning on day 1. 
 
A second cycle of treatment may begin when ANC ≥ 1,000/mm3, platelets ≥ 
75,000/ mm3 and all other treatment related toxicity has resolved to ≤ grade 1.  
 
Dose adjustments for toxicities may be found in Section 6. 
 
5.3 
Gemcitabine during Radiation Therapy 
 
Combined modality treatment will begin 2 weeks (plus or minus 2 days) after the 
last FOLFOX administration, provided the ANC ≥ 1,000/mm3, platelets ≥ 100,000/ 
mm3 and all other treatment-related toxicity has resolved to ≤ grade 1.   
 
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1, 8, 22, and 29 
during the 5-week course of radiation treatment. 
 
Dose adjustments for gemcitabine due to toxicity are detailed in section 6 and will 
be based on complete blood counts (done within 24 hours of starting the treatment), 
and non-hematologic toxicities experienced in the preceding week(s). If 
gemcitabine treatment is held for toxicity, radiation therapy will also be held and 
both treatments resumed when resolution of toxicity permits.  
 
5.4       RADIATION THERAPY  
 
Treatment Assignment: 

 
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All subjects will receive 45.0 Gy to the Clinical Tumor Volume (CTV) and 50.4 Gy 
to the Gross Tumor Volume  (GTV) using Intensity Modulated Radiation Therapy 
(IMRT). 
 
 
Physical Factors: 
 
All subjects will undergo radiographic imaging required for radiation treatment 
planning purposes using a CT scanner.  Digitally reconstructed radiographs from 
the CT will simulate the patient geometry during radiation treatment, including the 
localization and immobilization methods.  A virtual treatment planning procedure is 
used to design treatment fields mathematically from the CT images. 
 
Field Arrangement: 
 
IMRT will be used to cover the primary or planning target volume (PTV), provided 
that the normal tissue constraints described below are met. 
 
Beam Shaping: 
 
A multileaf collimation system will be used to comply with field margin and normal 
tissue dose requirements. 
 
Treatment Equipment: 
 
Treatment will be administered on an isocentrically mounted megavoltage linear 
accelerator with photon energy ≥ 6 MV.  Typically, the source-to-axis distance 
(SAD) will be 100 cm.  IMRT will be delivered using dynamic MLC technique. 
 
Target Volumes: 
 
The PTV will be defined with CT-based treatment planning.  Simulation of the 
clinical target volume (CTV) will be determined with intravenous bolus contrast 
administration given during CT and pre-CT oral contrast.  GTV is the gross tumor 
volume.  CTV (clinical tumor volume) will include GTV and surrounding nodal 
areas.  PTV1 (planning tumor volume 1) is defined as CTV plus 1.0 - 1.5 cm 
margins in all directions. PTV2 (planning tumor volume 2) is defined as the GTV 
plus 1.0 - 1.5 cm margins in all directions. 
 
Radiation Dose: 
 
The prescription point will be designated at the intersection of the multiple beams.  
The PTV1 will receive a total cumulative target dose of 45 Gy delivered in 25 
fractions at a daily fractional dose of 1.8 Gy.  Following this, the PTV2 will receive 
a boost dose of 5.4 Gy in 3 fractions at a daily fractionated dose of 1.8 Gy.  The 

 
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total dose to the GTV will be 50.4 Gy. 
 
 
 
Beam Verification: 
 
Beam verification films of each treatment field will be obtained during the first 
treatment until satisfactory.  Thereafter, beam verification films will be obtained 
every week and at the time of any field modification.  Daily KV-KV imaging may 
be used at the discretion of the treating physician. Standard IMRT QA procedures 
developed at our institution will be performed, including monitor units verification, 
intensity map verification, as well as point dose measurements. 
 
Dosimetry: 
 
The uniformity requirement will be +/- 5% of the total dose at the prescription point 
within the planning target volume. 
 
