Clinical trial NCT01897454
Conditions: Pancreatic Adenocarcinoma Stage IIA Pancreatic Cancer Stage IIB Pancreatic Cancer Stage III Pancreatic Cancer
Sponsor: Albert Einstein College of Medicine
Start date: 2012-01-27; Completion date: 2021-11-01
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well combination chemotherapy, gemcitabine hydrochloride, and radiation therapy before surgery works in treating patients with pancreatic cancer that has not spread to other places in the body and can be removed by surgery. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, irinotecan hydrochloride, oxaliplatin, and gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Fluorouracil, irinotecan hydrochloride, and gemcitabine hydrochloride may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and gemcitabine hydrochloride with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy, measured as the proportion of R0 resections, of fluorouracil-leucovorin calcium-irinotecan hydrochloride-oxaliplatin (FOLFIRINOX) chemotherapy regimen followed by gemcitabine based chemoradiotherapy when used as preoperative therapy in patients with borderline resectable adenocarcinoma of the pancreas.

SECONDARY OBJECTIVES:

I. To measure the overall response rate (ORR). II. To evaluate overall survival (OS). III. To evaluate progression free survival (PFS). IV. To evaluate safety and toxicity associated with chemotherapy and radiotherapy.

V. To assess adverse events related to surgery. VI. To assess the proportion of patients able to undergo resection. VII. To assess proportion of patients requiring vascular reconstruction.

OUTLINE:

CHEMOTHERAPY REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1, and fluorouracil IV over 46 hours on days 1-3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving disease progression proceed to chemoradiotherapy.

CHEMORADIOTHERAPY REGIMEN: Beginning 4-6 weeks after completion of chemotherapy, patients undergo intensity-modulated radiation therapy (IMRT) on 5 consecutive days per week for a total of 28 fractions and receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 30 months.

Arms: arm 1: CHEMOTHERAPY REGIMEN: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1, and fluorouracil IV over 46 hours on days 1-3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving disease progression proceed to chemoradiotherapy.

CHEMORADIOTHERAPY REGIMEN: Beginning 4-6 weeks after completion of chemotherapy, patients undergo IMRT on 5 consecutive days per week for a total of 28 fractions and receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Fluorouracil intervention 2: Gemcitabine Hydrochloride intervention 3: Intensity-Modulated Radiation Therapy intervention 4: Irinotecan Hydrochloride intervention 5: Leucovorin Calcium intervention 6: Oxaliplatin
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo IMRT intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Local Protocol #: 2012-570   
 
 
TITLE:   A phase II trial of preoperative FOLFIRINOX followed by gemcitabine based 
chemoradiotherapy in patients with borderline resectable pancreatic 
adenocarcinoma 
 
 
 
 
Coordinating Center: 
 
 
Montefiore-Einstein Center for Cancer Care 
1521 Jarret Place, 2nd Floor 
Bronx, NY 10461 
Phone 718- 379-6860 
Fax 718- 822-0335 
 
 
Principal Investigator: 
 
 
Jennifer Chuy, MD 
Montefiore-Einstein Center for Cancer Care  
Montefiore Medical Center 
1695 Eastchester Road 
Bronx, NY 10461 
Phone: 718-405-8404 
Fax: 718-405-8433 
jchuy@montefiore.org  
 
Co-Investigators: 
 
 
 
Medical Oncology 
Andreas Kaubisch, MD 
Montefiore-Einstein Center for Cancer Care  
Montefiore Medical Center 
Department of Medical Oncology 
111 E 210th Street (Hofheimer 111) 
Bronx, NY 10467 
Phone: 718-920-4826 
Fax: 718-798-7474 
 
 
Sanjay Goel, MD, MS 
Montefiore-Einstein Center for Cancer Care  
Montefiore Medical Center 
Department of Medical Oncology  
1695 Eastchester Road  
Bronx, NY 10461  
phone:  718-405-8404  
Fax: 718-405-8433  
 
 
 
IRB NUMBER: 2012-570
IRB APPROVAL DATE: 07/21/2016


Lakshmi Rajdev, MD, MS 
Montefiore-Einstein Center for Cancer Care 
Montefiore Medical Center  
Department of Medical Oncology  
1695 Eastchester Road  
Bronx, NY 10461  
phone:  718-405-8404  
Fax: 718-405-8433  
Karen Fehn, RN, CCRP 
Montefiore-Einstein Center for Cancer Care 
Montefiore Medical Center  
Department of Medical Oncology 
1695 Eastchester Road  
Bronx, NY 10461  
phone:  718-405-8446  
Fax: 718-405-8230  
 
Christina Valvano, PA-C 
Montefiore-Einstein Center for Cancer Care 
Montefiore Medical Center 
Department of Medical Oncology 
111 E 210th Street (Hofheimer Bldg.) 
Bronx, NY 10467 
Phone: 718-920-4826 
Fax: 718-798-7474 
Barbara Weinstein, PA-C 
Montefiore-Einstein Center for Cancer Care 
Montefiore Medical Center  
Department of Medical Oncology 
1695 Eastchester Road  
Bronx, NY 10461  
phone:  718-405-8446  
Fax: 718-405-8230 
Yoko Eng, ANP 
Montefiore-Einstein Center for Cancer Care 
Montefiore Medical Center 
Department of Medical Oncology 
111 East 210th Street (Hofheimer Bldg.) 
Bronx, NY 10467 
Phone: 718-920-2090 
Fax: 718-405-7412 
 
Radiation Oncology 
Chandan Guha, MD, Ph.D 
Montefiore Medical Center 
Department of Radiation Oncology  
Montefiore Medical Park  
1625 Poplar Street 
Bronx, NY 10461 
phone:  718-405-8550  
Fax: 718-405-8551  
Rafi Kabarriti, MD 
Montefiore Medical Center  
Department of Radiation Oncology  
111 East 210th Street  
Bronx, NY 10467  
Phone: 718-920-4361  
Fax: 718-882-6914 
Nitin Ohri, MD 
Montefiore Medical Center 
Albert Einstein College of Medicine  
Department of Radiation Oncology  
1300 Morris Park Avenue, Mazer 105  
Bronx, NY 10461  
Phone: 718-303-3143  
Fax: 718-430-8618 
 
Surgery 
Peter Shamamian, MD 
Montefiore Medical Center 
Milan Kinkhabwala, MD 
Montefiore Medical Center 
 
 
IRB NUMBER: 2012-570
IRB APPROVAL DATE: 07/21/2016


Department of Surgery 
MMC Greene Medical Arts Pavilion 
3400 Bainbridge Avenue  
Bronx, NY 10467 
phone:  718-920-4800  
Fax: 718-798-1883 
Department of Surgery 
MMC Greene Medical Arts Pavilion 
3400 Bainbridge Avenue  
Bronx, NY 10467 
phone:  718-920-6659 
Fax: 718-798-1883 
Sarah Bellemare, MD 
Montefiore Medical Center 
Department of Surgery 
Montefiore Medical Park 
1575 Blondell Avenue 
Bronx, NY 10461 
phone:  718-904-2047  
Fax: 718-405-8292 
 
Haejin In, MD 
Montefiore Einstein Center for Cancer Care 
Montefiore Medical Center 
Department of Surgery 
1521 Jarret Place, Bronx, NY 10461 
Telephone #: 718-379-6865 
Fax #: 718-862-8850 
Peter Muscarella, MD 
Montefiore Einstein Center for Cancer Care 
Montefiore Medical Center 
Department of Surgery 
1521 Jarret Place, Bronx, NY 10461 
Telephone #: 718-862-8840 
Fax #: 718-862-8850 
 
 
 
 
Statistician:  
 
Shankar Viswanathan 
 
 
 
 
Albert Einstein College of Medicine 
 
 
 
 
Jack and Pearl Resnick Campus 
 
 
 
 
1300 Morris Park Avenue 
 
 
 
 
Belfer Building, Room 1312D 
 
 
 
 
Bronx, NY 10461 
 
 
 
Radiology: 
 
 
Inessa A. Goldman 
 
 
 
 
Albert Einstein College of Medicine  
 
Montefiore Advanced Imaging 
 
 
 
 
200 East Gun Hill Road 
 
 
 
 
Bronx, NY 10467-2159 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
IRB NUMBER: 2012-570
IRB APPROVAL DATE: 07/21/2016


 
 
 
Commercially available agents: 5-fluorouracil, oxaliplatin, irinotecan, gemcitabine  
Protocol Type : Revision 5 
Version # 7.0 
Version Date: July 19, 2016
 
 
IRB NUMBER: 2012-570
IRB APPROVAL DATE: 07/21/2016


 
 
SCHEMA 
 
 
Elegibility Verification 
Borderline Resectable 
Pancreatic Cancer 
 
FOLFIRINOX (4 cycles) 
Borderline resectable or 
Resectable (SD, PR, CR) 
(
 
Unresectable (POD) 
Chemoradiotherapy 
(Gemcitabine + RT) 
Withdraw 
(continue therapy off protocol) 
Resectable or Borderline 
resectable (SD, PR, CR) 
 
Unresectable (POD) 
Withdraw 
(continue therapy off protocol) 
 
Exploration/Resection 
 i 
 
IRB NUMBER: 2012-570
IRB APPROVAL DATE: 07/21/2016


TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Page 
 
SCHEMA ........................................................................................................................................ i 
 
1.0  OBJECTIVES .........................................................................................................................1 
1.1 
Primary Objective .......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
 
2.0  BACKGROUND .....................................................................................................................1 
2.1 
Pancreatic cancer .........................................................................................................1 
2.2 
Neoadjuvant therapy in pancreatic cancer ................................................................1 
2.3 
FOLFIRINOX chemotherapy regimen ......................................................................3 
2.4  
Rationale .......................................................................................................................4 
 
 
3.0  PATIENT SELECTION ........................................................................................................4 
3.1 
Eligibility Criteria  .......................................................................................................4 
3.2 
Exclusion Criteria ........................................................................................................6 
3.3 
Inclusion of Women and Minorities ...........................................................................6 
 
4.0 TREATMENT PLAN ..............................................................................................................7 
4.1  
Treatment administration ...........................................................................................8 
4.2  
Chemotherapy Agent Administration ........................................................................8 
 
4.2.1 Oxaliplatin..........................................................................................................8 
 
4.2.2 Leucovorin .........................................................................................................8 
 
4.2.3 Irinotecan ...........................................................................................................8 
4.2.4 5-Fluorouracil…….............................................................................................9 
4.2.5 Gemcitabine .......................................................................................................9 
 
4.3  
Radiotherapy Administration .....................................................................................9 
 
4.4 
General Concomitant Medication and Supportive Care Guidelines ....................12 
 
4.5  
Duration of Therapy ..................................................................................................13 
 
4.6  
Duration of Follow Up ...............................................................................................13 
4.7 
Criteria for Removal from Study .............................................................................13 
 
