A Phase II-R and a Phase III Trial Evaluating Both Erlotinib (Ph II-R) and Chemoradiation (Ph III) as Adjuvant Treatment for Patients With Resected Head of Pancreas Adenocarcinoma
Phase: PHASE3
Conditions: Pancreatic Adenocarcinoma, Pancreatic Ductal Adenocarcinoma, Pancreatic Intraductal Papillary-Mucinous Neoplasm, Stage I Pancreatic Cancer AJCC v6 and v7, Stage II Pancreatic Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
1 
NRG ONCOLOGY 
RTOG 0848 
 
A PHASE II-R and A PHASE III TRIAL EVALUATING BOTH *ERLOTINIB (PH II-R) 
AND CHEMORADIATION (PH III) AS ADJUVANT TREATMENT FOR PATIENTS 
WITH RESECTED HEAD OF PANCREAS ADENOCARCINOMA 
 
This trial is part of the national NCI Clinical Trials Network (NCTN) program which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN researchers: the Alliance, ECOG-ACRIN, and SWOG 
 
 
*(PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 CLOSED TO ACCRUAL EFFECTIVE 
(04/02/14) 
 
Study Team (11-APR-2023) 
NRG Oncology 
       SWOG 
Principal Investigator 
Radiation Oncology 
Ross A. Abrams, MD 
See Appendix VIII 
 
 
Radiation Oncology  
William Regine, MD 
University of Maryland School of Medicine 
22 South Greene Street 
Baltimore, MD  21201 
410-328-2331/FAX 410-328-6911 
wregine@umm.edu  
 
Radiation Oncology 
Karyn A. Goodman, M.D 
Department of Radiation Oncology 
Mount Sinai Hospital 
One Gustave L. Levy Place 
Box 1128 
New York, NY 10029 
212-659-8609 
karyn.goodman@mountsinai.org  
 
Medical Oncology 
Lab Correlatives 
Philip A Philip, MD, PhD, FRCP 
Henry Ford Hospital 
Division of Hematology and Oncology 
2850 West Grand Boulevard 
Detroit, MI 48202 
313-576-8728 
pphilip1@hfhs.org 
  
Surgical Oncology 
Andrew M. Lowy, MD 
Univ of CA San Diego Moore Cancer Ctr 
3855 Health Sciences Dr MC0987 
La Jolla, CA 92093-0987 
858-822-2124/FAX 858-534-4813 
alowy@ucsd.edu  
 
Statistician, Lab Correlatives 
Katherine A. Guthrie, Ph.D. 
SWOG Statistical Center 
Fred Hutchinson Cancer Research Center 
PO Box 19024 
1100 Fairview Ave N #M3-C102 
Seattle Wa 98109 
206-667-5595/FAX 206-667-4408 
Kguthrie@fhcrc.org  
 
Study Chairs continued on next page 
 
 
 
 
 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
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NRG Oncology Study Chairs (Continued) 
 
Medical Oncology 
Howard Safran, MD 
Rhode Island Hospital 
Hematology and Oncology Division 
593 Eddy Street 
Providenc, RI 02903 
401-444-4830 
hsafran@lifespan.org 
 
Surgical Oncology 
Adam Berger, MD 
Rutgers Cancer Institute of New Jersey 
195 Little Albany Street 
Room 3005 
New Brunswick, NJ 08903 
732-235-7563 
ab2047@cinj.rutgers.edu  
 
Translational Research  
Chandan Guha, MD, PhD 
Albert Einstein College of Medicine 
1300 Morris Park Avenue 
Bronx, NY-10461 
718-430-3550/FAX 781-231-5064 
cguhamd@gmail.com  
 
Quality of Life 
Lisa Kachnic, MD 
Columbia University Medical Center/Herbert Irving 
Comprehensive Cancer Center 
Department of Radiation Oncology 
622 West 168th Street 
New York, NY 10032 
212-305-9987 
lak2187@cumc.columbia.edu 
 
Medical Physics 
Michael Gillin, PhD 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 94 
Houston, TX 77030 
713-563-2507/FAX 713-563-2545   
mgillin@mdanderson.org  
 
 
Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3198/FAX 215-928-0153 
winterk@nrgoncology.org  
 
 
Pathology 
Jining Feng, MD, PhD 
Beaumont Hospital, Royal Oak 
3601 W 13 Mile Rd 
Royal Ok, MI 48073 
248-898-9060 
jining.feng@corewellhealth.org  
 
Alliance 
Eileen O’Reilly, MD 
Memorial Sloan- Kettering Cancer Center 
300 East 66th Street, Office 1021,  
New York, NY 10065 
646-888-4182/FAX 646-888-4255 
oreillye@mskcc.org  
 
ECOG-ACRIN 
Dr. A. Bapsi Chakravarthy, MD 
Vanderbilt-Ingram Cancer Center 
2220 Pierce Avenue, B-1034A 
Nashville, TN 37232-5671 
615-322-2555/FAX 615-343-0161 
bapsi.chak@vumc.org 
 
 

RTOG 0848 
 
 
 
 
 
 
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NRG Oncology Contact Information 
 
 
Data Manager: 
For questions concerning eligibility or data 
submission 
Wendy Bergantz, RN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3230 
BergantzW@NRGOncology.org  
 
 
 
 
RTQA Questions:  
For questions concerning RT data submission 
 
Susan McNulty, BS, RT(R)(T), CMD 
IROC Philadelphia – RT QA Center 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102215-940-8907 
smcnulty@acr.org  
 
 
 
NRG Oncology Contact Information 
(Continued) 
 
 
 
RT Credentialing: 
http://irochouston.mdanderson.org  
OR 
IROC-Credentialing@mdanderson.org  
 
 
RT data submission to TRIAD: 
Triad-Support@acr.org  
 
 
Protocol Development:: 
For questions concerning protocol and informed 
consent versions & amendments 
Kathryn Okrent 
NRG Oncology  
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0856 
okrentk@nrgoncology.org  
 
 
Gastrointestinal Non-Colorectal Committee 
Chair: 
Christopher Crane, MD 
 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
*Erlotinib 
NCI/PMB 
718781 
 
Gemcitabine 
Commercial 
N/A 
Exempt 
Capecitabine 
Commercial 
N/A 
Exempt 
Fluorouracil 
Commercial 
N/A 
Exempt 
 
 
Participating Sites (4/26/16) 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved NRG International Member Sites 
 
      

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
4 
Document History  
 
Version/Update Date 
Broadcast Date 
Amendment 10 
January 17, 2024 
N/A 
Amendment 9 
May 4, 2023 
N/A 
Amendment 8 
April 11, 2023 
N/A 
Amendment 7 
April 12, 2018 
N/A 
Amendment 6 
May 12, 2016 
June 28, 2016 
 
 Update 
 
April 2, 2014 
April 2, 2014 
Amendment 5 
February 19, 2014 
April 2, 2014 
Amendment 4 
June 22, 2012 
July 23, 2012 
Update 
April 12, 2012 
April 12, 2012 
Amendment 3 
May 23, 2011 
June 14, 2011 
Update  
June 17, 2010 
June 17, 2010 
Amendment 2 
June 8, 2010 
June 17, 2010 
Amendment 1 
March 4, 2010 
March 25, 2010 
Update 
November 17, 2009 
November 17, 2009 
Activation 
October 28, 2009 
November 17, 2009 
 
 
 
 
 
NRG Oncology Headquarters 
215-574-3189 
1-800-227-5463, ext. 4189 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
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The following NCTN Group Study Champions have been added to this trial: 
Alliance: Eileen O’Reilly, MD 
ECOG-ACRIN: Anuradha Bapsi Chakravarthy, MD 
SWOG: Philip A Philip, MD, PhD 
CONTACT INFORMATION (17-JAN-2024) 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at http://www.ctsu.org,     
and select  Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
by phone or email: 1-866-651-
CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions by 
phone or email: 1-888-823-5923, 
or  ctsucontact@westat.com. 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
 
Submit data electronically via the 
NRG Oncology/RTOG web site, 
www.rtog.org 
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).   
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the  Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’ 
website. 
For clinical questions (i.e., patient eligibility or treatment-related)  
Contact the study data manager listed on the NRG Oncology contact information table on the protocol 
cover page. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line. 
For TRIAD access and installation support: 
TRIAD-Support@acr.org  
Triadhelp.acr.org     
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/  