Critical Normal Structures:  QUANTEC Dose Constraint Parameters will be used 
as follows: 
 
Kidneys (unilateral): <75% to get 20 Gy 
Kidneys (bilateral): mean dose< 15 Gy  
<55% to get 12 Gy 
<32% to get 20 Gy 
<30% to get 23 Gy 
<20% to get 28 Gy 
Spine: dose shall be limited to 45 Gy.  of the volume of the liver 
Liver: mean dose< 28 Cy, <70% to get 30 Gy 
 
Radiation Treatment Modifications: 
 
Radiation therapy will be withheld if ANC drops below 500/μL or if the platelet count is 
less than 50,000/μL.  Treatment will be reinstituted when hematologic toxicity has 
improved to below grade 3 level. 
Radiation will be withheld for 2 - 5 days or until symptoms resolve if severe nausea & 
vomiting occurs that does not resolve with antiemetics. 
 
5.5       Surgical Resection:  
Operative and surgical resection evaluation will be done at initial diagnosis as well 
as within 6 weeks after the completion of neoadjuvant treatment. 
To determine resectability, radiologic computer tomography (CT) imaging, 
preferably a pancreas protocol CT, will be utilized to identify: 

 
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1.  Absence of tumor extension to the adjacent visceral arteries (SMA, celiac, 
hepatic).  Intact tissue plan between the tumor and the Superior Mesenteric 
Artery(SMA)/Common Hepatic Artery Interface;  
2.  A patent Superior Mesenteric Vein/ Portal Vein (SMPV) confluence, and the 
absence of tumor-induced unilateral shift or narrowing of any aspect of the SMPV 
confluence; 
3.  Absence of extrapancreatic disease; 
The surgical procedure performed will be that required for a complete resection, 
and this will be based on the discretion of the operating surgeon.  
 
Information regarding any surgical therapy performed will be recorded including: 
type of surgery performed, type of vascular reconstruction performed, if any, extent 
of resection R0, R1 (or) R2 resection, duration of the operation, length of post-
operative hospital stay, complications, and need for re-admission within 30 days 
following surgical resection. Surgical resection will be performed for resectable 
pancreatic cancer as determined by the NCCN guidelines. All resection cases will be 
reviewed at Henry Ford Hospital’s  Multi-disciplinary GI Tumor Board.  
 
 
DETAILS ON SURGICAL RESECTION 
 
1. Pancreaticoduodenectomy with retroperitoneal lymphadenectomy will be performed 
for patients with ductal adenocarcinoma of the head of the pancreas.   
This will be assessed prior to the operation with high-quality 3-D imaging of the 
pancreas and associated mesenteric vessels for optimal categorization of tumors.  
Tumors will be considered resectable based on the following: 
- 
No distant metastases 
- 
No radiographic evidence of SMV and portal vein abutment, distortion, 
tumor thrombus, or venous encasement 
- 
Clear fat planes around the celiac axis, hepatic artery, and SMA.   
- 
**Those with venous involvement of the SMV/portal vein, namely tumor 
abutment, encasement, or short segment venous occlusion will be 
considered borderline resectable 
- 
**Gastroduodenal artery encasement up to the hepatic artery with either 
short segment encasement or direct abutment of the hepatic artery, without 
extension to the celiac axis will be considered borderline resectable 
- 
**Tumor abutment of the SMA not to exceed >180 degrees of the 
circumference of the vessel wall will be considered borderline resectable 
 
2.  Recent evidence suggests that the optimal number of lymph nodes to be examined 
following standard pancreaticoduodenectomy should be greater than or equal to 15 
(Tomlinson JS, Jain S, Bentrem DJ, Sekeris EG, Maggard MA, 
Hines OJ, et al.Accuracy of staging node-negative pancreas 
cancer: a potential quality measure. Arch Surg. 2007;142:767–23; 

 
13 
discussion 73–4.)  Cooperation between both the operating surgeon and the surgical 
pathologist should ensure analysis of sufficient number of lymph nodes. 
 
3.  If, at the time of operation, vascular resection is required, vein resection and 
reconstruction will be performed if there is short segment invasion of the portal vein or 
PV/SMV confluence, providing adequate inflow and outflow veins are present.   
 
4.  Whipple specimens will be inked, examined, and reported in conformity with 
College of American Pathologists (CAP) or AJCC.  Examination of the pancreatic 
margin, and bile duct margin will be assessed.  In addition, it will be critical to examine 
the retroperitoneal margin as well as the SMA margin to accurately determine the 
resection status.   
 