5.0 DOSING DELAYS/DOSE MODIFICATIONS ..................................................................13 
 
5.1  
Dose Modifications for FOFLIRINOX (chemotherapy) ........................................14 
 
 
 
5.1.1 Febrile Neutropenia .........................................................................................15 
 
5.2 
Dose Modifications for Gemcitabine (chemoradiotherapy) ...................................15 
 
5.3  
Dose Modifications/Interruption for radiotherapy.................................................16 
 
 
 
5.3.1 Radiotherapy Interruption ................................................................................16 
 
 
 
5.3.2 Radiotherapy dose Modifications ....................................................................17 
6.0 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................17 
6.1  
Adverse Events Lists for Commercial Agents .........................................................17 
6.2  
Adverse Event Characteristics..................................................................................18 
6.3  
Adverse events related to surgery….. ......................................................................18 
6.4  
Routine Adverse Event Reporting ............................................................................18 
 
7.0 PHARMACEUTICAL INFORMATION ............................................................................18 
 
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8.0 STUDY CALENDAR ............................................................................................................19 
 
9.0 CLINICAL LABORATORY TESTS AND PROCEDURES ............................................20 
 
10.0 MEASUREMENT OF EFFECT ........................................................................................20 
10.1 Antitumor Effect – Solid Tumors .................................................................................20 
 
11.0 STATISTICAL CONSIDERATIONS ...............................................................................24 
      11.1 Study Design/Endpoints ................................................................................................24 
 
11.2 Sample Size/Accrual Rate .............................................................................................25
 
11.3 Analysis of Secondary Endpoints .................................................................................25 
 
11.4 Reporting and Exclusions ..............................................................................................25 
 
12.0 REFERENCES .....................................................................................................................27 
 
13.0 APPENDICES ......................................................................................................................29 
 
APPENDIX A 
Performance Status Criteria .....................................................................................................29 
 
APPENDIX B 
1. 5-fluorouracil .......................................................................................................................30 
2. Oxaliplatin ............................................................................................................................31 
3. Irinotecan .............................................................................................................................33 
4. Gemcitabine .........................................................................................................................35 
 
APPENDIX C 
Dino-Clavien Scale……………… ..........................................................................................37 
 
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1.0 OBJECTIVES 
 
1.1 Primary Objective 
 
To assess the efficacy, measured as the proportion of R0 resections, of FOLFIRINOX 
chemotherapy regimen followed by gemcitabine based chemoradiotherapy when used as 
preoperative therapy in patients with borderline resectable adenocarcinoma of the pancreas. 
 
1.2 Secondary Objectives 
 
• To measure the overall response rate (ORR). 
• To evaluate overall survival (OS). 
• To evaluate progression free survival (PFS).  
• To evaluate safety and toxicity associated with chemotherapy and radiotherapy.  
• To assess adverse events related to surgery. 
• To assess the proportion of patients able to undergo resection. 
• To assess proportion of patients requiring vascular reconstruction. 
 
 
2.0 BACKGROUND 
 
2.1 Pancreatic Cancer 
 
The incidence of pancreatic cancer is 11.7 per 100,000 men and women of all races, being 
significantly higher in the black population (16.6 per 100,000). It is estimated that 44,000 people 
will be die of pancreas cancer in 2011.  It is the fourth leading cause of cancer deaths; ranking 
only behind lung, colorectal and breast. It is an aggressive disease with a generally grim 
prognosis, with a 5-year survival rate of 5.5%. [1-3]. Surgery is the only hope for prolonged 
survival, however only 7% of cases present with localized disease [2].  
The current standard of care for patients with “resectable” and “borderline resectable” disease is 
resection, generally involving a pancreatoduodenectomy, also known as Whipple procedure. 
Perioperative therapy is widely accepted as the standard of care for patients undergoing 
resection, given in the form of chemotherapy or chemoradiotherapy [4]. Ideally, patients should 
be exposed to all 3 modalities: surgery, radiation and chemotherapy. There is still debate among 
experts regarding which is the best approach in terms of sequence and combination of these 
modalities: chemotherapy followed by chemoradiotherapy vs. chemoradiotherapy vs. 
chemotherapy alone; postoperative (adjuvant) vs. preoperative (neoadjuvant) [5-6].  
Besides all these efforts in finding the best strategy, the 2 and 5 year survival rate for patients 
with pancreas cancer that undergo resection are 40-50% and 15-20%. 
 
2.2 Neoadjuvant therapy in pancreatic cancer 
 
 
Different strategies of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been 
used in resectable and borderline resectable pancreatic cancer in an attempt to achieve better 
outcomes. These treatment strategies demonstrated to be feasible and helped identifying two 2 
different groups of patients; 1) patients who respond and tolerate therapy well and will likely 
benefit from extensive surgery afterwards; and 2) patients who progress rapidly and develop 
 
 
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metastatic disease early on that probably would not have benefited from initial resection. 
The use of neoadjuvant therapy is of particular importance in “borderline resectable” pancreatic 
cancer since this subgroup of patients needs downstaging of the tumor in order increase the 
chances of achieving clear margins or R0 resections at the time of surgery. Prior trials evaluating 
neoadjuvant therapy in patients with borderline resectable pancreas cancer were not uniformly 
done. They analyzed different patient populations (resectable, borderline resectable, 
unresectable/locally advanced), sometimes including more than one subgroup in a single trial. 
Also, the definition used to define resectable and borderline resectable tumors varied between the 
different studies (NCCN, surgeon’s decision, and group guidelines). Furthermore, some of studies 
did not report resection margins (R0/R1) nor differentiate survival between resected or non-
resected patients [7-15].  
A group of trials conducted by the MD Anderson Cancer Center (MDACC) were done using the 
same inclusion criteria, making them appropriate for comparison [16-19] (see Table-1). These 
trials evaluated different chemoradiotherapy regimens in patients with “potentially respectable” 
(defined in Table-1) disease. The overall survival on patients who received preoperative 
chemoradiotherapy and underwent surgery was 20-34 months.  The best outcomes were reported 
by Evans et al using a combination of Gemcitabine + RT (30Gy), with an overall survival of 34 
months [17] . Patients who completed preoperative therapy but were unable to undergo resection 
had much worse outcomes with an overall survival of 7-10 months. The overall resection rate was 
60-90%, with an R0 resection rate of 70-95%. Among all these trials, the vast majority of patients 
who underwent resection had distant recurrences (60-80%), mainly in the liver. The local 
recurrence rate was 10-25%. Surprisingly all the local failures were in patients who had R0 
resection margins. The addition of induction chemotherapy followed by chemoradiotherapy 
(Gem/Cis, followed by Gem/RT) was attempted to decrease the distant recurrences and improve 
survival. This trial neither demonstrated survival benefit nor decrease in the percentage of distant 
failure. However, it showed that a longer course of neoadjuvant therapy can be done without 
compromising definitive therapy, since the resection rates were similar to prior trials in which 
shorter course of therapy was used [19].   
The MD Anderson Cancer Center group also reported a retrospective subset analysis of “borderline 
resectable” pancreatic subjects treated with preoperative chemoradiotherapy showed that the R0 
resection rate was 40% and the median overall survival was 18 months [20]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table-1: Studies from MDACC using neoadjuvant chemotherapy or chemoradiotherapy in 
potentially resectable pancreatic cancer 
 
 
 
Author 
Patient population 
Patients 
Regimen 
Resection  
Rate 
(based on all 
patients) 
Median OS 
All 
Resected 
Non-resected 
Pisters et al, 
JCO 1998 
[16] 
Potentially resectable: 
- no metastasis 
- no ext to SMA or      
celiac axis 
- patent SMPV 
35 
5-FU / RT 
(30 Gy, 10 
Fx) 
ORR  57% 
 
R0  90% 
R1  10% 
R2    0% 
- 
25 m 
7m 
Evans et al, 
JCO 2008 
[17] 
 
Potentially resectable: 
- no extrapancreatic 
disease 
- no SMA or celiac axis 
invasion 
- no occlusion of SMV or 
confluence of SMV-PV. 
86 
Gem / RT 
(30Gy,  10 
Fx) 
ORR  74% 
 
R0  89% 
R1  11% 
R2    0% 
22.7m 
 
34 m 
7.31 m 
 
Pisters et al, 
JCO 2002 
[18] 
 
Potentially resectable: 
- no extrapancreatic 
disease 
- no SMA or celiac axis 
invasion  
- no occlusion of SMV 
or confluence of SMV-
PV 
 
35 
Paclitaxel / 
RT (30Gy, 
10 Fx) 
ORR  57% 
 
R0  70% 
R1  30% 
R2   0% 
12 m 
19 m 
10 m 
 
Varadhachar
y et al, JCO 
2008 
[19] 
 
Potentially resectable: 
- no extrapancreatic 
disease 
- no SMA or celiac axis 
invasion  
- no occlusion of SMV or 
confluence of SMV-PV. 
90 
Gem-Cis / 
RT (30Gy 
on 10Fx) 
ORR 57% 
 
R0  96.2% 
R1    3.8% 
R2       0% 
17.4 m 
31 m 
10.5 m 
Notes:  
- OS: overall survival 
- ORR: overall resection rate 
 
 
2.3 FOLFIRINOX chemotherapy regimen 
 
Of particular interest for us is the FOLFIRINOX regimen (oxaliplatin, 85 mg per square meter 
of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; 
and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square 
meter given as a 46-hour continuous infusion, every 2 weeks), which was initially developed by 
Dr Conroy and his group in 2003  [21,22].  
In a recently published phase III trial, FOLFIRINOX regimen demonstrated a statistically 
significant improvement in median overall survival in patients with metastatic adenocarcinoma 
of the pancreas when compared to single agent gemcitabine  (hazard ratio for death, 0.57; 95% 
confidence interval [CI], 0.45 to 0.73; P<0.001). This clinical benefit was accompanied with 
significantly higher response rates in the FOLFIRINOX arm (31.6% vs. 9.4%, p = <0.001). In 
terms of side effects, FOLFIRINOX had higher rates of grade 3 or 4 toxicities. Most common 
toxicities were myelosupression, nausea, vomiting and diarrhea [23]. 
 