RTOG 0848 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
 
SCHEMA  ....................................................................................................................................... 10 
1.0  INTRODUCTION ...................................................................................................................... 17 
1.1  
Adjuvant Treatment of Pancreatic Cancer ......................................................................... 17 
1.2  
Does Adjuvant Chemoradiation Improve Survival? ............................................................. 17 
1.3  
Can the Addition of Adjuvant Erlotinib to Gemcitabine Improve Survival? ............................ 19 
1.4 
LAP 07 Trial: The Decision to Evaluate The Effect of Erlotinib in a Phase IIR Analysis  ........ 20 
1.5 
Decision To Allow Trial Entry After Up To 3 Months of Chemotherapy With Single-Agent 
Gemcitabine or Combination Chemotherapy  ................................................................................. 20 
1.6 
EGFR as Treatment Target: Molecular Determinants of Drug Sensitivity ............................. 21 
1.7 
MicroRNA ....................................................................................................................... 22 
1.8 
Rationale to Limit Patient Enrollment to Patients with Head of Pancreas Adenocarcinoma .... 22 
1.9  
Requirement for clear designation of tumor margin status .................................................. 23 
1.10 
Quality of Life/Patient-Reported Outcomes ........................................................................ 23 
2.0  OBJECTIVES ........................................................................................................................... 25 
2.1 
Primary Objectives ........................................................................................................... 25 
2.2 
Secondary Objectives ...................................................................................................... 25 
3.0  PATIENT SELECTION .............................................................................................................. 25 
3.1 
Conditions for Patient Eligibility ......................................................................................... 25 
3.2 
Conditions for Patient Ineligibility ...................................................................................... 27 
4.0  PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................... 27 
4.1 
Required Evaluations/Management .................................................................................. 28 
4.2 
Highly Recommended Evaluations/Management ............................................................... 28 
5.0  REGISTRATION PROCEDURES .............................................................................................. 28 
5.1 
Two-step registration process ........................................................................................... 29 
5.2  
General Pre-Registration Requirements ............................................................................ 29 
5.3 
Pre-Registration Requirements for IMRT Treatment Approach ............................................ 29 
5.4 
Digital RT Data Submission Using TRIAD ......................................................................... 30 
5.5 
Regulatory Pre-Registration Requirements ........................................................................ 30 
5.6 
Registration ..................................................................................................................... 33 
6.0  RADIATION THERAPY ............................................................................................................. 34 
6.1 
Dose Specifications (3D conformal and IMRT) ................................................................... 35 

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6.2 
Technical Factors ............................................................................................................ 35 
6.3 
Localization, Simulation, and Immobilization (3D Conformal and IMRT) ............................... 35 
6.4 
Treatment Volumes (3D Conformal and IMRT) .................................................................. 35 
6.5 
Normal Organ Dose Volume Considerations (3D Conformal and IMRT) .............................. 37 
6.6 
3D Conformal Beam Arrangements .................................................................................. 38 
6.7  
IMRT .............................................................................................................................. 39 
6.8 
Field verification .............................................................................................................. 39 
6.9 
Documentation Requirements .......................................................................................... 39 
6.10 
Compliance Criteria for Both IMRT and 3D Conformal ........................................................ 40 
6.11 
R.T. Quality Assurance Reviews ....................................................................................... 41 
6.12 
Radiation Therapy Adverse Events ................................................................................... 41 
6.13 
Radiation Therapy Adverse Event Reporting ..................................................................... 41 
7.0  DRUG THERAPY  .................................................................................................................... 41 
7.1 
First Step: Adjuvant Systemic Treatment ........................................................................... 41 
7.2 
Second Step: RT Randomization Treatment ...................................................................... 42 
7.3 
Erlotinib (OSI-774, Tarceva) NSC#718781 ........................................................................ 43 
7.4 
Gemcitabine HCl ............................................................................................................. 48 
7.5 
Capecitabine ................................................................................................................... 48 
7.6 
Fluorouracil ..................................................................................................................... 48 
7.7 
Non-Canadian International Institutions: ............................................................................ 48 
7.8 
Dose Modifications .......................................................................................................... 49 
7.9 
Modality Review .............................................................................................................. 51 
7.10 
Adverse Events ............................................................................................................... 51 
7.11 
CTEP-AERS Expedited Reporting Requirements ............................................................... 53 
8.0  SURGERY ............................................................................................................................... 58 
8.1  
Surgical Quality Assurance Reviews ................................................................................. 58 
8.2 
General Considerations ................................................................................................... 58 
8.3 
Resection Classification and Operative Note Dictation ....................................................... 59 
8.4 
Surgical Pathology ........................................................................................................... 59 
9.0  OTHER THERAPY .................................................................................................................... 60 
9.1 
Permitted Supportive Therapy .......................................................................................... 60 
9.2 
Non-permitted Supportive Therapy ................................................................................... 60 
10.0  TISSUE/SPECIMEN SUBMISSION .......................................................................................... 60 

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10.1 
General Information ......................................................................................................... 60 
10.2 
Specimen Collection for Tissue Banking (Highly Recommended) ........................................ 61 
10.3 
Storage Conditions .......................................................................................................... 62 
10.4 
Specimen Collection Summary ......................................................................................... 62 
10.5 
Submit materials as follows: ............................................................................................. 63 
10.6 
Reimbursement ............................................................................................................... 63 
10.7 
Confidentiality/Storage ..................................................................................................... 64 
11.0  PATIENT ASSESSMENTS ...................................................................................................... 64 
11.1 
Study Parameters: See Appendix I. .................................................................................. 64 
11.2 
Evaluation for Progression following Adjuvant Systemic Therapy ........................................ 64 
11.3 
Quality of Life Assessments ............................................................................................. 64 
11.4 
Criteria for Discontinuation of Protocol Treatment .............................................................. 65 
12.0  DATA COLLECTION ............................................................................................................... 66 
12.1 
Summary of Data Submission .......................................................................................... 66 
12.2 
Summary of Dosimetry Digital Data Submission ................................................................ 67 
13.0  STATISTICAL CONSIDERATIONS .......................................................................................... 68 
13.1 
Endpoint(s) ..................................................................................................................... 68 
13.2 
Stratification .................................................................................................................... 68 
13.3 
Sample Size and Power Justification ................................................................................. 69 
13.4 
Interim Analysis ............................................................................................................... 71 
13.5 
Statistical Methods Analysis for Laboratory Correlative Section .......................................... 74 
13.6 
Gender and Minorities ...................................................................................................... 75 
REFERENCES ................................................................................................................................ 77 
APPENDIX I .................................................................................................................................... 81 
APPENDIX II ................................................................................................................................... 84 
APPENDIX III .................................................................................................................................. 85 
APPENDIX IV .................................................................................................................................. 86 
APPENDIX V................................................................................................................................... 90 
APPENDIX VI .................................................................................................................................. 97 
APPENDIX VII ................................................................................................................................. 98 
APPENDIX VIII .............................................................................................................................. 984 
 
 

RTOG 0848 
 
 
 
 
 
 
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NRG ONCOLOGY 
 
RTOG 0848 
 
A PHASE II-R AND A PHASE III TRIAL EVALUATING BOTH *ERLOTINIB (PHII-R) AND 
CHEMORADIATION (PH III) AS ADJUVANT TREATMENT FOR PATIENTS WITH RESECTED HEAD 
OF PANCREAS ADENOCARCINOMA 
 
*(PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 CLOSED TO ACCRUAL EFFECTIVE 
4/02/14) 
 
CURRENT SCHEMA (12-APR-2018) 
 
 
 
FIRST STEP: 
ADJUVANT SYSTEMIC TREATMENT 
 
Note: Up to 3 months of chemotherapy 
may be initiated prior to registration-refer to 
Sections 3.1.2 and 7.1.1. 
 