Safe achievement of an R0 margin is the main surgical objectives of the 
pancreaticoduodenectomy.  The SMA margin is the most important driver of this 
outcome. 
 
5.6       Duration of Therapy  
                  In the absence of treatment delays due to adverse events, treatment may continue with 
chemo-radiotherapy as previously outlined prior to proceeding with surgical resection  
 
5.7        Duration of Follow Up  
 
Patients will be followed for 1 year after completion of neoadjuvant therapy or until 
removal (or) termination from study, or until death, whichever occurs first. Patients 
removed from study for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. Patients will be seen in follow-up every 3 ± 1 
months for 1 year from completion of protocol therapy.  At each interval visit, 
surveillance CT scans will be performed to assess local recurrence or metastatic 
disease.  If patients choose to receive the adjuvant chemotherapy elsewhere other than 
the treating institution, a 3 month follow-up evaluation in the different institution is 
permissible. The data from the 3 month follow-up visit will be captured by the data 
managers and provided to the study principal investigator. Toxicity notations and 
disease status will be recorded. If it is not possible to coordinate a follow-up evaluation 
at 3 ± 1 months, then a follow-up phone call will be made to the patient by the treating 
physician, or clinical trials office designee,  in lieu of a visit.  
 
5.8 
Criteria for Removal from Neoadjuvant Study  
 
Patients will be removed from this study when any of the following criteria are met:  
 
                   - Intercurrent illness that prevents further administration of treatment; 
 
                   - Unacceptable adverse events(s);  
 
                   - Pregnancy;  
 

 
14 
 
       - Patient decides to withdraw from the study;  
 
 
       - General or specific changes in the patient's condition which render the patient  
 
         unsuitable for further treatment, in the judgment of the investigator;  
 
- Patients with unresectable disease, noted on laparotomy (or) laparoscopic evaluation 
following completion of neoadjuvant therapy, will be removed from the protocol ; 
 
 
       - Patients who develop documented metastatic disease at any point during the trial 
 
         period . 
 
 
The reason for removal from study and the date the patient was removed must be 
documented in the Case Report Form. 
 
5.9        Adjuvant Therapy following Surgical Resection  
 
All patients who are enrolled in this study are eligible to receive adjuvant 
chemotherapy based on the discretion of their primary oncologist. These patients will 
be followed on protocol and details of their adjuvant therapy will be recorded. 
 
6.  DOSING DELAYS/DOSE MODIFICATIONS 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) version 4.0 for toxicity and Serious Adverse Event (SAE) reporting.  
 
6.1 General Considerations – FOLFOX treatment 
 
a. The second cycle of treatment may begin when the ANC is ≥ 1,000/mcl, the 
platelet count is ≥ 75,000/mcl, and any treatment-related GI toxicity has 
resolved to ≤ Grade 1. 
 
b.  If the initiation of the second cycle of treatment is delayed for > 4 weeks from 
date due, secondary to toxicity, the patient will be removed from protocol 
treatment. 
 
c. Doses will not be modified for cholangitis attributable to biliary 
obstruction/stent occlusion unless this occurs in the setting of > grade 3 
neutropenia.  
 
d. There are no dose reductions for leucovorin.  Dose reductions for the other 
agents in the FOLFOX combination are as follows: 
 
 
AGENT 
INITIAL 
DOSE 
Level -1 
Level -2 
Level -3 
5-FU Bolus 
400 mg/m2 
200 mg/m2 
0 
0 

 
15 
Oxaliplatin 
85 mg/m2 
70 mg/m2 
60 mg/m2 
50 mg/m2 
5-FU infusion       2400 mg/m2     2000 mg/m2     1600 mg/m2  
1200 mg/m2  
 
 
 
Note: laboratory abnormalities that are not directly attributable to treatment (i.e., 
hyperglycemia) or not clinically relevant (i.e., lymphopenia) do not require 
modification of dosing.  
 
Efforts to attribute toxicity experienced to a single component or some 
combination of the cytotoxic agents will be made by treating investigator and 
doses of the responsible agent(s) modified according to that judgment. Dose 
adjustments for toxicity will be described in the clinical record.  
 
Once doses are reduced for toxicity, they will not be subsequently increased.  
 
An agent(s) may be discontinued (i.e., oxaliplatin for neuropathy or 
hypersensitivity) and protocol therapy continue with remaining agents.  
 