 
 
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2.4 Rationale 
 
Surgery is the only modality that offers prolonged survival and a potential cure for patients with 
pancreatic cancer. Preoperative chemoradiotherapy is an accepted treatment strategy in patients 
with borderline resectable disease. Prior reports showed that: 1) selects patients that will likely 
not benefit from extensive surgery upfront (pancreatoduodenectomy-Whipple), since 10-20% of 
patients will develop metastasis after preoperative CRT; 2) permits delivery of therapy to a high 
percentage of patients (>90%). This eliminates the risk of delaying adjuvant therapy due to 
morbidity associated with upfront surgery.   
Prior studies using preoperative chemoradiotherapy showed poor outcomes with resection rates 
of 60% (50-75%) and a median overall survival of 10-20 months. There are still 25-35% of the 
participants who never undergo surgical resection due to either development of metastatic 
disease or because they are found to have unresectable disease at the time of surgery [16-19]. 
There is an urgent need for more effective preoperative treatment strategies in order to increase 
the proportion of patients who are able to undergo a potentially curative R0 resection.  
To this end we aim to test a preoperative strategy in a group of patients who have borderline 
resectable pancreatic cancer. We hypothesize that preoperative therapy will: 1) achieve partial 
responses translating into more R0 resections; and 2) deliver radiation more efficiently since the 
tumor bed is well oxygenated. 
Our rationale to use an aggressive chemotherapy backbone as our initial approach is based on: 1) 
after neoadjuvant CRT, the majority of recurrences were seen at distant sites, suggesting that a 
more aggressive chemotherapy regimen should be used to treat micrometastatic disease early; 
and 2) FOLFIRINOX demonstrated to have the highest reported response rates when used in 
patients with metastatic disease with manageable toxicities.  
We hypothesize that patients borderline resectable disease will achieve similar responses, 
allowing higher rates of R0 resections. Higher perioperative mortality in patients receiving 
preoperative chemotherapy was seen in patients requiring vascular reconstructions [24].   We 
hypothesize that our subgroup of patients will not have such complications, since we will not 
include patients with locally advanced pancreas cancer, which in general have more invasion of 
local vascular structures.  
 
 
3.0 PATIENT SELECTION 
 
3.1 Eligibility Criteria: 
 
- 
Histologically or cytologically confirmed adenocarcinoma of the pancreas. 
 
- 
Only patients that have not received any prior treatment for pancreas cancer are eligible 
for this treatment protocol. 
 
- 
Patients are not required to have measurable disease by traditional RECIST criteria, as 
lesions in the pancreas are notoriously hard to measure radiographically. However, 
patients must have disease which is evaluable for resection. 
 
- 
Disease should be determined as “Borderline resectable” according to the Expert 
Consensus Statement published by Callery et al. (5): 
 
 
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• No distant metastasis 
 
• Venous involvement of the SMV/portal vein demonstrating tumor abutment with or 
without impingement and narrowing of the lumen, encasement of the SMV/portal 
vein but without encasement of the nearby arteries, or short segment venous 
occlusion resulting from either tumor thrombus or encasement but with suitable 
vessel proximal and distal to the area of vessel involvement, allowing for safe 
resection and reconstruction. 
 
• 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. 
 
• Tumor abutment of the SMA not to exceed greater than 180 degrees of the 
circumference of the vessel wall. 
 
-  Age >18 years.   
 
- 
Life expectancy of greater than 6 months. 
 
- 
ECOG performance status <1 (Karnofsky >80%; see Appendix A). 
 
- 
Patients must have normal organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count  
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
<2 mg/dl 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
within normal institutional limits 
 
 
OR 
- 
creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
- 
Ability to understand and the willingness to sign a written informed consent document. 
 
- 
Patients may not be receiving any other concurrent chemotherapy, immunotherapy, or 
radiotherapy.  
 
 
 
 
 
 
 
 
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3.2 Exclusion Criteria:  
 
- 
Patients who have had prior chemotherapy or radiotherapy for the treatment of pancreas 
cancer.  
 
- 
Patients may not be receiving any other investigational agents. 
 
- 
Evidence of extent of pancreatic cancer beyond that defined as “borderline resectable” 
above (locally advanced or distant disease).  Peripancreatic lymph node involvement, 
either confirmed or suspected, will not be considered distant disease unless the lymph 
node involvement extends outside of the field of resection.   
 
 
- 
Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
 
- 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to 5-fluorouracil, oxaliplatin, irinotecan or gemcitabine. 
 
- 
Any concurrent active malignancy other than non-melanoma skin cancers or carcinoma-
in-situ of the cervix.  Patients with previous malignancies but without evidence of disease 
for > 3 years will be allowed to enter the trial. Patients with a history of a T1a or b  
prostate cancer (detected incidentally at TURP and comprising less than 5% of resected 
tissue) may participate if the PSA remained within normal limits since TURP removal. 
 
- 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
- 
Pregnant women are excluded from this study because 5-fluorouracil, oxaliplatin, 
irinotecan and gemcitabine are Class D agents with the potential for teratogenic or 
abortifacient effects.  Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother, breastfeeding should be 
discontinued if the mother is treated. 
 
- 
HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with 5-fluorouracil, oxaliplatin, irinotecan and 
gemcitabine.  In addition, these patients are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  Appropriate studies will be undertaken in 
patients receiving combination antiretroviral therapy when indicated. 
 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women and members of all races and e*thnic groups are eligible for this trial.  
 
 
 
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4.0 TREATMENT PLAN 
 
This is an open-label, single-arm, phase II trial that evaluates the efficacy (measured as 
percentage of R0 resections) of preoperative FOLFIRINOX chemotherapy combination (initial 
phase or first phase), followed by gemcitabine based chemoradiotherapy (second phase) in 
patients with borderline resectable adenocarcinoma of the pancreas.   
 
The study will evaluate the median overall survival, the median progression free survival, 
toxicity and safety of this preoperative regimen.  
 
Patients will be assigned to receive oxaliplatin at a dose of 85 mg/m2, given as a 2-hour 
intravenous infusion, immediately followed by leucovorin at a dose of 400 mg/m2, given as a 2-
hour intravenous infusion, with the addition, after 30 minutes, of irinotecan at a dose of 
180mg/m2, given as a 90-minute intravenous infusion through a Y-connector. This treatment will 
be immediately followed by 5-fluorouracil at a dose of 400 mg/m2, administered by intravenous 
bolus, followed by a continuous intravenous infusion of 2400 mg/m2 over a 46-hour period every 
2 week intervals. This will be given for a total of 4 cycles (first phase).  
Within 4-6 weeks of termination of chemotherapy, patients that do not have progression of 
disease by cross sectional imaging (CT scan or MRI) will go into the second phase of the study. 
During this second phase they will receive chemoradiotherapy with narrow radiation fields 
(IMRT, 50.4Gy, delivered in 28 fractions, 1.8 Gy per fraction) and weekly gemcitabine given at 
400 mg/m2 (given on days 1, 8 15, 22, 29 and 36). 
 
 
CHEMOTHERAPY REGIMEN DESCRIPTION 
 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Oxaliplatin 
85 mg/m2 in  
500 cc D5W 
IV over 2 hours, before 
leucovorin  
Day 1 
2 weeks 
(14 days) 
 
Leucovorin 
400 mg/m2 in 
250 cc D5W 
IV over 2 hours, after oxaliplatin 
Day 1 
Irinotecan 
180 mg/m2 in 
500 cc D5W 
IV over 90 minutes, after 30 min 
of initiation of leucovorin via a Y- 
connector   
Day 1  
5-fluorouracil 
bolus 
400 mg/m2 
 
 
IV bolus, after irinotecan 
Day 1 
 
5-fluorouracil 
Infusion 
2400 mg/m2 in 
92 cc NS 
46 hour infusion, after bolus 5-
fluororuacil 
Days 1-3 
 
 
 
 
CHEMORADIOTHERAPY REGIMEN DESCRIPTION 
 
 
 
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Agent 
 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length 
Gemcitabine 
400 mg/m2 in 
250 cc NS 
IV over 30 minutes  
Days 1, 8, 
15, 22, 29, 
36 of RT 
35 days 
 
 
4.1 Treatment Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for 5-fluorouracil, oxaliplatin, irinotecan and gemcitabine are described in Section 6.  
Appropriate dose modifications for FOLFIRINOX regimen and gemcitabine are described in 
Section 5.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
Before dose administration for each patient, the total dose of each of the drugs (oxaliplatin, 
irinotecan, 5-fluorouracil, leucovorin, gemcitabine) must be calculated by the following 
equation: 
 
Dose (mg) = Scheduled Dose (mg/m2) × Body Surface Area (BSA) (m2) 
 
BSA will be calculated at the beginning of each cycle, using any method that is accepted and 
customarily used by the clinical site (e.g., the Mosteller formula): 
BSA (m2) = ([Height (cm) × Weight (kg)]/3600)1/2 
 
 
4.2 Chemotherapy Agent Administration 
 
4.2.1 Oxaliplatin 
 
Oxaliplatin will be administered as a 2-hour intravenous infusion at a dose of 85 mg/m2 on day 1 
of a 14 day cycle.  
For more information about oxaliplatin see appendix B 2. 
 
4.2.2 Leucovorin 
 
Leucovorin will be administered at a dose of 400 mg/m2, given as a 2-hour intravenous infusion 
on day 1 of a 14 day cycle. Leucovorin can be replaced by levoleucovorin  (Fusilev) due to the 
current national shortage of the first one. Levoleucovorin will be used at a dose of 200 mg/m2, 
given as a 2-hour intravenous infusion on day 1 of a 14 day cycle.  
 
4.2.3 Irinotecan 
 
Irinotecan will be administered as a 90 min. intravenous infusion through a Y connector dosed at 
180 mg/m2 on day 1 of a 14 day cycle. This will be given 30 minutes after finalization of the 
leucovorin infusion. 
For more information about irinotecan see appendix B 3. 
 
 
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4.2.4 5-Fluorouracil 
 
5-fluorouracil will be administered as a 2-5 minute intravenous bolus at a dose of 400 mg/m2, 
followed by a 46 hours continuous intravenous infusion of 2400 mg/m2. Both bolus and infusion 
will be administered on day 1 of a 14 day cycle. 5-fluorouracil will be administered immediately 
following the administration of the irinotecan infusion. 
For more information about 5-fluorouracil see appendix B 1. 
 
4.2.5 Gemcitabine 
 
Gemcitabine will be administered at a dose of 400 mg/m2, as a 30 min intravenous infusion of on 
days 1,8,15, 22, 29, 36 of radiation. 
For more information about gemcitabine see appendix B 4. 
 
 
4.3 Radiotherapy Administration 
 
 
 
Patients who did not have disease progression after completion of four cycles of neoadjuvant 
FOLFIRINOX chemotherapy will receive one course of radiation therapy (RT). Patients will 
undergo CT-based simulation after completion of neoadjuvant chemotherapy.  
 
The course of RT  will be intensity modulated (IMRT) and administered concurrently with 
gemcitabine, preferably starting within 2-4 weeks after completion of FOLFIRINOX, but no 
later than 6 weeks after FOLFIRINOX.    
 
External beam radiation therapy using intensity modulated radiation therapy (IMRT) 
technique 
 
Localization: Fiducial marker placement in the pancreas will be optional for better localization of 
the tumor.  When available, fiducial markers will be used for daily tracking of the target during 
treatment delivery with kV imaging.  
 