R 
E 
G 
I 
S 
T 
E 
R 
Arm 1: 
Gemcitabine alone or combination 
chemotherapy x 5 months 
 
 
Arm 2: 
Gemcitabine + Erlotinib x 5 cycles 
(Arm 2 closed to accrual effective 
4/02/14) 
 
 
 
 
 
Evaluate To Confirm No Progression 
 
 
 
 
If no progression, then:  
 
 
 
SECOND STEP: 
RT RANDOMIZATION 
For Non-Progressing Patients 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
Nodal Status: 
1. involved 
2. uninvolved 
 
CA19-9 Result: 
1. d 90 
2. > 90 – 180 
 
Surgical Margins: 
1. positive (R1) 
2. negative (R0) 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
 
Arm 3: 
1 month of gemcitabine or combination 
chemotherapy 
 
 
 
Arm 4: 
1 month of gemcitabine or combination 
chemotherapy followed by XRT with 
either capecitabine or 5-FU 
 
Adjuvant Systemic Treatment: 
1. Gemcitabine alone 
 
2. FOLFIRINOX or 
mFOLFIRINOX 
 
3. Non-oxaliplatin gemcitabine 
combinations 
 
 
 
 
 
 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
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NRG ONCOLOGY 
 
RTOG 0848 
 
A PHASE II-R AND A PHASE III TRIAL EVALUATING BOTH *ERLOTINIB (PHII-R) 
AND CHEMORADIATION (PH III) AS ADJUVANT TREATMENT FOR PATIENTS 
WITH RESECTED HEAD OF PANCREAS ADENOCARCINOMA 
 
*(PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 CLOSED TO ACCRUAL EFFECTIVE 
4/02/14) 
 
 
SCHEMA (2/19/14 to 6/28/16) 
 
FIRST STEP:  
ADJUVANT SYSTEMIC TREATMENT 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
If no progression, then: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
E
G 
I 
S 
T 
E 
R 
 
Nodal Status: 
1: involved 
2: uninvolved 
 
CA19-9 result: 
1: d 90 
2: > 90 – 180 
 
Surgical margins: 
1: positive (R1) 
2: negative (R0) 
Arm 1: 
Gemcitabine x 5 cycles 
Arm 2: 
Gemcitabine + Erlotinib x 5 cycles 
(Arm 2 closed to accrual effective 
4/02/14) 
First Randomization Treatment 
Arm: (For patients registered prior 
to 4/02/14) 
1.  Arm 1 gemcitabine vs.  
2.  Arm 2 gemcitabine + erlotinib 
Evaluate to Confirm No Progression 
SECOND STEP: 
RT RANDOMIZATION 
For Non-Progressing Patients 
Arm 3: 
1cycle of chemotherapy 
Arm 4: 
1 cycle of chemotherapy followed by  
XRT with either capecitabine or 5-FU 
 
S 
T 
R 
A 
T 
I 
F 
Y 
R 
A 
N 
D 
O 
M 
I 
Z 
E 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
11 
 
SCHEMA (activation to 2/28/14) 
 
 
 
 
 
 
 
FIRST RANDOMIZATON 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If no progression, then: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE: It is mandatory that the treating physician determine radiation therapy technique (3D-CRT or IMRT) that will   
be used prior to re-registering the patient. 
XRT treatment plan to be submitted for review no sooner than 7 days and no later than 14 to 21 days after RT 
randomization AND completion of first chemotherapy month of ARM 4 
RT treatment plan must be APPROVED prior to XRT start. 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Resected head of pancreas adenocarcinoma. This includes the pancreatic head, uncinate process, and 
neck of the pancreas, status post a curative-intent pancreaticoduodenectomy  
 
Required Sample Size: 545 
 
S 
T 
R 
A 
T 
I 
F 
Y 
Nodal Status: 
1: involved 
2: uninvolved 
 
CA19-9 result: 
1: d 90 
2: > 90 – 180 
 
Surgical margins: 
1: positive (R1) 
2: negative (R0) 
First Randomization Treatment 
Arm: 
1.  Arm 1gemcitabine vs.  
2.  Arm 2gemcitabine + erlotinib 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm 1: 
Gemcitabine x 5 cycles 
*Arm 2: 
Gemcitabine + Erlotinib x 5 
cycles 
Evaluate to Confirm No Progression 
SECOND RANDOMIZATON 
For Non-Progressing Patients 
Arm 3: 
1cycle of chemotherapy 
Arm 4: 
1 cycle of chemotherapy followed 
by  
XRT with either capecitabine or 5-
FU 
S 
T 
R 
A 
T 
I 
F 
Y 
R 
A 
N 
D 
O 
M 
I 
Z 
E 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
12 
ELIGIBILITY CHECKLIST—STEP 1 (5/12/15) 
 
 
 
 
(page 1 of 4) 
NRG Oncology Institution # 
 
RTOG 0848 
 
 
Case #  
 
      
 
 
_______  (Y)  
1.     Histologic proof of primary head of pancreas invasive adenocarcinoma managed 
with a potentially curative resection (i.e., removal of all gross tumor) involving a 
classic pancreaticoduodenectomy (Whipple) or a pylorus preserving pancreatico-
duodenectomy.  
 
_______(Y)          2.  Does the operative report contain a statement from the surgeon documenting that a 
total gross excision of the primary tumor was achieved? 
 
 
 
 
 
_______ (Y)  
3. 
AJCC 6th edition pathologic stage T1-T3, N0-1, M0? 
 
 
_______ (Y) 
4. 
Does the pathology report document all margins including the status of the three 
major surgical margins (bile duct, pancreatic parenchyma, and retroperitoneal 
[uncinate]) and document the size of the primary tumor?  
 
_______ (Y) 
5.    Abdominal/pelvic CT scan with contrast (or MRI if allergic to contrast) and either 
chest CT or chest x-ray within 31 days of study entry (or within 31 days prior to day 
1 of chemotherapy post-surgery for those patients having started chemotherapy 
prior to first step registration)?  
 
_______(Y) 
6.  Is the patient’s Zubrod performance status 0 or 1? 
 
_______(Y) 
7. 
Do the patient’s laboratory values meet the criteria in Section 3.0? 
 
_______(Y) 
8. 
Is the patient’s total oral caloric intake ≥ 1500 calories/day? 
 
_______(Y) 
9. 
Is the patient willing to practice adequate contraception while on study (women of 
childbearing potential and men)? 
 
_______(Y) 
10.    Post resection serum CA19-9 < 180 IU/L and prior to any systemic treatment?  
 
_______(N) 
11. Has the patient had prior radiotherapy to the region of the study cancer that would 
result in overlap of radiation therapy fields?  
 
_______(N) 
12. Has the patient had any prior systemic chemotherapy for the study cancer other 
than up to 3 months of the acceptable agents noted in section 3.2.3?  
 
_______(N) 
13. Has the patient undergone total pancreatectomy, distal pancreatectomy or central 
pancreatectomy?  
 
(Continued on next page) 
 
 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
13 
ELIGIBILITY CHECKLIST—STEP 1 (5/12/15) 
(page 2 of 4)  
NRG Oncology Institution #   
RTOG 0848 
 
Case #  
 
 
 
      
       
 
 
 
_______(N) 
15. Does the patient have coexistent medical condition that would preclude protocol 
therapy (as outlined in Section 3.2)? 
 
_______(N) 
16. Is the patient pregnant or lactating? 
 
 
 
 
 
_______(N/Y) 
17. Has the patient had prior invasive malignancies, except for non-melanomatous skin 
cancers? (Patients with a history of carcinoma in situ are eligible. 
 
 
 
           _______(Y) If yes, has the patient been disease free for ≥ 2 years prior to 
registration for patients who have not received any chemotherapy OR ≥ 2 years 
prior to the first day of chemotherapy for patients having started chemotherapy.? 
 
________(Y)     18. Has a radiation oncologist evaluated this patient and agreed and documented that 
patient is suitable to receive radiotherapy as administered in this protocol? 
 
________(N,Y)    19. Does the patient have active HIV infection? 
 
 
 
________(Y) If yes, is the CD4 count > 499/cu mm and a viral load < 50 copies/ml?  
________(Y)        20. Age ≥ 18? 
 
________(Y)     21. Is the interval between definitive tumor-related surgery and 1st step registration between 
21-70 days for patients who have not received any chemotherapy OR between 21-77 
days for patients entering the study who have already received up to 3 months of adjuvant 
chemotherapy as per the treating institution? 
 
________(Y/N) 
22. Has the patient received up to 3 months of chemotherapy at the time of registration 
for his/her pancreatic cancer? 
 
The following questions will be asked at Step 1 Study Registration:  
 
3D-CRT and IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION 
 
 
         
1. 
Institutional person registering case 
 
                  (Y) 2. 
Has the Eligibility Checklist (above) been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible for this study? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last)   
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient’s ID 
 

RTOG 0848 
 
 
 
 
 
 
Version Date:  January 17, 2024 
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ELIGIBILITY CHECKLIST—STEP 1 (5/12/16) 
(page 3 of 4)  
 
 
NRG Oncology Institution #   
 
RTOG 0848 
 
Case #  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of payment 
 
 
         
15. 
Any care at VA or military hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date: This date will be populated automatically. 
 