An agent(s) or FOLFOX combination therapy will be discontinued if more than 
2 dose reductions for toxicity are needed.  
 
6.2 Supportive Care 
 
White blood cell colony stimulating factors may be administered as primary 
prophylaxis following each FOLFOX administration.  
 
6.3 Dose Modifications 
 
a. Dose modifications for toxicities during FOLFOX 
 
i. Hematologic Toxicities 
 
 
Dose Modification 
ANC <1000/mm3 
and/or 
Platelets <75,000/mm3 
Hold all chemotherapy and re-evaluate weekly. 
When toxicity resolves, treatment will be continued 
with one dose level  reduction of oxaliplatin and 
bolus 5FU. 
Platelets > 75,000/mm3-< 
99,000/mm3 
Reduce oxaliplatin one dose level  
 
 
Febrile Neutropenia 
If a patient experiences neutropenic fever at any 
point in the treatment cycle, chemotherapy will be 
delayed until ANC > 1,000/mm3 and antibiotic 
treatment of the event, if required, is completed. 
When treatment resumes,  reduce agents oxaliplatin 

 
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and infusional 5FU if grade III or IV diarrhea and/or 
stomatitis > are part of the adverse event profile, by 
one dose level 
 
 
 
 
*Note: There are no dose reductions for anemia or lymphopenia  
 
 
 
 
ii. Diarrhea 
 
Grade 
Dose Modification 
3-4 
Hold all chemotherapy.  When diarrhea resolves to 
<Grade 1, chemotherapy may be resumed with a 
reduction in 5FU-bolus and 5FU infusion by one 
dose level.   
*Note: No dose reductions of oxaliplatin for diarrhea.   
 
 
 
 
iii. Mucositis 
 
Grade 
Dose Modification 
3-4 
Hold all chemotherapy.  If mucositis resolves to 
<Grade 1, chemotherapy may be resumed with 
reduction in 5FU-bolus and infusion by one dose 
level.   
*Note: No dose reductions of oxaliplatin for mucositis.   
 
iiii Neuropathy 
 
Grade 
Dose Modification 
3-4 
Hold oxaliplatin.  If neuropathy resolves to <Grade 
2, oxaliplatin  may be resumed with reduction  of 
two dose levels or discontinued.   
*Note: No dose reductions for 5-FU for neuropathy.   
 
b. Other non-hematologic toxicities attributable to 5-FU and/or oxaliplatin. 
 
For all other ≥ Grade 3 non-hematologic toxicities attributable to treatment and 
not described above, hold all protocol treatment and monitor toxicity at least 
weekly. If toxicity resolves to ≤ Grade 1 within 4 weeks, treatment may resume 
with 5-FU and oxaliplatin at one lower dose level. 
 
c. Dose modifications for toxicities during combined modality therapy (RT/Gemcitabine)  
 
Agent 
Initial Dose 
Level -1 
Level -2 
Gemcitabine* 
750 mg/m2 
600 mg/m2 
500 mg/m2 
 
*Note: all infusions of Gemcitabine and RT may begin when the ANC is ≥ 
1,000/mm3, the platelet count is ≥ 100,000/mm3, and any treatment-related 
toxicity to FOLFOX is resolved to ≤ Grade 1. 

 
17 
 
During combined modality treatment, gemcitabine will be given days 1, 8, 22 
and 29.  
 
During gemcitabine/RT the dose of gemcitabine for days 8 and 29 will be 
based on toxicities experienced as follows: 
 
i. Hematologic toxicity  
 
 
Dose Modification 
ANC ≥ 1,000 /mm3 and 
platelets ≥ 75,000/mm3 
Full dose due will be given 
 
ANC of 500- 999/mm3 
and/or platelets of 50,000 to 
74,999/mm3 
50% of the gemcitabine dose due will be given 
 
ANC < 500/mm3 or 
platelets < 50,000/mm3 
Gemcitabine treatment and radiation therapy will 
be held. Combined modality treatment will resume 
upon recovery to values permitting chemotherapy 
with one dose level reduction of gemcitabine 
 
* Note:  dose adjustments of gemcitabine will be made based on the 
ANC and platelet counts taken within 24 hours of the start of therapy. 
 