Immobilization: A custom immobilization device with a universal leg rest and a wing board will 
be used to minimize set-up variability.  
 
Simulation and Planning: The simulation scan will be done with the patient in the supine 
position with arms raised above the head using a CT-simulator with 2.5 mm slice thickness.  All 
tissues to be irradiated will be included in the CT scan along with additional centimeters of 
superior and inferior margin for dose calculations.  The simulation CT scan will be acquired with 
the patient in the treatment position using the same immobilization devices as for treatment.  
Oral and intravenous (IV) contrast agents will be used when possible to help delineate organs on 
3D images.  An additional 4D CT simulation will be done with respiratory gating to assess the 
extent of tumor/liver movement.  If gated treatment is chosen, three to four gating phases with 
the least amount of target motion will be selected for generation of plans and treatment delivery. 
The maximum intensity projection (MIP) image and the average intensity projection (Ave-IP) 
image will be recorded. The movement of the target due to respiration will be assessed and 
 
 
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motion in superior-inferior, medial-lateral and anterior- posterior directions will be recorded at 
the center of the primary tumor or fiducial markers.  The treatment planning (simulation) CT 
scan will be used to define gross tumor volume (GTV) and clinical tumor volumes (CTV).  The 
GTV and CTV will be outlined on all CT slices of the MIP image set in which the structures 
exist.  Normal tissues will be outlined on the AVE-IP. 
 
Treatment Planning/Target Volumes  
 
The definition of volumes will be in accordance with the 1993 ICRU Report #50, as follows:  
 
The Gross Tumor Volume (GTV) will be defined as all known gross disease determined from CT 
scans (plus MRI or PET, if available), clinical information, endoscopic findings and biopsy. 
There will be two GTVs for node positive patients and one for node negative patients.  Target 
tumor volumes will delineated slice by slice on the treatment planning CT images 
• GTV-primary will include the gross primary tumor volume (as documented by CT, PET or 
MRI, if available).  
• GTV-Node will include all involved nodal regions (as documented by biopsy or imaging) 
(plan to deliver 50.4 Gy).  
 
The Clinical Target Volume (CTV) will be defined as the areas of subclinical risk around the 
GTV. Elective nodal irradiation for microscopic disease will not be performed.   
 
The Planning Target Volume (PTV) will provide a margin around the CTV to compensate for 
treatment set-up uncertainty and internal organ motion.  The margin expansion determined from 
the 4D CT simulation will be used to generate the treatment volume.  The PTVs will spare non-
target skin surfaces (manually or automatically trimmed to 3-5 mm within the skin surface).  
 
Organs at Risk: Surrounding critical normal structures (small bowel, stomach, duodenum, liver, 
kidneys, lung and heart) will be delineated on the Ave-IP image set of the 4D CT sim. The 
normal tissues will be contoured and considered as solid organs. The tissue within the skin 
surface and outside all other critical normal structures and PTVs will be designated as 
unspecified tissue.  
 
Heterogeneity Corrections: All dose distributions will include corrections for tissue 
heterogeneities.  The method used for heterogeneity calculations will be reported.  
 
Dose Specifications  
The treatment plan used for each patient will be based on an analysis of the volumetric dose, 
including dose-volume histogram (DVH) analyses of the planning tumor volume (PTV) and 
organs at risk. The treatment aim will be dose optimization to the PTV while minimizing dose to 
uninvolved tissue.  
 
Target prescription dose:  
• For N0 disease: The primary tumor PTV (PTV_primary) will receive 50.4 Gy in 28 daily 
fractions at 1.8 Gy per fraction. 
• For N1 disease: The PTV_primary and the positive lymph node PTV (PTV_node) will 
receive 50.4 Gy in 28 daily fractions at 1.8 Gy per fraction.  
 
 
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Treatment Schedule: Treatment will be delivered once daily, 5 consecutive fractions per week 
(with the exception of holidays).  All targets will be treated simultaneously.  Breaks in treatment 
will be avoided as much as possible. 
 
Dose specifications: The prescription isodose surface will encompass at least 95% of the primary 
and involved nodal PTVs  
• No more than 5% of any PTV will receive < 90% of the prescription dose.  
• No more than 2% of any PTV will receive < 80% of the prescription dose.  
• No more than 2% of the primary PTV will receive > 115% of the prescription dose.  
 
Planning priorities: Target volume prescription goals followed by organs at risk dose constraints 
will be the most important planning goals.  
 
Treatment Delivery  
Megavoltage equipment capable of delivering dynamic intensity modulation will be used with 
inverse-planned IMRT software. Treatment machine–generated CT images through at least one 
plane within the PTV, with tumor and critical structures turned on for display, will be used for 
set-up verification.  Reference simulation images used for set-up verification will include the 
target volumes.  Setup verification images will be obtained at levels where cephalocaudad and 
transverse positioning can be verified.  Respiratory gating will be used for treatment delivery 
only in the phases selected during the treatment simulation. 
 
Critical Structures   
Critical normal structures: Dose volume histograms (DVHs) will be generated for all critical 
normal structures. Effort will be made to achieve the dose constraints to normal tissues listed 
below. The dose constraints are listed in order from most to least important.  
Small bowel:  
• No more than 200 cc above 30 Gy 
• No more than 150 cc above 35 Gy  
• No more than 20 cc above 45 Gy 
• None above 50 Gy  
Kidney:  
• No more than 75% above 12 Gy  
• No more than 50% above 15 Gy  
• No more than 33% above 18 Gy  
Liver:  
• No more than 40% above 30 Gy  
• No more than 30% above 40 Gy  
• No more than 5% above 50 Gy  
Lung:  
• No more than 20% above 20 Gy  
• No more than 5% above 42 Gy  
Heart:  
• No more than 50% above 35 Gy  
• No more than 15% above 40 Gy  
• No more than 5% above 50 Gy  
 
 
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Large bowel:  
• No more than 200 cc above 30 Gy  
• No more than 150 cc above 35 Gy  
• No more than 20 cc above 45 Gy  
 
 
4.4 General Concomitant Medication and Supportive Care Guidelines 
 
All supportive measures consistent with optimal patient care will be given throughout treatment.  
 
Loperamide (Imodium): Patients will be instructed to begin taking loperamide at the earliest 
signs of a poorly formed or loose stool. Loperamide should be taken in the following manner: 4 
mg at the first onset of diarrhea, then 2 mg every two hours around the clock until the patient is 
diarrhea-free for at least 12 hours (not to exceed 16 mg in one day/24hour period).  
 
Antiemetics: Oxaliplatin is emetogenic. All patients should be pre-medicated with an acceptable 
anti-emetic regimen. Patients may receive dexamethasone 10 mg IV as pre-treatment antiemetic 
unless there is a relative or absolute contraindication to corticosteroids. Other antiemetics may be 
used in addition to the suggested regimen, if clinically indicated. As the majority of patients on 
previous trials have not experienced significant nausea, antiemetics other than decadron are 
recommended only for those patients who demonstrate nausea and/or vomiting despite treatment 
with decadron.  
 
Anticoagulants: Patients who are taking warfarin sodium (Coumadin) may participate in this 
study; however, they must be on a stable, therapeutic dose and have close monitoring of their 
levels.  Subcutaneous heparin is also permitted.  
 
Hypersensitivity: Platinum hypersensitivity can cause dyspnea, bronchospasm, itching and 
hypoxia. Appropriate treatment includes supplemental oxygen, steroids, antihistamines, and 
epinephrine; bronchodilators and vasopressors may be required. Platinum hypersensitivity  
is an extremely rare event and should be treated promptly. Oxaliplatin hypersensitivity occurs in 
approximately 0.5% of patients receiving this agent.  
 
Pharyngo-laryngodysesthesias: Oxaliplatin may cause discomfort in the larynx or pharynx 
associated with dyspnea, anxiety, swallowing difficulty and is exacerbated by cold. Appropriate 
therapy includes use of anxiolytics, cold avoidance and monitoring.  
 
Growth Factors: Prophylactic use of G-CSF or GM-CSF is permitted on this trial at the 
investigator’s discretion, during the FOLFIRINOX period, but not during chemoradiotherapy 
part. Therapeutic G-CSF use in patients with serious neutropenic complications may be given at 
the investigator's discretion and should follow ASCO Guidelines for G-CSF use. Erythropoietin 
stimulating agents may be used according to ASCO guidelines. 
 
 
4.5 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
 
 
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the following criteria applies: 
 
• Grade 3 or Grade 4 toxicities that are deemed to be too unsafe to continue with therapy. 
 
• Radiological evidence of disease progression. 
 
• Withdrawal of consent by patient. 
 
• Presence of other medical conditions that prohibit continuation with therapy. 
 
• Failure of the patient to comply with study procedures that compromise safety, despite 
repeated efforts of the investigator to contact the patient with complete documentation of 
the circumstances. 
 
• In the opinion of the investigator, it is in the best interest of the patient to be discontinued 
from therapy. 
 
4.6 Duration of Follow Up 
 
Patients will be followed every 3 months after removal from study. They will be followed every 
3 months for 30 months, until death or loss of follow up, whichever occurs first. These visits will 
include a clinical history for symptom assessment, physical examination and measurement of 
serum CA 19-9 tumor marker. Imaging studies will be left at the criteria of each investigator 
based on their clinical suspicion of recurrence.   Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
 
4.7 Criteria for removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 4.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
5.0 DOSING DELAYS/DOSE MODIFICATIONS 
 
All toxicities should be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  
 
According to the following tables, the final dose modification should be based upon the worst  
grade of toxicity experienced. If patients require dose reductions lower than level -2, protocol  
therapy will be discontinued. Any dose reduction is continued for all subsequent cycles;  
therefore, dose re-escalation is not allowed following a dose reduction. NOTE: there are no dose 
reductions for leucovorin; the dose remains fixed at 400 mg/m2 and without modification.  
 
5.1 Dose Modifications for FOLFIRINOX (chemotherapy):  
 
 
 
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Dose reduction steps: FOLFIRINOX 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
5-Fluorouracil 
infusion 
2400 mg/m2 
2000 mg/m2 
1600 mg/m2 
5- Fluorouracil bolus 
400 mg/m2 
0 
0 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
*leucovorin dose remains fixed at 400mg/m2 
 
The following table describes the recommended dose modifications at the start of  
each subsequent course of therapy. All dose modifications should be based on the  
worst preceding toxicity.  
 
Note: Dose modifications must be based on AEs observed during the cycle  
(column 2) and on the scheduled cycle day 1 (column 3). Dose modifications  
must be based on the AE requiring the greatest modification. Toxicity NCI  
CTCAE v4.  
 