 
         
18. 
Medical oncologist’s name 
 
              (Y/N)    19. 
Patient has given permission to keep sample(s) for use in future research to learn 
about, prevent, or treat cancer  
 
              (Y/N) 20.  
Patient’s Initial Consent given for specimen use for research unrelated to the 
patient’s cancer?  
                                      
              (Y/N) 21. 
Did patient consent to future contact about more research? 
 
_______(Y/N)  22.       If randomized to radiation, is there a possibility that this patient will be treated   with 
IMRT?           
 
 
         
23. 
Nodal status: involved vs uninvolved? 
 
 
 
 
24. 
CA 19-9:  ≤ 90 vs > 90-180      
 
 
    
25. 
Surgical margins: positive (R1) vs negative (R0)? 
 
 

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15 
ELIGIBILITY CHECKLIST—STEP 1 (5/12/16) 
(page 4 of 4)  
 
 
NRG Oncology Institution #   
 
RTOG 0848 
 
Case #  
 
______(N/Y/NA) 26. 
For patients who have not started chemotherapy prior to study entry, has patient 
consented to take part in the quality of life study  
 
 
 
 
(Note: Due to the QOL hypothesis, as of the amendment to allow chemotherapy 
to start before study entry, QOL is not available for patients who have started 
chemotherapy prior to study entry.)? 
 
 
 
If no, provide reason: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
 
              (Y/N) 27. 
Tissue/Blood obtained at progression (if occurs) kept for cancer research? 
 
              (Y/N) 28.  
Tissue/Blood obtained at progression (if occurs) kept for medical research? 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 

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16 
ELIGIBILITY CHECKLIST STEP 2    REGISTRATION (A2)  
(5/12/16) 
 
NRG Oncology Institution # 
 
 
RTOG 0848 
Case #  
 
 
 
 
 
 
1. Institutional person registering 
 
 
(Y/N) 
2. Patient able to continue protocol treatment 
 
 
(1,2,3,4) 
3. If no, provide reason 
1. Progression of disease 
2. Patient refusal 
3. Did not start 5th month 1st step: adjuvant systemic treatment 
4. Other,Specify______________ 
 
 
 
4. Patients initials (Last, First) 
 
 
 
5. Verifying physician 
 
 
 
6. Patient ID# 
 
 
 
7. Calendar Base Date 
 
 
 
8. Randomization Date 
 
 
(1, 2) 
9. First Randomization treatment (For patients registered prior to 4/02/14) 
1. Gemcitabine 
2. Gemcitabine + Erlotinib 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
INTRODUCTION  
1.1  
Adjuvant Treatment of Pancreatic Cancer   
Despite potentially curative resection for pancreatic adenocarcinoma, the 5-year survival 
rate in these patients is <20%. [Nitecki, 1995; Piorkowski, 1982; Gudjonsson, 1987] The 
pattern of failure demonstrates both a significant component of local-regional relapse 
(50%-85%) and distant liver / intraabdominal failure.[Gudjonsson, 1987; Tepper, 1976] 
Adjuvant treatment is used to attempt to prevent recurrence and improve survival.  
 
1.2  
Does Adjuvant Chemoradiation Improve Survival? (5/12/16) 
1.2.1 
The GITSG Experience 
The Gastrointestinal Tumor Study Group (GITSG) performed a small, randomized trial 
that demonstrated an improvement in survival for patients receiving adjuvant 5-FU 
chemoradiation followed by maintenance bolus 5-FU compared to surgery alone.[Kalser, 
1985] Twenty-one patients receiving adjuvant 5-FU chemoradiation followed by 
additional 5-FU had a median survival of 21 months and 5-year survival of 19% 
compared with 11 months and 5%, respectively, for patients undergoing surgery alone 
(p = 0.03).  
1.2.2 
EORTC Trial 
In an effort to reproduce the findings reported by the GITSG, a study sponsored by the 
European Organization for Research and Treatment of Cancer (EORTC) randomly 
assigned 114 patients with resected pancreatic cancer to receive either postoperative 
concurrent 5-FU (25 mg/kg per day by continuous infusion) and radiotherapy (40 Gy, 
split course) or observation. Postoperative chemoradiotherapy was associated with a 
trend toward improvement in median survival and 2-year survival that did not reach 
statistical significance (26% versus 34% for control and treated patients, respectively, p 
= 0.099). [Klinkenbijl, 1999]  
1.2.3 
ESPAC-1 
Worldwide, the administration of adjuvant radiation remains controversial. The European 
Study Group for Pancreatic Cancer –1 (ESPAC-1) trial was a phase III, postoperative 
adjuvant trial that sought to determine the role of adjuvant chemotherapy and 
chemoradiation. This trial demonstrated a favorable impact of chemotherapy but a 
detrimental effect of chemoradiation.[Neoptolemos, 2001; Neoptolemos, 2004] However, 
the conclusions of ESPAC-1 are controversial because of trial design and execution 
concerns.[Abrams, 2001] A 62% local recurrence rate was reported in the ESPAC trial. 
Similar high local recurrence rates have been reported in multiple other adjuvant 
trials.[Griffin, 1990] 
1.2.4 
RTOG 9704 
RTOG 9704 was the first United States cooperative group adjuvant pancreatic trial in 
three decades. It was designed to evaluate whether the addition of gemcitabine to 5-
FU−based chemoradiation improved survival for patients with resected pancreatic 
adenocarcinoma when compared to only a 5-FU systemic therapy regimen. Patients with 
resected pancreatic adenocarcinoma were randomized to receive either 5-FU 
(continuous infusion at 250 mg/m2/day) or gemcitabine (1000 mg/m2 IV weekly) pre- and 
post-chemoradiation. [Regine, 2008] Both groups of patients were given chemotherapy 
over 3 weeks of pre- and 12 weeks post-chemoradiation. Chemoradiation was the same 
for all patients (daily fractions of 1.8 Gy, 5 days/week for 5.5 weeks, for a total of 50.4 
Gy, with continuous infusion 5-FU). Grade 4 hematologic toxicity was 2% in the 5-FU 
arm and 14% in the gemcitabine arm (p<0.0001), without difference in the rates of febrile 
neutropenia/infection. There were no differences in the ability to complete chemotherapy 
(86%, 5-FU vs. 90%, gemcitabine) or radiation (85%, 5-FU vs. 88%, gemcitabine).  
 
Overall survival and survival among patients with lesions of the pancreatic head 
(descriptor used for periampullary pancreatic lesions) were the primary endpoints of the 
study. A total of 451 patients were randomized, eligible, and analyzable. Patients with 
pancreatic head tumors (n = 381) experienced improved survival, with median and 3-
year survival of 20.5 months and 31% for the gemcitabine arm vs. 16.9 months and 22% 

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for the 5-FU arm (p=0.09; HR=0.82, CI=0.65 -1.03). Pretreatment CA19-9 level > 90 IU/l 
strongly predicted survival. The median and 3-year overall survival for patients with CA 
19-9 ≤ 90 were 22.8 months and 33% versus 9.6 months and 2% for patients with CA 
19-9>90 (p <0.0001), respectively. The median and 3-year survival in patients in the 
gemcitabine arm who received radiation according to protocol requirements were 25.2 
months and 46%, respectively.  
 
The pattern of tumor relapse was recorded on the site of the first relapse only and 
categorized as local, regional, or distant. The distribution of relapse was similar among 
all patients and among patients with pancreatic head tumors. Local relapse occurred in 
28% of patients in the 5-FU arm and 23% in the gemcitabine arm. Regional relapse was 
similar in both arms at 7%-8%. Distant relapse was > 70% in both arms.  
 