During combined gemcitabine/RT, dose of gemcitabine for day 22 will be 
based on toxicities experienced as follows: 
 
ii. Hematologic toxicity  
 
 
Dose Modification 
ANC ≥ 1,000 /mm3 and 
platelets ≥ 75,000/mm3 
Full dose due will be given 
 
ANC of 500- 999/mm3 
and/or platelets of 50,000 to 
74,999/mm3 
75% of the gemcitabine dose due will be given. If 
gemcitabine is dose reduced on this day, this dose 
will be dose due on day 29 and starting dose of 
post-combined modality therapy.  
 
 
 
 
ANC < 500/mm3 or 
platelets < 50,000/mm3 
Gemcitabine treatment and radiation therapy will 
be held. Combined modality treatment will resume 
upon recovery to values permitting chemotherapy 
with one dose level reduction of gemcitabine 
 
* Note:  dose adjustments of gemcitabine will be made based on the 
ANC and platelet counts taken within 24 hours of starting therapy. 
 
 
 
 

 
18 
 
 
 
 
iii. Non-hematologic toxicity-Any organ system  
 
Grade 
Dose Modification 
> Grade 3 
Hold all chemotherapy.  If gemcitabine is held, 
radiation therapy will also be held while appropriate 
physical, laboratory, radiologic assessments are 
undertaken to define cause and direct supportive 
therapy. Treatment may be resumed upon recovery 
to toxicity < grade 2 at the discretion of the 
physician investigator. 
 
*Note: Dose adjustments of chemotherapy will be made following 
assessment of non-hematologic toxicity on the day of therapy. 
 
If combined modality therapy is interrupted, when resumed, chemotherapy will be 
given on the first day of the next week of radiation therapy with gemcitabine dose 
reduced one level to complete the treatment cycle. A maximum of four doses of 
chemotherapy will be given during the course of radiation therapy. 
 
d. General Guidelines 
  
A cycle of FOLFOX treatment is 14 days.   A second cycle of FOLFOX treatment may 
begin when ANC ≥ 1,000/mm3, platelets ≥ 100,000/ mm3 and all other treatment related 
toxicity has resolved to ≤ grade 1.  
 
FOLFOX treatment may be delayed for up to 2 weeks, after which time the second cycle 
of treatment will be dropped and not made up if conditions for treatment are not met. The 
patient may then be continued on to the combined modality treatment, once toxicities are 
resolved to grade 0 or 1. 
 
Protocol therapy may be shortened and patient may go directly to surgery following 
combined modality therapy in a scenario where toxicities and/or response and resectability 
suggest surgery is in the best interest of the patient.  
 
 
7.    ADVERSE EVENT REPORTING:  
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for reporting of adverse events (AEs).  
Serious Adverse Events (SAE) and adverse events will be carefully recorded, and SAEs will be 
reported to Henry Ford Hospital’s IRB if they meet the IRB’s SAE reporting criteria. 
 
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 

 
19 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite).  
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
• Death; 
• A life-threatening adverse drug experience; 
•  Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent or significant disability/incapacity; 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition. Any pregnancy, including a male patient’s 
impregnation of his partner, occurring on study must be reported to the IRB as a 
medically significant event. 
 
SAEs (more than 30 days after last treatment) attributed to the protocol treatment (possible, 
probable, or definite) should be reported to the IRB if the reporting criteria is met. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1      5-Fluorouracil (5-FU) 
 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – 5-FU is an antimetabolite considered to act primarily as an inhibitor 
of thymidylate synthase.  
 
b. Pharmaceutical Data – Kinetics: After IV injection, it is distributed widely 
throughout the tissues of the body and diffuses readily across the blood-brain 
barrier. The mean half-life of elimination from plasma is 16 minutes. Drug is 
primarily metabolized by the liver.  Formulation: 5-FU is a colorless to faint yellow 
solution supplied in 10 ml single use vials. Each 10 ml contains 500 mg 
fluorouracil. The pH is adjusted to approximately 9.2 with sodium hydroxide. 
 
c.  Administration – Intravenous. 
 
d. Storage and Stability - : Store unopen vials at room temperature and protect from 
light. 
 
e. Supplier – 5-FU is commercially available. 
 