 
Toxicity NCI CTAE v4.0 Grade 
(value) 
Note: Dose modifications must be based on AE’s observed during the 
cycle (column 2) and on the scheduled cycle day 1 (column 3). Dose 
modification must be based on the AE requiring the greatest 
modification. 
Worst interval toxicity 
(modifications for AE’s that occurred 
during a cycle but did note require 
delay in treatment)  
Day of treatment 
(modifications for AE’s that 
require a delay in treatment) 
Neutrophils (ANC)  
Grade 1 (ANC<LLN-1500/mm3)  
Grade 2 (ANC<1499-1000mm/m3)  
Grade 3 (ANC<999- 500mm/m3)  
Grade 4 (ANC<500mm/m3)  
 
Maintain dose level  
Maintain dose level  
Omit bolus 5-FU  
Omit bolus 5-FU and reduce oxaliplatin 
and irinotecan one dose level  
 
If ANC<1000 at start of cycle,  
hold and check weekly then  
treat based on worst interval  
toxicity.  If ANC <1000 after 4  
weeks, discontinue therapy 
Platelets  
Grade 1 (PLT<LLN-75,000/mm3)  
Grade 2 (PLT<74,999-50,000mm/m3)  
Grade 3 (PLT<49,999- 25,000mm/m3)  
 
 
Maintain dose level  
Maintain dose level  
Omit bolus 5-FU  
Omit bolus 5-FU and reduce oxaliplatin 
and irinotecan one dose level  
 
 
Grade 4 (PLT<25,000mm/m3)  
If PLT<60,000 at start of cycle,  
hold and check weekly then  
treat based on worst interval  
toxicity. If PLT <60,000 after 4  
weeks, discontinue therapy 
Other hematologic toxicities do not 
require dose modification; however, red 
blood cell transfusion should be strongly 
considered for hemoglobin <8g/dl 
 
  
Diarrhea  
Grade 1  
Grade 2  
Grade 3  
 
 
Grade 4 
 
Maintain dose level  
Maintain dose level  
Omit bolus 5-FU and reduce infusional 
5-FU and irinotecan one dose level  
Omit bolus 5-FU and reduce infusional 
5-FU, oxliplatin and irinotecan one dose 
level.   
 
Hold if > grade 2 diarrhea is present. 
Reduce drugs per worst interval toxicity 
upon resolution of diarrhea.  If Grade > 2 
after 4 weeks, discontinue therapy. 
Mucositis/Stomatitis  
Grade 1  
 
Maintain dose level  
 
Hold until <grade 2, then treat  
 
 
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5.1.1 Febrile neutropenia  
  
Hold FOLFIRINOX during the febrile neutropenia. Doses missed will be made up at a following 
date.   
  
Resume FOLFIRINOX at one dose level lower than the dose administered in the last cycle. 
This dose should be used for all subsequent cycles.   
  
If febrile neutropenia develops in a given cycle, the use of colony stimulating factors is  
may be instituted at the discretion of the investigator until resolution of febrile neutropenia or 
septic episode. Growth factors may be considered at the discretion of the investigator on the 
following cycle of FOLFIRINOX. 
 
 
5.2 Dose Modifications for Gemcitabine (chemoradiotherapy):  
 
Dose reduction steps: chemoradiotherapy 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
Gemcitabine 
400 mg/m2 
320 mg/m2 
250 mg/m2 
 
 
 
 
Dosage adjustments will be made based on weekly blood counts obtained within 1 day prior to weekly 
gemcitabine dose:  
  
Grade 2  
Grade 3  
 
Grade 4  
 
Maintain dose level  
Omit bolus 5-FU and reduce infusional 
5- FU one dose level  
Omit bolus 5-FU and reduce infusional 
5- FU, irinotecan and oxaliplatin one 
dose level  
based on worst interval toxicity.  
 
Vomiting (despite antiemetics)  
Grade 1  
Grade 2  
Grade 3  
 
Grade 4  
  
 
 
Maintain dose  
Maintain dose  
Reduce oxaliplatin and irinotecan one 
dose level  
Reduce oxaliplatin, irinotecan and 
infusion 5-FU one dose level and omit 
bolus 5-FU  
 
 
Hold until resolved then:  
Maintain dose  
Maintain dose  
Reduce oxaliplatin and irinotecan one 
dose level  
Reduce oxaliplatin, irinotecan and 
infusion 5-FU one dose level and omit 
bolus 5-FU 
Other non-hematologic toxicities  
  
 
Dose modifications for other 
nonhematologic adverse events at the 
start of subsequent cycles of therapy, and 
at time of retreatment are the same as 
recommended for vomiting (above) with 
the following exception: Omit bolus 5-
FU and decrease infusion 5-FU by one 
dose level for other Grade>3 
non-hematologic events 
 
 
 
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   ANC             
          Platelets 
Last dose level of gemcitabine 
given 
Dose level of gemcitabine to be given  
≥ 1000  
and 
≥ 100,000  
Level 0  
Level 0  
≥ 1000  
and 
≥ 100,000  
Level -1  
Level -1  
≥ 1000  
and 
≥ 100,000   
Level -2  
Level -2  
500-999  
or 
50,000 to 99,999  
Level 0  
Level -1  
500-999  
or 
50,000 to 99,999  
Level -1  
Level -2  
500-999  
or 
50,000 to 99,999  
Level -2  
Hold and recheck in one week 
<500  
or 
< 50, 000  
Any  
Hold and recheck in one week  
 
 
Non-hematologic toxicity   
 
 
Toxicity NCI 
CTAE v4.0 
Grade (value) 
Worst interval toxicity 
(modifications for AE’s that 
occurred during a cycle but 
did note require delay in 
treatment) 
Day of treatment 
(modifications for AE’s that 
require a delay in treatment) 
Edema 
Grade 1  
Grade 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Maintain dose level 
Decrease one dose level 
Hold 
 
If hold: When the toxicity improves to grade < 2, resume gemcitabine at 
one dose level lower than the previous dose level administered.   
Liver toxicity 
Grade 1  
Grade 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Maintain dose level 
Decrease one dose level 
Hold 
 
*Patients with grade 4 hepatic toxicity should be evaluated for disease 
progression.  If disease progression is found, discontinue protocol 
therapy. If no disease progression is found, resume gemcitabine at one 
dose level lower than the previous dose when toxicity resolves to grade 
0-2.  If toxicity does not resolve to grade 0-2 within 4 weeks, discontinue 
protocol therapy.  
 
**Patients who have a repeated episode of Grade 3 hepatic toxicity upon 
resumption of gemcitabine therapy should discontinue gemcitabine  
 
Nausea/vomiting 
Grade 1  
Grade 2 
Grade 3 
Grade 4 
 
Maintain dose level 
Maintain dose level 
Maintain dose level 
Hold 
 
For grade 4 nausea/vomiting  the dose of gemcitabine should be held 
until it is grade 2 or less, then patient should resume gemcitabine at one 
dose level lower    
 
Other non-
hematological 
toxicity 
Grade 1  
Grade 2 
Grade 3 
Grade 4 
 
 
 
Maintain dose level 
Maintain dose level 
Decrease one dose level 
Hold 
 
For other grade 4 non-hematological toxicities the dose of gemcitabine 
should be held until it is grade < 2 , then patient should resume 
gemcitabine at one dose level lower    
 
 
 
5.3 Dose Modifications/Interruption for radiotherapy 
 
5.3.1 Radiotherapy Interruption  
 
Therapy interruptions will usually not be necessary. However, if radiation is held for any reason, 
all systemic therapy must also be held. Interruptions may be kept to a minimum by the use of 
ancillary therapy and vigorous nutritional support. Interruptions are permitted only on the basis 
of toxicity. Therapy may be interrupted for grade 3 and 4 hematological and non-hematological 
 
 
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toxicity. 
Interruption of therapy may continue until the toxicity has regressed to ≥ grade 2 to allow 
resumption of therapy; however, every effort should be made to limit treatment interruptions to 
1-2 weeks. 
 
5.3.2 Radiotherapy Dose Modifications  
 
Every effort must be made to deliver the full 50.4 Gy to all patients. Toxicity may be 
encountered that is sufficiently severe to require treatment interruption. Once the toxicity has 
resolved, the patient's therapy should resume and full protocol dose should be delivered. The 
toxicity that forced any dose reduction must be documented. If interruption of therapy (up to 2 
weeks) becomes necessary, radiation therapy should be completed to the prescribed doses. Total 
number of fractions and elapsed days should be carefully reported. If an interruption of more 
than 2 weeks is necessary, resumption of treatment is at the discretion of the radiation oncology 
chairs. The patient's treatment plan will be considered a major deviation, but follow-up will be 
continued. 
 
 
6.0 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 6.1) and the characteristics of an observed AE (Section 6.2) will 
determine whether the event requires expedited (via AdEERS) reporting in addition to routine 
reporting. 
 
6.1 Adverse Event List(s) for Commercial Agent(s)  
 
Oxaliplatin  
For a comprehensive list of adverse events please refer to the package insert. Appendix B 2 
provides an overview of toxicities related to oxaliplatin. 
 
Irinotecan 
For a comprehensive list of adverse events please refer to the package insert. Appendix B 3 
provides an overview of toxicities related to irinotecan. 
 
5-Fluorouracil  
 For a comprehensive list of adverse events please refer to the package insert. Appendix B 1  
provides an overview of toxicities related to 5-fluorouracil.  
 
Gemcitabine 
For a comprehensive list of adverse events please refer to the package insert. Appendix B 4 
provides an overview of toxicities related to gemcitabine. 
 
 
 
6.2 Adverse Event Characteristics  
 
 
 
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• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.   
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.   
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected.  
 
 
6.3 Adverse events related to surgery. 
 
All adverse effects related to the surgical resection will be documented and graded, based on the 
Dino-Clavien Scale. See Appendix C. 
 
 
6.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions. 
 
 
7.0 PHARMACEUTICAL INFORMATION 
 
See Appendix B. 
 
 
 
 
 
 
 
 
 
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8.0 STUDY CALENDAR 
 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate. 
 