This trial compared favorably with the outcome in similar phase III trials in patients with 
pancreatic adenocarcinoma. This was despite the greater proportion of patients with T3 
disease, lymph node positive disease, and microscopically positive margins when 
compared to GITSG and EORTC trials. In RTOG 9704, 75% of patients had T3 disease, 
66% had lymph node positive disease, and 60% had microscopically positive or unknown 
margins. In the GITSG study only patients with negative surgical margins were included 
and 28% had lymph node positive disease. In the EORTC study, only patients with T1/T2 
disease were included, 50% had lymph node positive disease, and only 23% had 
microscopically positive or unknown margins. In the CONKO trial, patients were required 
to have a preoperative CA 19-9 level <2.5 times the upper limit of normal. 
1.2.5 
Hopkins and Mayo Clinic Analysis 
At the 2008 GI Cancer symposium, a collaborative study was reported evaluating the 
effect of adjuvant chemoradiation from the Johns Hopkins Hospital and the Mayo Clinic 
and later published as full manuscripts.[Hsu, 2008] The study consisted of 1,045 patients 
with resected pancreas cancer; 530 (50.7%) received 5-fluorouracil/XRT.  Cox 
proportional hazards models were used with covariates age, sex, institution, margin 
status, node status, differentiation, surgery type, and T-stage. Overall survival was longer 
with adjuvant chemoradiation; median overall survival was 22.5 versus 16.3 months, 
respectively (P<0.001). After adjustment for covariates, adjuvant chemoradiation was 
associated with improved survival among all patients (univariate RR=0.71, multivariate 
RR=0.62, p<0.001) and in all sub-groups (multivariate RR=0.54 to 0.74, P<0.05). 
Therefore, adjuvant chemoradiation was significantly associated with improved survival 
after resection, regardless of age, tumor size, margin status, node status, and tumor 
differentiation. 
 
Currently, the use of adjuvant radiation for patients with resected pancreatic cancer 
represents one of the most contentious and passionate debates in gastrointestinal 
oncology. We hypothesize that this North American/European trial will definitively 
demonstrate that adjuvant radiation with concurrent fluoropyrimidine will increase 
survival for patients with resected head of pancreas adenocarcinoma who remain 
disease free after adjuvant chemotherapy with gemcitabine (or gemcitabine and 
erlotinib). 
1.2.6 
Radiation Issues and Quality Control 
The RTOG performed a secondary analysis of RTOG 9704 based on radiation therapy 
quality assurance (RTQA). Of 416 patients analyzed for RTQA, 216 (52%) had radiation 
per protocol and 200 (48%) were less than per protocol.[Abrams, 2008] The frequency 
of per protocol and not per protocol did not differ by treatment arm (per protocol = 55% 
on 5-FU arm and 48% on gemcitabine arm). Based on the per protocol versus not per 
protocol radiation delivery, the frequency of grade 3/4 toxicity did not vary significantly 
on the 5-FU arm but did show a trend of less toxicity for patients on the gemcitabine arm. 
Survival was significantly increased for patients treated per protocol (p=0.019). 
 

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Based on the above analysis, this study will have prospective radiation quality control 
built into the trial. The RT randomization (-/+ fluoropyrimidine sensitized 
radiotherapy) will occur after the first 5 months of adjuvant systemic therapy. 
Patients will be randomized to receive either one additional month of systemic therapy 
or one additional month of systemic therapy followed by chemoradiation. Radiation will 
be initiated within 21 days of the last treatment of adjuvant systemic therapy. This design 
will give sufficient time for prospective radiation quality control to prevent a large gap 
between completion of chemotherapy and initiation of chemoradiation. During this 
period, radiation treatment plan will be required to be prospectively reviewed by senior 
NRG Oncology radiation oncologists Drs. Ross Abrams and William Regine.  
 
1.3  
Can the Addition of Adjuvant Erlotinib to Gemcitabine Improve Survival? 
1.3.1 
Gemcitabine in Pancreatic Cancer 
Gemcitabine is considered the most active cytotoxic drug for pancreatic cancer. In a 
randomized trial of 126 patients with advanced pancreatic cancer, the median and 1-
year survival for patients treated with gemcitabine was 5.7 months and 18%, compared 
with 4.4 months and 2% for patients treated with 5-FU (p = 0.0025), respectively.[Burris, 
1997] 
1.3.2 
CONKO-1 – Adjuvant Gemcitabine Improves Survival 
A multinational German trial (the CONKO-1 trial) randomly assigned 368 patients with a 
preoperative CA 19-9 level <2.5 times the upper limit of normal to gemcitabine (1000 
mg/m2 days 1, 8, and 15 every 4 weeks for 6 months) or no treatment after surgery. 
[Oettle, 2007] Patients were stratified by resection margins (which were positive in 19% 
of those assigned to gemcitabine and 16% of the control group), tumor size, and nodal 
status. The primary endpoint was disease-free survival. Median disease-free survival 
was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 
months in the control group (95% confidence interval, 6.1-7.8; p < 0.001, log-rank). 
Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the 
gemcitabine group and 7.5% and 5.5% in the control group, respectively. Subgroup 
analyses showed that the effect of gemcitabine on disease-free survival was significant 
in patients with either R0 or R1 resection. There was no difference in overall survival 
between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-
25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group 
(median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 
years and 11.5% at 5 years; p = 0.06, log-rank). An update of study outcome presented 
in ASCO 2008 demonstrated a significant median and 3-year survival advantage in the 
gemcitabine group (median 22.8 versus 20.2 months, p = 0.005, five-year survival 21 
versus 9 percent). [Neuhaus, 2008] 
1.3.3 
Erlotinib in Pancreatic Cancer 
Erlotinib is an orally administered quinazoline, tyrosine kinase inhibitor with potent, 
reversible inhibitory effects on the EGFR receptor related tyrosine kinases. The National 
Cancer Institute of Canada trial PA.3 evaluated the combination of erlotinib and 
gemcitabine versus gemcitabine alone.[Moore, 2007a] In this phase III trial of 569 
patients, 25% had locally advanced disease and 75% had distant metastases. Patients 
were randomized to receive standard-dose gemcitabine, 1000 mg/m2/week for 7 of 8 
weeks followed by 3 out of every 4 weeks plus either erlotinib or placebo. The erlotinib 
dose in this trial was started at 100 mg daily and the plan was to escalate the dose to 
150 mg daily on the first prescheduled interim toxicity analysis. Secondary to the high 
accrual rate only 23 patients were entered at the higher dose.  
 
The addition of erlotinib to gemcitabine was associated with a significant increase in the 
1-year (24% versus 17%) and median survival (6.4 vs. 5.9 months) when compared with 
single-agent gemcitabine.[Moore, 2007a]  A significant improvement in performance 
status was also observed. The incidence of adverse events were comparable in both 
arms with the exception of rash (72% vs. 29%), diarrhea (56% vs. 41%), and stomatitis 
(23% vs. 14%), which were more commonly observed in the erlotinib/gemcitabine arm. 

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The development of a rash from erlotinib predicted significantly improved survival. 
Patients developing a grade 2 rash had a 10.5 month median survival and a 1-year 
overall survival of 43%. 
 
Agents that have proven benefit in the metastatic setting should be evaluated in earlier-
stage disease where the magnitude of observed benefit may be increased. For example, 
in the metastatic/locally advanced context gemcitabine achieved only a 4-week 
improvement in median survival compared to fluorouracil. However, in the adjuvant 
context gemcitabine increased median survival by 2.6 months (10 – 11 weeks) in the 
CONKO-001 trial. The earlier-stage disease, with its lower tumor burden and greater 
sensitivity to therapy, may demonstrate a better proportional benefit. Furthermore, a 
confirmatory phase III trial of erlotinib in pancreatic cancer would give us confidence 
investigating the addition of other agents to EGFR tyrosine kinase inhibitors in pancreatic 
cancer as part of multitargeted therapies.  The inclusion of correlative science to study 
the mechanisms of resistance to erlotinib provides a unique opportunity to understand 
mechanisms of resistance to anti-EGFR agents. 
 
As reviewed above, for patients with metastatic disease, while erlotinib increased median 
survival by only 2 weeks, the 1-year survival with erlotinib increased by a relative 
increase of 40% (from 17%-24%) for patients with metastatic pancreatic cancer. We 
hypothesize that the addition of erlotinib to adjuvant gemcitabine will increase survival 
for patients with resected head of pancreas adenocarcinoma and that the magnitude of 
the benefit of erlotinib will increase over time of follow-up by at least the same relative 
increase as previously demonstrated for patients with metastatic disease.  
 