 

 
20 
8.2    Oxaliplatin 
 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – Oxaliplatin (cis-[(1R,2R )-1,2-cyclohexanediamine- N,N ] [oxalate(2-
)- O,O ] is an organoplatinum complex in which the platinum atom is complexed 
with 1,2-diaminocyclohexane with an oxalate ligand as a leaving group. Oxaliplatin 
undergoes nonenzymatic conversion in physiologic solutions to active derivatives 
by displacement of the labile oxalate ligand.  Several reactive species are formed 
including the monoaquo and diaquo DACH platinum which covalently bind with 
macromolecules.  Crosslinks are formed between adjacent guanine N7 positions. 
These crosslinks inhibit DNA replication, transcription and repair.  Reactive 
oxaliplatin derivatives are present as a fraction of unbound platinum in plasma 
ultrafiltrate.  The decline of platinum levels following oxaliplatin administration is 
triphasic, characterized by two short distribution phases (t1/2(alpha) 0.43 hrs, t1/2 
(beta) 16.8 hrs) and a long terminal phase (t1/2 (gamma) 391 hrs).  At the end of a 2 
hour infusion approximately 15% of the administered platinum is present in the 
systemic circulation with the remaining 85% rapidly distributed into tissues or 
eliminated in urine.  The major route of elimination is renal excretion and the renal 
clearance of ultrafilterable platinum is significantly correlated with GFR.   
 
b. Pharmaceutical Data– Oxaliplatin is supplied as a sterile, preservative free, aqueous 
solution in clear glass single-use vials containing 50 mg, 100 mg or 200 mg of 
oxaliplatin at a concentration of 5 mg/ml. The solution must be further diluted in 
250-500 ml 5% dextrose for injection and is stable up to 24 hours under 
refrigeration or for 6 hours at room temperature. Needles or IV infusion sets 
containing aluminum must not be used.  
 
c. Administration – Intravenous. 
 
d. Storage and Stability – Store lyophilized powder under normal lighting conditions 
at 25o C.  Store aqueous solution at 25o C; excursions permitted to 15-30o C. Do not 
freeze and protect from light (keep in original outer carton). 
 
e. Supplier – Oxaliplatin is commercially available 
 
8.3 Leucovorin 
 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – Leucovorin is a mixture of the diastereoisomers of 5-formyl 
derivative of tetrahydrofolic acid. The active component is the (-)-L-isomer known 
as Citrovorum factor.  
 
b. Pharmaceutical Data– Kinetics: Leucovorin is rapidly absorbed from the 
gastrointestinal tract after oral administration and enters the general body pool of 

 
21 
reduced folates. Serum folate half-disappearance time is around 3.5 hours. Oral 
tablets yielded areas under the serum folate concentration-time curves (AUCs) that 
were 12% greater than equal amounts of leucovorin given intramuscularly and 
equal to the same amounts given intravenously. After IV administration, peak 
concentration was at 10 minutes. Terminal half-life of its active metabolite, 5-
methyl derivative, was 6.2 hours. IM administration revealed similar terminal half-
life. Formulation: Leucovorin is provided in vials containing 
cryodessicated/leucovorin calcium powder which is reconstituted in sterile diluent.  
 
c. Administration – Intravenous 
 
d. Storage and Stability – Store dry powder, reconstituted solution and tablets at 
controlled room temperature. Protect from light. When reconstituted with 
Bacteriostatic Water for Injection, the resulting solution must be used within seven 
days. If reconstituted with Sterile Water for Injection, use immediately and discard 
any unused portion. Because of the benzyl alcohol contained in Bacteriostatic 
Water for Injection, when doses greater than 10 mg/m2 are administered, Sterile 
Water for Injection should be used. 
 
e. Supplier – Leucovorin is commercially available. 
 