 
Pre therapy 
 
FOLFIRINOX 
(4 cycles) 
 
D 
15,
29, 
43c 
Restaging 
(2-6 weeks after 
cycle 4 of 
FOLFIRINOX) 
Chemoradiotherapy 
 
Restag
ing 
(2-6 
weeks 
after 
CRT) 
(Day 
-28 to 
start) 
(Day 
-14 to 
start) 
D 1 
D 2 
D3 
Days 
1 
8 
15 
22 
29 
36 
Informed consent 
♦ 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
including weight 
 
♦ 
♦ 
 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
Toxicity assessment 
 
 
♦ 
 
 
♦ 
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
Vital Signs 
 
♦ 
♦ 
 
 
♦ 
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
Height 
 
♦ 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
 
♦ 
♦ 
 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
AE/SAE Monitoring 
 
 
♦ 
 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
CT scan or MRIa 
♦ 
 
 
 
 
 
♦ 
 
 
 
 
 
 
♦ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Measurements 
♦ 
 
 
 
 
 
♦ 
 
 
 
 
 
 
♦ 
CBC 
 
♦ 
♦ 
 
 
♦ 
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
Chemistry-7 
 
♦ 
 
 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
Ca, Mg, Phosphorus  
 
♦ 
♦ 
 
 
♦ 
 
♦ 
 
 
 
 
 
♦ 
LFT 
 
♦ 
 
 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
 
♦ 
Beta-HCG  
 
♦ 
 
 
 
 
 
 
 
 
 
 
 
 
Ca 19-9 
 
♦ 
 
 
 
♦ 
 
♦ 
 
 
 
♦ 
 
♦ 
5-Fluorouracil dosing 
 
 
♦ 
♦ 
♦ 
♦ 
 
 
 
 
 
 
 
 
Oxaliplatin dosing 
 
 
♦ 
 
 
♦ 
 
 
 
 
 
 
 
 
Irinotecan dosing 
 
 
♦ 
 
 
♦ 
 
 
 
 
 
 
 
 
Gemcitabine dosing 
 
 
 
 
 
 
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
 
Radiation 
 
 
 
 
 
 
 
      ♦ 
 
Respectability 
evaluation 
♦ 
 
 
 
 
 
 
 
 
 
 
 
 
♦ 
 
a :CT abdomen/pelvis should ideally be done with pancreas protocol. Chest imaging with Chest X-ray or CT chest is accepted. 
 
 
 
 
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9.0 CLINICAL LABORATORY TESTS AND PROCEDURES 
 
Prior to study treatment each patient will have the following assessments. 
 
Within 4 weeks of study treatment: 
Radiologic studies for baseline tumor measurements with CT of the abdomen and pelvis with 
pancreas protocol or MRI scanning of the abdomen and pelvis. Chest should be imaged with 
chest X-ray or CT scan of the chest.   
Sign the informed consent document.  
 
Within 2 weeks of study treatment: 
Medical history and physical examination, including clinical measurement of tumor lesions.   
Demographics including measurements of height and weight.   
Evaluation of performance status (ECOG).   
Vital signs (blood pressure, pulse rate and temperature) 
HIV testing  
Hematology – CBC with differential 
Chemistry – Chem-7 (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose) 
LFT – (total bilirubin, direct bilirubin, total protein, albumin, AST, ALT, alkaline phosphatase) 
Other chemistry - Calcium, LDH, Magnesium, Phosphorus.  
 
 
10.0 MEASUREMENT OF EFFECT 
 
10.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be reevaluated for response 2 times: 1) after 4 
cycles of FOLFIRINOX chemotherapy. 2) after finalization of gemcitabine base 
chemoradiotherapy.  
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. 
 
10.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with FOLFIRINOX chemotherapy. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
10.1.2 Disease Parameters 
 
 
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Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will 
be calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 10 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor 
effect of a treatment. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
 
 
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neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US)  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation has 
not yet been fully and widely validated.  Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers.  Therefore, 
the utilization of such techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific additional criteria for standardized usage of prostate-specific antigen 
(PSA) and CA-125 response in support of clinical trials are being developed. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
10.1.4 Response Criteria 
 
10.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
10.1.4.2 Evaluation of Non-Target Lesions 
 
 
 
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Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
10.1.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
10.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
 
 
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
10.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression. 
 
 
11.0 STATISTICAL CONSIDERATIONS 
 
11.1 Study Design/Endpoints 
 
11.1.1 Primary Endpoint:  
 
The primary endpoint of this study is to examine the proportion of R0 resection rate in 
participants receiving at least one cycle of FLOFIRINOX chemotherapy. We will test the R0 
resection rate by one-sided one sample Z test for proportion with null hypothesis set at 40%.  
 
This phase II study will use the Simon two-stage design. This design was chosen to allow early 
rejection of an ineffective treatment. The protocol will be open to patients with borderline 
resectable pancreatic cancer who did not receive any prior therapy.   
The null hypothesis is that FOLFIRINOX chemotherapy, followed by gemcitabine based 
chemoradiotherapy has an R0 resection rate 40%. This is based on prior report from Katz et al 
where patients with borderline resectable pancreatic cancer treated with preoperative therapy had 
an R0 resection rate of 40% [20]. This phase II study will use the Simon two-stage design. This 
design was chosen to allow early rejection of an ineffective treatment. The protocol will be open 
to patients with borderline resectable pancreatic cancer who did not receive any prior therapy.   
The null hypothesis is that FOLFIRINOX chemotherapy, followed by gemcitabine based 
chemoradiotherapy has an R0 resection rate 40%. This is based on prior report from Katz et al 
where patients with borderline resectable pancreatic cancer treated with preoperative therapy had 
an R0 resection rate of 40% [20]. This study will achieve a 80% power to test the null hypothesis 
that R0 resection rate <=0.4 versus the alternative that resection rate R0>=0.6 at 5% level of 
significance. If the treatment is actually not effective, there is a 0.049 probability of concluding 
that  it is (the target for this value was 0.050) and if the treatment is effective, there is a 0.199 
probability of concluding that it is not ( the target value was 0.2).  The new treatment will be 
tested on 16 patients in the first stage, the trial will be terminated if 7 or fewer R0 resections are 
achieved. If the total number of R0 resections is less than or equal to 23, the new treatment will 
be rejected. This study will enroll 50 patients within 36 months. 
 
 
11.2 
Sample Size/Accrual Rate 
 
This study will accrue 50 patients. The estimation is that will accrue 1-2 patients a month, 
 
 
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completing accrual in 36 months. 
 
 
11.3 
Analysis of Secondary Endpoints 
 
11.3.1 Secondary Endpoints: 
 
• The overall response rate (assessed by RECIST criteria) will be examined using one sample 
Z-test for proportion.   
• Overall Survival: The overall survival rate in the study will be examined for survival 
probabilities using Kaplan-Meier procedure and association of clinical covariates with 
overall survival status will be examined using log-rank test and Cox regression procedure. 
Median overall survival with confidence interval will be presented.  
 
Progression free survival (PFS): The time to progression will be analyzed using Kaplan–Meier 
procedure followed by log-rank tests and Cox regression model to investigate the association 
between clinical covariates and progression free survival. Median progression free survival will 
be presented.  Brookmeyer and Crowley method will be used to estimate a 95% confidence 
interval for median PFS and median OS.  
• Toxicity (evaluated by NCI CTCAE v4.0). Toxicity will be evaluated every clinic visit (on 
day 1, 8, 15, 22, 28, 35 or radiotherapy, after restaging and after pancreatoduodenectomy). 
We will tablet the toxicity outcome. 
• Adverse events related to surgery (evaluated by Dino-Clavien scale). We will tablet the 
toxicity outcome. 
• Proportion of patients able to undergo resection. We will tablet resection rate with 
appropriate 95% confidence interval. 
• Proportion of patients requiring vascular reconstruction. We will tablet vascular 
reconstruction rate with 95% confidence interval. 
 
11.4 Reporting and Exclusions 
 
11.4.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment. This analysis will include patient that received at least 1 one cycle of 
FOLFIRINOX chemotherapy. 
 
11.4.2 Evaluation of response.  All patients included in the study must be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they are ineligible.  Each 
patient will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
 
 
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exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be provided.  
 
 
 
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12.0 REFERENCES 
 
1. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, 
Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, 
Edwards BK (eds). 
2. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2006/, based on November 2008 SEER data submission, 
posted to the SEER web site, 2009. 
3. Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CA: Cancer J Clin;55:10–30, 
2005. 
4. National Comprehensive Cancer Network Website 2011. 
http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. 
5. Callery MP, Chang KJ, Fishman EK, et al. Pretreatment Assessment of Resectable and 
Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg Oncol 
(2009) 16:1727–1733. 
6. Abrams RA, Lowy AM, O´Reilly AM, et al. Combined Modalty Treatment for 
Resectable and Borderline Resectable Pancreas Cancer: Expert Consensus Statement. 
Annals of Surg Oncol: 16:1751–1756, 2009. 
7. Pilepich MV, Miller HH, erta al. Preoperative irradiation in carcinoma of the pancreas. 
Cancer; 46:1945, 1980. 
8. Brunner TB,  Grabenbauer GG, Kastl  S, et al. Preoperative Chemoradiation in Locally 
Advanced Pancreatic Carcinoma: A Phase II Study. Onkologie 23:436–442, 200. 
9. Kastl S, Brunner T, Herrmann O, et al. Neoadjuvant radio-chemotherapy in advanced 
primarily non-resectable carcinomas of the pancreas. European Journal of Surgical 
Oncology 26: 578–582, 2000.  
10. Palmer DH, Stocken DD, PhD, Hewitt H, et al. A Randomized Phase 2 Trial of 
Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone 
Versus Gemcitabine Combined with Cisplatin. Annals of Surgical Oncology 
14(7):2088–2096, 2007. 
11. Satoi S, Yanagimoto H, Toyokawa H, et al. Surgical Results After Preoperative 
Chemoradiation Therapy for Patients With Pancreatic Cancer. Pancreas 38, 282-288, 
2009. 
12. Takai S, Satoi S, Yanagimoto H, et al. Neoadjuvant Chemoradiation in Patients With 
Potentially Resectable Pancreatic Cancer. Pancreas 36; 26-32, 2008. 
13. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 Fluorouracil-Cisplatin 
Chemoradiation Effect on Survival in Patients with Resectable Pancreatic Head 
Adenocarcinoma: A Ten-Year Single Institution Experience. Oncology 76:413–419, 
2009. 
14. Hoffman JP, Lipsitz S, Pisansky T et al. Phase II Trial of Preoperative Radiation 
Therapy and Chemotherapy for Patients With Localized, Resectable Adenocarcinoma of 
the Pancreas: An Eastern Cooperative Oncology Group Study. J Clin Oncol 16; No 1: 
317-323, 1998. 
15. Evans DB, Rich TA, Byrd DR, et al. Preoperative Chemoradiation and 
Pancreaticoduodenectomy for Adenocarcinoma of the Pancreas. Arch Surg 127:1335-
1339, 1992. 
16. Pisters PWT, Abbruzzese JL, Janjan NA, et al. Rapid-Fractionation Preoperative 
Chemoradiation, Pancreaticoduodenectomy, and Intraoperative Radiation Therapy for 
 