1.4 
LAP 07 Trial: The Decision to Evaluate The Effect of Erlotinib in a Phase IIR Analysis 
(2/19/14) 
The addition of erlotinib to gemcitabine for patients with locally advanced pancreatic 
cancer was recently reported in the LAP 07 trial (Hammel, 2013). In this trial, 442 
patients with locally advanced pancreatic cancer were first randomized to gemcitabine 
alone or gemcitabine plus erlotinib (100 mg/day) for 4 months. Patients without 
progression were then randomized to 2 additional months of chemotherapy or 
chemoradiation. After a median follow-up of 36 months, 221 deaths had occurred 
allowing the planned interim analysis. When analyzed by the initial randomization to 
gemcitabine alone versus gemcitabine plus erlotinib, the median survival was 13.6 
months versus 11.9 months respectively, p =.09, favoring gemcitabine alone.  There 
was an increase in grade 3 diarrhea in the erlotinib arm (p=0.005). Given these results 
in locally advanced pancreatic cancer, the decision was made to change the evaluation 
of the effect of erlotinib in RTOG 0848, an adjuvant pancreatic cancer population, to a 
randomized phase II (Ph II-R) design.  
 
1.5 
Decision To Allow Trial Entry After Up To 3 Months of Chemotherapy With Single-Agent 
Gemcitabine or Combination Chemotherapy (5/12/16) 
A primary objective of this trial is to determine the role of radiation after completion of 
systemic chemotherapy. To facilitate accrual to answer this question, up to 3 months of 
systemic chemotherapy may be administered prior to study registration. Single-agent 
gemcitabine, or combination regimens such as gemcitabine/abraxane, and fluorouracil, 
leucovorin, oxaliplatin and irinotecan (FOLFIRINOX), as per institutional standard of 
care may be utilized. We acknowledge that institutional policies may modify 
FOLFIRINOX (Conroy 2011), such as reducing irinotecan dosage or omitting the bolus 
of 5-FU, or other published combination regimens such as gemcitabine and nab-
paclitaxel, (Von Hoff 2013) with respect to timing and precise doses. Therefore, single-
agent gemcitabine, or combination regimens that include gemcitabine, nab-paclitaxel, 
oxaliplatin, fluoropyrimidine, or irinotecan, will be allowed.  
 
 

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1.6 
EGFR as Treatment Target: Molecular Determinants of Drug Sensitivity 
Erlotinib is the only targeted therapy that has been shown to exert a significant, but minor, 
effect on survival in metastatic pancreatic cancer by blocking EGFR signaling. There is 
therefore a rationale to understand the biology of EGFR activation and its association with 
anti-EGFR treatment outcome.  
 
Recent data indicate a role for Ras mutations in response to anti-EGFR therapies in other 
tumor types, such as lung and colorectal cancers.[Eberhard, 2005] However, the 
contribution of such mutations in the outcome of treatment in pancreas cancer remains 
unknown despite the high frequency of K-Ras mutations in this disease. In pancreatic 
cancer, K-Ras mutations have been demonstrated in approximately 70%-80% of 
patients.[Baselga, 2008;Moore, 2007b] The effect of K-Ras mutations on response to 
erlotinib is uncertain in pancreatic cancer. Investigators from Johns Hopkins tested the 
hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor 
efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the 
EGFR inhibitors erlotinib and cetuximab and analyzed for biological features.[Jimeno, 
2008] Two of 10 tumors were sensitive, and by global gene expression profiling with gene 
set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared 
with resistant tumors. EGFR and K-Ras mutations were neither predictive nor responsible 
for the EGFR pathway activation. Therefore, coordinated overexpression of the EGFR 
pathway, and not K-Ras mutations, may predict susceptibility to EGFR inhibitors in 
pancreatic cancer.  
 
Pancreas cancer cells are characterized by multiple genetic mutations that challenge the 
success of targeting a single pathway, such EGFR, in successful anti-cancer therapy for 
this disease.  Clinical studies have concluded that the expression of EGFR protein that is 
measured by immunohistochemistry is insufficient and unable to predict response to anti-
EGFR therapy. Our proposal therefore includes the study of molecular changes that may 
closely mimic the activated pathway based on downstream effector molecules such as 
MAPK, Akt, NFkB, and EGFR ligands. EGFR mutations similar to those found in lung 
cancer that may predict sensitivity to erlotinib have not been demonstrated in this disease. 
 
There is evidence that epithelial to mesenchymal transition (EMT)  limits sensitivity to anti-
EGFR therapies.[Jimeno, 2008] Biomarkers associated with EMT status (e.g., E-Cadherin, 
vimentin) have been reported to be predictors of EGFR inhibitor sensitivity in several 
human cancer cells including non-small cell lung cancer, in xenografts, and patients 
samples.[Buck, 2007;Thomson, 2005] EMT may also be a factor in resistance to 
gemcitabine therapy based on some early preclinical work.[Shah, 2007] Multiple genetic 
mutations can be responsible and/or associated with EMT including K-Ras and C-Met. 
 
Identification of biomarkers that predict anti-EGFR therapy outcome will influence new drug 
development in pancreas cancer. The data obtained in the adjuvant setting from this study 
will help develop biomarkers that will be used in the selection of patients undergoing anti-
EGFR therapy for early and advanced stages of pancreas cancer. Moreover, such data 
may be applicable to other cancers. Identification of a biological role of such biomarkers 
(e.g., EMT and K-Ras) will lead to the development of targeted therapies against these 
molecules that can also be applied in therapies for advanced disease. 
 
There is also a need to define mechanisms of resistance to erlotinib and gemcitabine and 
identify molecules that may be targeted to modulate resistance to therapy. For example, 
evidence from in vitro assays suggests that drug-resistant pancreatic tumor cells are 
associated with EMT, a more-aggressive and invasive phenotype in several solid 
tumors.[Thiery, 2003]  Other changes, such as the increased phosphorylation of c-Met, 
may also be related to chemoresistance through its effect on EMT.  
 

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1.7 
MicroRNA  (5/23/11) 
miRNAs play important roles in many normal biological processes; however, the aberrant 
miRNA expression and its correlation with the development and progression of cancers is 
an emerging field. Therefore, miRNAs could be used as biomarkers not only for diagnosis 
of pancreas cancer but also in prediction of prognosis. Importantly, some miRNAs could 
regulate the formation of cancer stem cells and the acquisition of epithelial-mesenchymal 
transition, which are critically associated with drug resistance as has been discussed 
above. Moreover, some miRNAs could target genes related to drug sensitivity, resulting in 
the altered sensitivity of cancer cells to anti-cancer drugs. We compared the expression 
profile of microRNAs in the plasma of patients diagnosed with pancreas cancer (n=50) and 
compared with healthy volunteers (n=10). Data was further validated by quantitative real-
time PCR and cell-based assays. Thirty-seven miRNAs were down-regulated and 54 were 
up-regulated in plasma from patients with PC. The expression of miR-21 was significantly 
higher, and the expression of let-7 family (especially let- 7d) and miR-146a was significantly 
lower. Most interestingly, the expression of miR-21 was correlated with worse survival, and 
the expression of let-7 was inversely correlated with survival in this pilot study with mixed 
patient population. Moreover, we found that miR-21 family was markedly over-expressed 
in chemo-resistant pancreas cancer cell lines, which was consistent with the plasma data 
from patients. Our previous studies have shown increased expression of miR-21 with 
concomitant loss of PTEN expression in PC cells, which is consistent with our current 
findings showing the loss of three additional targets of miR-21 (PDCD4, Maspin and 
TPM1). These results suggest that identifying and validating the expression of miRNAs 
could serve as potential biomarker for tumor aggressiveness, and such miRNAs could be 
useful for the future of drug development (Ali 2011). 
 
1.8 
Rationale to Limit Patient Enrollment to Patients with Head of Pancreas Adenocarcinoma  
Eighty to eighty-five percent of all pancreatic adenocarcinomas arise to the right of the 
superior mesenteric vein and artery and are resected by a pancreaticoduodenectomy. 
This anatomic part of the pancreas is the head of the pancreas. It is also often referred to 
as the periampullary part of the pancreas. The pancreatic neck and uncinate process are 
also part of the pancreatic head. This is in contradistinction to the parts of the pancreas 
arising to the left of the superior mesenteric artery, generally known as the body and tail 
of the pancreas (see figure).  
 