8.4     Gemcitabine 
 
 
Please refer to the FDA-approved package insert for additional information. 
 
a. Description – Gemcitabine hydrochloride (2’,2’-difluoro-2’deoxycytidine) is a 
deoxycytidine analog with structural and metabolic similarities to cytarabine. 
Gemcitabine is metabolized intracellularly by nucleoside kinases to active di- and 
triphosphate nucleosides.  The active nucleosides interfere with ribonucleotide 
reductase and compete with dCTP for incorporation into DNA, respectively, 
resulting in inhibition of DNA synthesis. Gemcitabine pharmacokinetics are linear 
and are described by a two compartment model.  Half-life varies with age, gender, 
and infusion length; for a short infusion it is generally less than 70 minutes.  Nearly 
all of an administered dose is recovered in the urine as active drug (<10%) or 
inactive uracil metabolite.  The maximum plasma concentrations of the inactive 
metabolite are achieved 30 minutes after discontinuation of the infusions, and the 
metabolite is excreted in the urine without undergoing further biotransformation.  
The metabolite does not accumulate with weekly dosing, but its elimination is 
dependent on renal excretion, and could accumulate with decreased renal function. 
 
b. Pharmaceutical Data – Gemcitabine is supplied as a lyophilized powder in sterile 
vials containing 200 mg or 1 g of gemcitabine as the hydrochloride salt, with 
mannitol and sodium acetate.  Gemcitabine is reconstituted with 0.9% sodium 
chloride without preservatives and used within 24 hours. 
 
c. Administration – Intravenous infusion over 30 minutes on days 1, 8, 22 and 29 

 
22 
 
d. Storage and Stability – Store at controlled room temperature. 
 
e. Supplier – Gemcitabine is commercially available 
 
9.    STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Scans and x-rays must be done within 4 weeks prior to start of therapy.   
 
    
 
Pre- 
Study 
 
Pre-
Cycles 
1-2 
 
Re-Eval (Pre 
chemo/XRT) 
 
Weekly 
during 
Chemo/ 
XRT 
 
Re-Eval 
(Post 
chemo/XRT) 
 
Surgery 
 
Post Surgery and 
Follow up Q 3 
months from the 
end of 
neoadjuvent 
treatment  
 
Protocol Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
History/Physical 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
CBC,diff, pltsa 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Biochemical profileb 
MG, Calcium 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
Ca 19-9 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Urine/serum pregnancyc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT chest/abdomen 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Tumor Measurement 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Assessment by radiation 
oncologist 
 
X 
 
 
 
 
 
 
 
 
 
 
Assessment by surgeon 
      X 
 
 
 
          X 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
D 
 
 
 
Radiation 
 
 
 
 
 
 
B 
 
 
 
 
 
 
5FU, Oxaliplatin, 
Leucovorin 
 
 
A 
 
 
 
 
 
 
Gemcitabine 
 
 
 
 
 
C 
 
 
 
 
 
 
Toxicity Evaluation 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
a within 24 hours prior to chemotherapy administration, at re-evaluation visits and per post 
treatment followup 
b comprehensive biochemical profile to include albumin, alkaline phosphatase, ALT or AST, 
glucose, total bilirubin, creatinine, MG, Ca++ and electrolytes 
c in women of child bearing potential only 
 
Formatted: Italian (Italy)

 
23 
A  FOLFOX section 5.2 
B  RT section 5.3 
C  Gemcitabine section 5.4 
D  Surgical exploration/resection section 5.10 
 
Post therapy follow-up at 3 month intervals through 1 year post completion of neoadjuvant 
therapy. All times are approximate. 
 
 
 
 
10. MEASUREMENT OF EFFECT 
 
10.1 
Primary Tumor Response 
 
Diagnostic imaging and RECIST criteria will be used to evaluate and record 
response of the primary tumor as defined below. 
 
Complete Response (CR): Disappearance of measurable and evaluable disease 
without the appearance of any new lesions. 
 
Partial Response (PR): At least 30% decrease in the LD of the primary lesion 
without the appearance of any new lesions. 
 
Progression (PD): At least 20% increase in the LD of the primary lesion 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. 
 