 
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Resectable Pancreatic Adenocarcinoma. J Clin  Oncol 16; 12; 3843-3850, 1998.  
17. Evans DB,  Varadhachary GR, Crane CH, et al. Preoperative Gemcitabine-Based 
Chemoradiation for Patients With Resectable Adenocarcinoma of the Pancreatic Head. J 
Clin Oncol 26:3496-3502, 2008. 
18. Pisters PWT, Wolff RA, Janjan NA, et al.  Preoperative Paclitaxel and Concurrent 
Rapid-Fractionation Radiation for Resectable Pancreatic Adenocarcinoma: Toxicities, 
Histologic Response Rates, and Event-Free Outcome. J Clin Oncology, Vol 20, No 10; 
2537-2544, 2002. 
19. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative Gemcitabine and Cisplatin 
Followed by Gemcitabine-Based Chemoradiation for Resectable Adenocarcinoma of the 
Pancreatic Head. J Clin Oncol 26:3487-3495, 2008. 
20. Katz M, Pisters P, Evans D, et al. Borderline Resectable Pancreatic Cancer: The 
Importance of This Emerging Stage of Disease. J Am Coll Surg. 2008 May;206(5):833-
46; discussion 846-8. Epub 2008 Mar 17. 
21. Ychou M, Conroy T, Seitz JF, et al. An open phase I study assessing the feasibility of 
the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 
weeks in patients with advanced solid tumors. Annals of Oncol 14: 481–489, 2003. 
22. Conroy T, Paillot B, francois E, et al. Irinotecan Plus Oxaliplatin and Leucovorin-
Modulated Fluorouracil in Advanced Pancreatic Cancer—A Groupe Tumeurs Digestives 
of the Fédération Nationale des Centres de Lutte Contre le Cancer Study. J Clin Oncol 
23(6); 1228-1236, 2005. 
23. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for 
Metastatic Pancreatic Cancer. N Engl J Med; 364: 1817-25, 2011.   
24. Allendorf JD, Lauerman M, Bill A et al. Neoadjuvant Chemotherapy and Radiation for 
Patients with  Locally Unresectable Pancreatic Adenocarcinoma: Feasibility, Efficacy, 
and Survival. J Gastrointest Surg; 12:91–100, 2008.  
25. Callery PM, Chang KJ, Fishman EK et al. Pretreatment Assessment of Resectable and 
Borderline Resectable Pancreatic Cancer: Expert Consensus Statement. Ann Surg 
Oncol; 16:1727–1733, 2009. 
 
 
 
 
 
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13.0       APPENDICES 
 
APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX B 
 
1. 5- fluorouracil 
 
Other names: 
Adrucil® 
 
Classification: 
Antimetabolite 
 
Mode of action: 
A pyrimidine antimetabolite that interferes with DNA synthesis by blocking the methylation of 
deoxyuridylic acid; fluorouracil inhibits thymidylate synthetase (TS), or is incorporated into 
RNA. The reduced folate cofactor is required for tight binding to occur between the 5-FdUMP 
and TS. 
 
Storage and stability: 
Store at room temperature 15° to 30°C (59° to 86°F). Protect from light. Retain in carton until 
time of use. 
 
Preparation: 
No dilution necessary for usual injection formulation 
 
Route of administration: 
I.V. bolus as a slow push or short (5-15 minutes) bolus infusion, or as a continuous infusion. 
Doses >1000 mg/m2 are usually administered as a 24-hour infusion, although some protocols 
may be continuous infusion with lower doses. Toxicity may be reduced by giving the drug as a 
constant infusion. Bolus doses may be administered by slow IVP or IVPB.  
 
Incompatibilities/Interactions: 
Stable in D5LR, D5W, NS, bacteriostatic NS; incompatible with concentrations >25 mg/mL of 
fluorouracil and >2 mg/mL of leucovorin calcium (precipitation occurs).  
 
Availability: 
5-fluorouracil is commercially available in the USA. Is an FDA approved agent for the treatment 
of patients with adenocarcinoma of the pancreas. However, when used in combination as 
directed by this protocol, the agents are classified as “unapproved use of an agent” and, by 
definition, are considered investigational. While this combination is not currently approved by 
the FDA, the use in this protocol is exempt from the requirements of an IND as described under 
Title 21 CFR 312.2 (b). 
 
Side effects: 
 
Cardiovascular: Angina, myocardial ischemia. 
Central nervous system: Acute cerebellar syndrome, confusion, disorientation, euphoria, 
headache, nystagmus.  
Dermatologic: Alopecia, dermatitis, dry skin, fissuring, palmar-plantar erythrodysesthesia 
 
 
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syndrome, pruritic maculopapular rash, photosensitivity, vein pigmentations, nail changes.  
Gastrointestinal: Anorexia, bleeding, diarrhea, esophagopharyngitis, nausea, sloughing, 
stomatitis, ulceration, vomiting.  
Hematologic: Myelosuppression (nadir: 9-14 days; recovery by day 30), agranulocytosis, 
anemia, leukopenia, pancytopenia, thrombocytopenia.  
Local: Thrombophlebitis.  
Ocular: Lacrimation, lacrimal duct stenosis, photophobia, visual changes.  
Respiratory: Epistaxis.  
Miscellaneous: Anaphylaxis, generalized allergic reactions, nail loss. 
 
2. Oxaliplatin 
 
Other names: 
Eloxatin® 
 
Classification: 
Alkylating agent 
 
Mode of action: 
Oxaliplatin, a platinum derivative, is an alkylating agent. Following intracellular hydrolysis, the 
platinum compound binds to DNA forming cross-links which inhibit DNA replication and 
transcription, resulting in cell death. Cytotoxicity is cell-cycle nonspecific. 
 
Storage and stability: 
After reconstitution in the original vial, the solution may be stored up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, 
USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under 
refrigeration [2-8°C (36-46°F)]. 
 
Preparation: 
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 5% Dextrose Injection, USP. Do not administer the 
reconstituted solution without further dilution. The reconstituted solution must be further diluted 
in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. 
 
Route of administration: 
Administer as I.V. infusion over 2 hours. Flush infusion line with D5W prior to administration of 
any concomitant medication. Patients should receive an antiemetic premedication regimen. 
Avoid mucositis prophylaxis with ice chips during oxaliplatin infusion (may exacerbate acute 
neurological symptoms).  
 
Incompatibilities/Interactions: 
Incompatible with alkaline solutions (e.g., fluorouracil) and chloride-containing solutions. Flush 
infusion line with D5W prior to, and following, administration of concomitant medications via 
same I.V. line.  
 
 
 
 
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Availability: 
Oxaliplatin is commercially available in the USA. Is an FDA approved agent for the treatment of 
patients with adenocarcinoma of the pancreas. However, when used in combination as directed 
by this protocol, the agents are classified as “unapproved use of an agent” and, by definition, are 
considered investigational. While this combination is not currently approved by the FDA, the use 
in this protocol is exempt from the requirements of an IND as described under Title 21 CFR 
312.2 (b). 
 
Side effects: 
>10%:  
Central nervous system: Fatigue (61%), fever (25%), pain (14%), headache (13%), insomnia 
(11%). Gastrointestinal: Nausea (64%), diarrhea (46%), vomiting (37%), abdominal pain (31%), 
constipation (31%), anorexia (20%), stomatitis (14%).  
Hematologic: Anemia (64%; grades 3/4: 1%), thrombocytopenia (30%; grades 3/4: 3%), 
leukopenia (13%).  
Hepatic: AST increased (54%; grades 3/4: 4%), ALT increased (36%; grades 3/4: 1%), total 
bilirubin increased (13%; grades 3/4: 5%).  
Neuromuscular & skeletal: Peripheral neuropathy (may be dose limiting; 76%; acute 65%; 
grades 3/4: 5%; persistent 43%; grades 3/4: 3%), back pain (11%).  
Respiratory: Dyspnea (13%), cough (11%)  
 
1% to 10%:  
Cardiovascular: Edema (10%), chest pain (5%), peripheral edema (5%), flushing (3%), 
thromboembolism (2%). Central nervous system: Dizziness (7%).Dermatologic: Rash (5%), 
alopecia (3%), hand-foot syndrome (1%). 
Endocrine & metabolic: Dehydration (5%), hypokalemia (3%).  
Gastrointestinal: Dyspepsia (7%), taste perversion (5%), flatulence (3%), mucositis (2%), 
gastroesophageal reflux (1%), dysphagia (acute 1% to 2%).  
Genitourinary: Dysuria (1%).  
Hematologic: Neutropenia (7%).  
 
Local: Injection site reaction (9%; redness/swelling/pain).  
Neuromuscular & skeletal: Rigors (9%), arthralgia (7%).  
Ocular: Abnormal lacrimation (1%).  
Renal: Serum creatinine increased (5% to 10%).  
Respiratory: URI (7%), rhinitis (6%), epistaxis (2%), pharyngitis (2%), pharyngolaryngeal 
dysesthesia (grades 3/4: 1% to 2%).  
Miscellaneous: Allergic reactions (3%); hypersensitivity (includes urticaria, pruritus, facial 
flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, syncope: grades 3/4: 2% 
to 3%); hiccup (2%). 
 
<1%:  
Acute renal failure, alkaline phosphatase increased, anaphylactic/anaphylactoid reactions, 
anaphylactic shock, angioedema, aphonia, ataxia, colitis, cranial nerve palsies, deep tendon 
reflex loss, deafness, diplopia, dysarthria, dysphonia, eosinophilic pneumonia, extravasation 
(including necrosis), fasciculations, gait abnormal, hematuria, hemolysis, hemolytic anemia 
(immuno-allergic), hemolytic uremia syndrome, hemorrhage, hepatic failure, hepatitis, 
hepatotoxicity, hypertension, hypomagnesemia, hypoxia, ileus, INR increased, interstitial lung 
 
 
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diseases, interstitial nephritis (acute), intestinal obstruction, intracerebral bleeding, Lhermittes' 
sign, metabolic acidosis, muscle spasm, myoclonus, neutropenic fever, neutropenic sepsis, 
nodular regenerative hyperplasia, optic neuritis, pancreatitis, peliosis, prothrombin time 
increased, ptosis, rectal hemorrhage, rhabdomyolysis, seizure, sepsis, thrombocytopenia 
(immuno-allergic), trigeminal neuralgia, tubular necrosis (acute), veno-occlusive liver disease 
(sinusoidal obstruction syndrome and perisinusoidal fibrosis), visual disturbance (acuity 
decreased, field disturbance, transient loss). 
 
3. Irinotecan 
 
Other names: 
Camptosar®;  
 
Classification: 
Topoisomerase I inhibitor 
 
Mode of action: 
Irinotecan and its active metabolite (SN-38) bind reversibly to topoisomerase I-DNA complex 
preventing religation of the cleaved DNA strand. This results in the accumulation of cleavable 
complexes and double-strand DNA breaks. As mammalian cells cannot efficiently repair these 
breaks, cell death consistent with S-phase cell cycle specificity occurs, leading to termination of 
cellular replication. 
 
Storage and stability: 
The solution is physically and chemically stable for up to 24 hours at room temperature 
(approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose 
Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C), and protected 
from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 
0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence 
of visible particulates. 
 