 
 
Uncinate 
process 
neck 
 

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(Figure from AJCC web page accessed at www.cancerstaging.org/education/tnmschema 
on January 8th, 2009) 
 
The decision to limit enrollment to head of pancreas lesions was made based on the 
following considerations:  
a. This is the group of patients for whom most data and past experience in adjuvant 
therapy are available. 
b. The role of chemoradiotherapy in the adjuvant management of patients with body 
and tail lesions is even more uncertain than for patients with head of pancreas 
adenocarcinoma; in RTOG 9704 it appeared that only patients with pancreatic head 
lesions benefited from gemcitabine. 
c. Both the operation required and the regions treated with radiation are substantially 
different for body and tail lesions as opposed to pancreatic head lesions. Therefore, 
exclusion of patients with body and tail lesions removes potentially important sources 
of patient heterogeneity that may be relevant to the chemotherapy and 
chemoradiation questions being asked. 
d. Body and tail pancreas cancers may be biologically different than those arising in the 
head of the pancreas with earlier micrometastases, thereby limiting the benefit of 
locoregional therapy. 
1.8.1  
Implication and Importance of Limiting Patient Enrollment to Patients With Head of 
Pancreas Adenocarcinoma  
There are four adenocarcinomas for which a pancreaticoduodenectomy can be an 
appropriate operation done with curative intent. These are adenocarcinoma of pancreas, 
distal common bile duct, proximal duodenum, and the true ampulla However, the non-
pancreatic adenocarcinomas are less common than the pancreatic adenocarcinomas 
and the prognoses associated with pancreaticoduodenectomy for these other three, non-
pancreatic sites, especially the duodenum and ampulla, are significantly different (better) 
than those seen with pancreaticoduodenectomy for head of pancreas adenocarcinoma 
[Yeo, 1997]. Therefore, this protocol is specifically limited to head of pancreas 
adenocarcinoma. 
 
1.9  
Requirement for clear designation of tumor margin status (5/12/16) 
RTOG 9704 had a 23% and 26% unknown margin rate in the 5-FU and gemcitabine arms, 
respectively. The major cause of this designation was the absence of a clear statement 
within the operative report as to the status of the visible margins, especially the SMA or 
uncinate margin. The definition of margin status is of crucial importance prognostically. 
This has been widely recognized and described [AJCC, 2006; Staley, 2006; Raut, 2007; 
CAP, 2009].The distinction among R0, R1, and R2 resections helps to capture this 
information nicely. However, since the SMA margin (also known as the uncinate margin), 
is typically down to the adventitia of the superior mesenteric artery (SMA) which cannot be 
resected, the only way for the status of this margin to be documented is for the surgeon to 
document whether there was or was not visible tumor left behind on the surface of the SMA 
at the conclusion of the operation. This distinguishes between R0 and R1 resections on 
the one hand (no visible tumor left behind, without or with microscopically positive margin) 
and R2 resections (visible tumor remaining within patient) on the other hand. Pathology 
reports will be reviewed by the surgical oncology protocol chairs for interpretation of margin 
status. If margin status is uncertain from the pathology report, the surgical chairs will speak 
directly with the submitting surgeon and pathologist to clarify margin status prior to study 
enrollment. Standardized reporting of the pathology information is encouraged. An 
example of a standardized reporting form from the College of American Pathologists 
webpage (www.cap.org/apps on January 8, 2009) in Appendix V. 
 
1.10 
Quality of Life/Patient-Reported Outcomes 
1.10.1 
Importance of Patient-reported Outcomes in Pancreas Cancer  
Patient-reported outcomes, in addition to overall survival, are now accepted by 
oncologists as an important clinical endpoint in phase III trial design for patients with 

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advanced pancreatic cancer. This is largely based on the landmark randomized trial of 
Burris et.al.[Burris, 1997], which reported, for patients with advanced pancreatic cancer, 
a significant increase using gemcitabine (rather than fluorouracil) in the “clinical benefit 
response” that included non-traditional measures related to symptoms, including pain, 
performance status and weight [Burris, 1997]. To date, there has been limited available 
literature using formal patient reported measures for patients with pancreatic cancer 
[Rocha Lima, 2004]. This is unfortunate, because the majority of patients with this cancer 
have incurable disease and palliation and quality of their remaining life become the major 
goals.  
1.10.2 
Patient-Reported Fatigue Using FACIT-Fatigue May Predict for Overall Survival in 
Patients With Pancreatic Cancer  
Fatigue has been described as the most frequent and distressing symptom related to 
cancer and its treatment [Bower, 2005]. The etiology of fatigue, its correlates, and 
prevalence in the context of pancreas cancer and its treatment are poorly understood. 
Moreover, patient-reported fatigue may provide important prognostic information for 
patients with pancreatic cancer. Tracking of this symptom may be useful for management 
decisions (local and systemic vs. systemic only) and medical monitoring. To this end, 
recent data from a clinical study of 86 patients with stage II-IV pancreatic cancer and 
involuntary weight loss explored patient-reported cancer fatigue and overall 
survival[Robinson, 2008]. In this study population, 28 patients were given gemcitabine 
plus 3 mg/kg of infliximab (Remicade), 28 received gemcitabine plus 5 mg/kg of 
infliximab, and 30 were administered gemcitabine plus placebo in a double-blinded, 
randomized phase II, multicenter setting. Patient-reported outcome (PRO) endpoints 
included scores from the Functional Assessment of Chronic Illness Therapy–Fatigue 
(FACIT–Fatigue).  
 
The FACIT-Fatigue, version 4, is a 13-item questionnaire that assesses self-reported 
tiredness, weakness, and difficulty conducting usual activities due to fatigue [Yellen, 
1997]. A 5-point intensity type of rating scale (from “not at all” to “very much”) is used. 
The FACIT-Fatigue is a psychometrically sound instrument and has been widely used to 
measure fatigue for patients with various chronic illnesses including cancer [Yellen, 
1997], as well as for the U.S. general population [Cella, 2002]. Interestingly in this study 
of advanced pancreatic cancer [Robinson, 2008], a high baseline FACIT–Fatigue score 
(> 30), indicating low fatigue, was the best predictor of longer overall survival in a 
stepwise, Cox proportional hazards multiple-regression analysis (HR, 0.47; CI: 0.30–
0.74). Fatigue scores predicted survival when a baseline FACIT–F score of 30 was used 
as the cut-point for defining high and low fatigue. The median overall survival was 9.1 
months (CI: 7.2–11.4) for patients having low fatigue (indicated by higher scores [> 30] 
and 5.2 months (CI: 4.0–7.2) for those with high fatigue (indicated by low score [< 30]), 
log rank P = 0.002. In fact, patient perception of fatigue was the best predictor of overall 
survival, in comparison to baseline Karnofsky Performance Status, lean body mass and 
hemoglobin level. These findings support several features of an a priori clinical-benefit 
model and as such, warrant confirmation by large prospective trials.  
 
Based in part on Robinson and colleagues’ intriguing data described above [Robinson, 
2008], we hypothesize that patients reporting low baseline fatigue, as measured by the 
FACIT-Fatigue 13 item questionnaire, will experience longer overall survival. 
1.10.3 
PROMIS-Fatigue : A Novel Short Form Fatigue Scale 
Most recently, the National Institutes of Health (NIH) Patient-Reported Outcomes 
Measurement Information System (PROMIS) Roadmap initiative (www.nihpromis.org) 
was initiated. PROMIS is a 5-year cooperative group program of research designed to 
develop, validate, and standardize item banks to measure patient-reported outcomes 
(PROs) relevant across common medical conditions, including cancer [Cella, 2007; 
Garcia, 2007]. Integral to the work of this group, includes the creation of a PROMIS-
derived fatigue short form (using limited questions to minimize patient burden) that was 
developed for ease of use in oncology populations. While the psychometric properties of 

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25 
this 7-question short fatigue scale have been validated in the general population [Garcia, 
2007; Lai, 2008], validation in patients with cancer is underway. A “cross-walk” has been 
successfully developed between the PROMIS fatigue item bank and the PROMIS-
Cancer fatigue item bank that produced the short form measure. These two item banks, 
sharing 54 common items, were linked by equating item parameters using items that 
held stable psychometric properties between the cancer and general population 
populations in which they were tested. Results showed that cancer patients reported 
more severe fatigue (1/3 standard deviation more severe, but the same scale 
characteristic curve slope) than the general population, which matches clinical 
expectations [Cella, 2008] 
 
Since the PROMIS-derived fatigue short form and the FACIT-Fatigue were successfully 
co-calibrated onto the same fatigue measurement continuum by using Item Response 
Theory model, we hypothesize that similar clinical validity will be demonstrated again. 
Specifically, the PROMIS-derived fatigue short form scale can be used as a surrogate 
for the FACIT-Fatigue, and will also be able to predict for overall survival. 
 