 
10.2 
Surgical Data  
 
 
The following information regarding any surgical therapy will be recorded: 
 
Operation performed 
             
Standard Whipple (pancreaticoduodenectomy) 
            Pyloric-preserving Whipple 
             
Total Pancreatectomy 
 
 
Distal/Subtotal Pancreatectomy 
 
 
Laparoscopic/Robotic Distal Pancreatectomy 
 
 
Biliary Bypass 
 
 
GastroJejunostomy 
 
 
Laparoscopy or Laparotomy, abort 
 
Any of above with vascular resection and reconstruction 

 
24 
 
 
V1 (patch) 
 
 
V1a (venorraphy no patch) 
 
 
V2 (primary, SV ligation) 
 
 
V3 (graft, SV ligation) 
 
 
V4 (primary, no SV ligation) 
 
 
V5 (graft, no SV ligation) 
 
 
V6 (splenorenal shunt) 
 
 
IVC (any) 
 
 
Common Hepatic Artery (any) 
 
 
Right Hepatic Artery (any) 
 
 
Left Hepatic Artery (any) 
 
 
Other:  
 
 
 
Extent of Visceral Extension:  
 
 
Colon, stomach, adrenal, other 
 
 
Metastatic Disease 
 
 
Liver, Peritoneum, other 
 
Exploratory laparotomy (no resection) 
 
 
With gastric bypass 
 
 
With biliary bypass 
 
 
With both 
 
Duration of operation, Blood loss, blood product transfused, #units 
 
transfused, and complications/notable events.   
 
Pathologic findings: Tumor size, grade, nodal status, lymphovascular 
 
invasion, perineural invasion, microscopic assessment of margins, including 
 
retroperitoneal margin (R0 vs R1 vs. R2 ). 
 
• 
RO Resection:  Complete resection with no microscopic residual tumor (margins 
microscopically negative according to the pathologist).  
• 
R1 Resection:  Complete resection with no grossly visible tumor as defined by the 
surgeon, but microscopic cancer may be left behind (margins are microscopically 
positive according to the pathologist).   
• 
R2 Resection:  Partial resection, with grossly visible tumor left behind.  
 
 
Length of stay, need for re-admission within 30 days of discharge. 
 
10.3 Assessment of Pathologic Response 
 
The surgical pathology slides will be reviewed at the Department of Pathology, 

 
25 
Henry Ford Hospital.  All histologic slides from surgical resections will be 
reviewed by a single pathologist and assessment of therapeutic response will be 
graded using a system previously described by Evans et al as per the table 
below. 
 
Grade  
Histologic Appearance 
I 
Characteristic cytologic changes of malignancy are 
present, but very little (<10%) or no tumor cell 
destruction is evident  
II 
In addition to characteristic cytologic changes of 
malignancy, 10%-90% of tumor cells are destroyed   
IIa 
Destruction of 10%-50% of tumor cells 
IIb 
Destruction of 51%-90% of tumor cells 
III 
 
Few (<10%) viable-appearing tumor cells are present   
IIIM 
Sizable pools of mucin are present 
IV 
No viable tumor cells are present   
IVM 
Acellular pools of mucin are present  
 
 
 
 
 
  
11.  
STATISTICAL CONSIDERATIONS 
 
Planned Data Analysis  
 
Primary Objective:  The proportion of patients who achieve R0 resection will be estimated, 
along with a 95% confidence interval for that proportion. 
 
Secondary Objectives: 2a  Kaplan-Meier survival estimates will be made for progression-free 
survival and for overall survival. 
2b  Tolerabilitiy and toxicity will be assessed by estimating the proportion of patients with 
dose limiting toxicities, and 95% confidence intervals for those proportions. 
2c  The proportions of patients with CR, PR, PD or SD will be estimated along with 95% 
confidence intervals. 
 
Justification of Sample Size 
 
With a total sample size of 20, the 95% confidence interval width will be equal to 0.22 if the 
proportion is ~0.5.  For proportions greater or less then 0.5, the confidence interval width will 
be narrower.  For instance, for a proportion around 0.2, the confidence interval width will be 
0.175. 
 
12.             BIBLIOGRAPHY 
 
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Formatted: Dutch (Netherlands)
Formatted: Danish

 
27 
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Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization of 
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Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, and cellular 
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Conroy T, Desseigne F, Ychou M, et al. Randomized phase III trial comparing 
FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus 
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29. FOLFOX-6 combination as the first-line treatment of locally advanced and/or metastatic 
pancreatic cancer. Am J Clin Oncol. 2007;30(1):15 
 
 
 
 
 
 
 
 
 
 

 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.             APPENDIX 
 
 
 
APPENDIX A 
 
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
 
 
 

 
29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 

 
30