Preparation: 
CAMPTOSAR Injection (irinotecan hydrochloride) must be diluted prior to infusion. 
CAMPTOSAR should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium 
Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL.  
 
Route of administration: 
Administer by I.V. infusion, usually over 90 minutes. Premedication with dexamethasone and a 
5-HT3 blocker is recommended 30 minutes prior to administration; prochlorperazine may be 
considered for subsequent use. Consider premedication of atropine 0.25-1 mg I.V. or SubQ in 
patients with cholinergic symptoms (e.g., increased salivation, diaphoresis, abdominal cramping) 
or diarrhea. 
 
Incompatibilities/Interactions: 
Stable in D5W, NS.  
Y-site administration: Compatible: Leucovorin calcium; Incompatible: Gemcitabine.  
 
 
 
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Availability: 
Irinotecan is commercially available in the USA. Is an FDA approved agent for the treatment of 
patients with metastatic colorectal cancer. However, when used in combination as directed by 
this protocol, the agents are classified as “unapproved use of an agent” and, by definition, are 
considered investigational. While this combination is not currently approved by the FDA, the use 
in this protocol is exempt from the requirements of an IND as described under Title 21 CFR 
312.2 (b). 
 
Side effects: 
>10%:  
Cardiovascular: Vasodilation (9% to 11%). 
Central nervous system: Cholinergic toxicity (47% - includes rhinitis, increased salivation, 
miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis); fever (44% to 45%), 
pain (23% to 24%), dizziness (15% to 21%), insomnia (19%), headache (17%), chills (14%). 
Dermatologic: Alopecia (46% to 72%), rash (13% to 14%). 
Endocrine & metabolic: Dehydration (15%). 
Gastrointestinal: Diarrhea, late (83% to 88%; grade 3/4: 14% to 31%), diarrhea, early (43% to 
51%; grade 3/4: 7% to 22%), nausea (70% to 86%), abdominal pain (57% to 68%), vomiting 
(62% to 67%), cramps (57%), anorexia (44% to 55%), constipation (30% to 32%), mucositis 
(30%), weight loss (30%), flatulence (12%), stomatitis (12%). 
Hematologic: Anemia (60% to 97%; grades 3/4: 5% to 7%), leukopenia (63% to 96%, grades 
3/4: 14% to 28%), thrombocytopenia (96%, grades 3/4: 1% to 4%), neutropenia (30% to 96%; 
grades 3/4: 14% to 31%).  
Hepatic: Bilirubin increased (84%), alkaline phosphatase increased (13%). 
Neuromuscular & skeletal: Weakness (69% to 76%), back pain (14%). 
Respiratory: Dyspnea (22%), cough (17% to 20%), rhinitis (16%).  
Miscellaneous: Diaphoresis (16%), infection (14%). 
 
1% to 10%:  
Cardiovascular: Edema (10%), hypotension (6%), thromboembolic events (5%). 
Central nervous system: Somnolence (9%), confusion (3%). 
Gastrointestinal: Abdominal fullness (10%), dyspepsia (10%). 
Hematologic: Neutropenic fever (grades 3/4: 2% to 6%), hemorrhage (grades 3/4: 1% to 5%), 
neutropenic infection (grades 3/4: 1% to 2%). 
Hepatic: AST increased (10%), ascites and/or jaundice (grades 3/4: 9%). 
Respiratory: Pneumonia (4%). 
 
<1%:  
ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, arterial 
thrombosis, bleeding, bradycardia, cardiac arrest, cerebral infarct, cerebrovascular accident, 
circulatory failure, colitis, dysrhythmia, embolus, gastrointestinal bleeding, gastrointestinal 
obstruction, hepatomegaly, hyperglycemia, hypersensitivity, hyponatremia, ileus, interstitial lung 
disease, intestinal perforation, ischemic colitis, lipase increased, lymphocytopenia, megacolon, 
MI, myocardial ischemia, pancreatitis, paresthesia, peripheral vascular disorder, pulmonary 
embolus; pulmonary toxicity (dyspnea, fever, reticulonodular infiltrates on chest x-ray); renal 
failure (acute), renal impairment, thrombophlebitis, thrombosis, typhlitis, ulcerative colitis. 
 
 
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4. Gemcitabine 
 
Other names: 
Gemzar® 
 
Classification: 
Antimetabolite (Pyrimidine Analog) 
 
Mode of action: 
Gemcitabine is an antimetabolite of the pyrimidine analog type. Gemcitabine is cell cycle–
specific for the S phase and for the G 1/S phase. Gemcitabine is phosphorylated intracellularly 
by deoxycytidine kinase to gemcitabine monophosphate, which is further phosphorylated to 
active metabolites gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine 
diphosphate inhibits the enzyme responsible for catalyzing synthesis of deoxynucleoside 
triphosphates required for DNA synthesis, and gemcitabine triphosphate competes with 
endogenous deoxynucleoside triphosphates for incorporation into DNA. The gemcitabine 
diphosphate–induced reduction in intracellular concentrations of deoxynucleoside triphosphates 
results in increased incorporation of gemcitabine triphosphate into DNA and, consequently, in 
inhibition of DNA synthesis. DNA polymerase epsilon is unable to remove the incorporated 
gemcitabine triphosphate and repair the DNA strands. 
 
 
Storage and stability: 
Gemcitabine vials are stored intact at room temperature of 20°C to 25°C (68°F to 77°F). 
Reconstituted vials are stable for up to 35 days and infusion solutions diluted in 0.9% sodium 
chloride are stable up to 7 days at 23°C when protected from light; however, the manufacturer 
recommends use within 24 hours for both reconstituted vials and infusion solutions. Solutions of 
reconstituted Gemcitabine should not be refrigerated, as crystallization may occur. The 
compatibility of Gemcitabine with other drugs has not been studied. No incompatibilities have 
been observed with infusion bottles or polyvinyl chloride bags and administration sets. Caution 
should be exercised in handling and preparing Gemcitabine solutions. The use of gloves is 
recommended. If Gemcitabine solution contacts the skin or mucosa, immediately wash the skin 
thoroughly with soap and water or rinse the mucosa with copious amounts of water. Procedures 
for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines 
on this subject have been published. There is no general agreement that all of the procedures 
recommended in the guidelines are necessary or appropriate.  
 
Preparation: 
To reconstitute, 5 mL of 0.9% Sodium Chloride Injection will be added to the 200 mg vial or 25 
mL of 0.9% Sodium Chloride Injection to the 1 g vial. Shake to dissolve. These dilutions each 
yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement 
volume of the lyophilized powder (0.26 mL for the 200 mg vial or 1.3 mL for the 1 g vial). The 
total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal 
of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. The appropriate 
amount of drug may be administered as prepared or further diluted with 0.9% Sodium Chloride 
to concentrations as low as 0.1 mg/mL.  
 
 
 
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Route of administration: 
Gemcitabine will be administered intravenously over 30 minutes. 
 
Incompatibilities/Interactions: 
Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity 
associated with this multimodality therapy is dependent on many different factors, including 
dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning 
technique, the target tissue, and target volume. 
 
Availability: 
Gemcitabine is commercially available in the USA. Is an FDA approved agent for the treatment 
of patients with locally advanced and metastatic pancreatic cancer. However, when used in 
combination as directed by this protocol, the agents are classified as “unapproved use of an 
agent” and, by definition, are considered investigational. While this combination is not currently 
approved by the FDA, the use in this protocol is exempt from the requirements of an IND as 
described under Title 21 CFR 312.2 (b). 
 
Side effects: 
>10%:  
Hematologic: Anemia (65% to 73%; grade 4: 1% to 3%), leukopenia (62% to 71%; grade 4: 
≤1%), neutropenia (61% to 63%; grade 4: 6% to 7%), thrombocytopenia (24% to 47%; grade 4: 
≤1%), hemorrhage (4% to 17%; grades 3/4: <1% to 2%); myelosuppression is the dose-limiting 
toxicity 
Cardiovascular: Peripheral edema (20%), edema (13%) 
Central nervous system: Pain (10% to 48%), fever (30% to 41%), somnolence (5% to 11% 
Dermatologic: Rash (24% to 30%), alopecia (15% to 18%), pruritus (13%) 
Gastrointestinal: Nausea/vomiting (64% to 71%; grades 3/4: 1% to 13%), constipation (10% to 
31%), diarrhea (19% to 30%), stomatitis (10% to 14%)  
Hepatic: Transaminases increased (67% to 78%; grades 3/4: 1% to 12%), alkaline phosphatase 
increased (55% to 77%; grades 3/4: 2% to 16%), bilirubin increased (13% to 26%; grades 3/4: 
<1% to 6%) 
Renal: Proteinuria (10% to 45%; grades 3/4: <1%), hematuria (13% to 35%; grades 3/4: <1%), 
BUN increased (8% to 16%; grades 3/4: 0%)  
Respiratory: Dyspnea (6% to 23%) 
Miscellaneous: Flu-like syndrome (19%), infection (8% to 16%; grades 3/4: <1% to 2%)  
 
1% to 10%:  
Local: Injection site reactions (4%)  
Neuromuscular & skeletal: Paresthesia (2% to 10%)  
Renal: Creatinine increased (2% to 8%)  
Respiratory: Bronchospasm (<2%) 
 
<1%:  
Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arrhythmias, bullous skin 
eruptions, cellulitis, cerebrovascular accident, CHF, chills, cough, desquamation, diaphoresis, 
gangrene, GGT increased, headache, hemolytic uremic syndrome (HUS), hepatotoxic reaction 
(rare), hypertension, insomnia, interstitial pneumonitis, liver failure, malaise, MI, peripheral 
 
 
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vasculitis, petechiae, pulmonary edema, pulmonary fibrosis, radiation recall, renal failure, 
respiratory failure, rhinitis, sepsis, supraventricular arrhythmia, weakness. 
 
 
APPENDIX C 
 
Dino-Clavien Scale 
 
 
Grade 
Definition 
 
Grade I 
 
Any deviation from the normal postoperative course without the need 
for pharmacological treatment or surgical, endoscopic and radiological 
interventions. 
 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, 
analgetics, diuretics and electrolytes and physiotherapy. This grade also 
includes wound infections opened at the bedside. 
 
 
Grade II 
 
Requiring pharmacological treatment with drugs other than such 
allowed for grade I complications. 
Blood transfusions and total parenteral nutrition are also included. 
 
 
Grade III 
 
 
 
Requiring surgical, endoscopic or radiological.  
 
      III-A: intervention not under general anesthesia 
      III-B: intervention under general anesthesia 
 
 
Grade IV 
 
 
 
 
Life-threatening complication (including CNS complications) requiring 
IC/ICU-management. 
 
IV-A: single organ dysfunction (including dialysis) 
 
IV-B: multi organ dysfunction 
 
 
Grade V 
 
Death of a patient 
 
 
 
 
 
 
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