2.0 
OBJECTIVES (2/19/14) 
(NOTE:  Ph II-R Erlotinib randomization completed, Arm 2 closed to accrual effective 4/02/2014) 
 
2.1 
Primary Objectives (5/12/16) 
2.1.1  
Ph II-R: To determine whether the addition of erlotinib to gemcitabine adjuvant 
chemotherapy shows a signal for improved survival as compared to gemcitabine alone 
following R0 or R1 resection of head of pancreas adenocarcinoma (including 
adenocarcinoma of the head, neck, and uncinate process). 
2.1.2  
Ph III:To determine whether the use of concurrent fluoropyrimidine and radiotherapy 
following adjuvant gemcitabine based chemotherapy or non-gemcitabine based 
chemotherapy such as modified FOLFIRINOX further enhances survival for such 
patients who are without evidence of progressive disease after 5 months of adjuvant 
chemotherapy.  
 
2.2 
Secondary Objectives (5/12/16) 
(NOTE: Ph II-R, Erlotinib randomization completed, Arm 2 closed to accrual effective 4/02/14) 
 
2.2.1 
To evaluate disease-free survival of adjuvant chemotherapy followed by radiotherapy 
and concurrent fluoropyrimidine for patients with resected head of pancreas 
adenocarcinoma who are disease free after 5 months of adjuvant chemotherapy. 
2.2.2 
To evaluate disease-free survival of standard adjuvant gemcitabine chemotherapy with 
and without erlotinib for patients with resected head of pancreas adenocarcinoma. 
2.2.3 
To evaluate adverse events with and without erlotinib for patients with resected head of 
pancreas adenocarcinoma. 
2.2.4 
To evaluate adverse events of adjuvant chemotherapy ± radiation therapy and 
concurrent fluoropyrimidine for patients with resected head of pancreas adenocarcinoma 
who are disease free after adjuvant chemotherapy.  
2.2.5 
To evaluate preoperative cross-sectional imaging of the primary head of pancreas 
adenocarcinoma in order to determine the frequency with which objective criteria of 
resectability are present. 
2.2.6  
To determine if patients reporting low baseline fatigue, as measured by the FACIT-
Fatigue, predicts survival and to explore correlations between baseline fatigue, as 
measured by PROMIS, and survival. 
 
3.0 
PATIENT SELECTION (2/19/14) 
             NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED 
3.1 
Conditions for Patient Eligibility (5/12/16) 
For questions concerning eligibility, please contact the study data manager. 

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26 
 
3.1.1 
Histologic proof of primary head of pancreas invasive adenocarcinoma managed with a 
potentially curative resection (i.e., removal of all gross tumor) involving a classic 
pancreaticoduodenectomy (Whipple) or a pylorus preserving 
pancreaticoduodenectomy. Patients with invasive adenocarcinoma that also contains a 
component of intraductal papillary mucinous neoplasm (IPMN) are eligible 
The operating surgeon must document in the operative note that a complete 
gross excision of the primary tumor was achieved. The pathology report must 
include documentation of the margin status and the size of the tumor. The 
pathology report must also include the status of the three major margins—bile 
duct, pancreatic parenchyma, and retroperitoneal (uncinate). 
3.1.2 
For patients who have not started their chemotherapy prior to registration, the interval 
between definitive tumor-related surgery and 1st step registration must be between 21-
70 days. For patients entering on the study who have already received up to 3 months 
of adjuvant chemotherapy as per the treating institution, the interval between definitive 
tumor-related surgery and day one of adjuvant chemotherapy must have between 21-77 
days. 
3.1.3 
Patients will be staged according to the 6th edition AJCC staging system with pathologic 
stage T1-3, N0-1, M-0 being eligible. Pathologic reporting using the CAPS format is 
strongly encouraged (see Appendix IV).  
3.1.4 
Age ≥ 18. 
3.1.5 
Zubrod performance status 0 or 1. 
3.1.6 
Complete history and physical examination including weight and Zubrod status within 31 
days of study entry (or within 31 days prior to day 1 of chemotherapy post-surgery for 
those patients having started chemotherapy prior to first step registration).  
3.1.7 
Before starting therapy the patient should be able to maintain adequate oral nutrition of 
t 1500 calories estimated caloric intake per day and be free of significant nausea and 
vomiting.  
 
3.1.8 
CBC/differential obtained within 21 days of registration on study (or 
within 21 days prior to day 1 of chemotherapy post-surgery for those patients 
having started chemotherapy prior to first step registration), with adequate bone 
marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 
cells/mm3  
 
Platelets ≥ 100,000 cells/mm3  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable.) 
3.1.9 
Post resection serum CA19-9 ≤ 180 units/mL AND prior to any systemic treatment 
 
3.1.10 Patients must have: Serum total bilirubin ≤ twice the institutional upper 
limit of normal within 21 days of registration on study (or within 21 days prior to 
day 1 of chemotherapy post-surgery for those patients having started 
chemotherapy prior to first step registration). 
 
Creatinine levels ≤ twice the institutional upper limit of normal within 21 days of 
registration on study (or within 21 days prior to day 1 of chemotherapy post-
surgery for those patients having started chemotherapy prior to first step 
registration). 
 
SGOT must be ≤ 2.5 x the institutional upper limit of normal within 21 days of 
registration on study (or within 21 days prior to day 1 of chemotherapy post-
surgery for those patients having started chemotherapy prior to first step 
registration). 
3.1.11 
Negative serum pregnancy test for women of childbearing potential within 14 days of 
study registration. 
3.1.12    Abdominal/pelvic CT scan with contrast is preferred. Abdominal CT alone is acceptable 
only if insurance restrictions are experienced. Chest CT/x-ray (CT of chest preferred) 
within 31 days of registration on study (or within 31 days prior to day 1 of chemo post-
surgery for those patients having started chemotherapy prior to first step registration). 
Patients allergic to IV contrast can have MRI of the abdomen/pelvis instead.  

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27 
3.1.13 
Signed study-specific informed consent  
3.1.14 
Consultation, agreement, and documentation in the patient’s chart by a radiation 
oncologist that patient is suitable to receive radiotherapy per this protocol. 
3.1.15 
Women of childbearing potential and male participants must practice adequate 
contraception. 
3.1.16 
Patients with active HIV infection are eligible if their CD4 count is > 499/cu mm and their 
viral load is < 50 copies/ml; use of HAART is allowed.  
 
3.2 
Conditions for Patient Ineligibility (5/12/16) 
3.2.1 
Patients 
with 
non-adenocarcinomas, 
adenosquamous 
carcinomas, 
islet 
cell 
(neuroendocrine) tumors, cystadenomas, cystadenocarcinomas, carcinoid tumors, 
duodenal carcinomas, distal bile duct, and ampullary carcinomas.: Patients with tumors 
that are largely intraductal papillary mucinous neoplasms (IPMN) with a minimal or minor 
component of invasive carcinoma are not eligible. Patients with acinar carcinomas are 
not eligible. Patients with IPMN’s that contain some secondary (minor) foci of 
adenocarcinoma are also not eligible. 
3.2.2   
Patients managed with a total pancreatectomy, a distal pancreatectomy, or central 
pancreatectomy. 
3.2.3 
Patients entering on the study after pancreaticoduodenctomy, who have not already 
started chemotherapy must not have had prior systemic chemotherapy for pancreas 
cancer; note that prior chemotherapy for a different cancer is allowable.  
 
For patients entering on the study who have already received up to 3 months of adjuvant 
chemotherapy as per the treating institution, patients must not have received adjuvant 
chemotherapy with agents other than gemcitabine, nab-paclitaxel, oxaliplatin, 
fluoropyrimidine, or irinotecan for the current pancreatic cancer.  Prior chemotherapy for 
a different cancer is allowable.   
3.2.4 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields 
3.2.5 
Previous history of invasive malignancy (except non-melanoma skin cancer) unless the 
patient has been disease free for at least 2 years prior to study entry (or first day of 
chemotherapy for patients having started chemotherapy prior to first step registration). 
Patients with a previous history of carcinoma in situ are eligible. 
3.2.6 
Severe, active co-morbidity, defined as follows per time points indicated below (or per 
time points indicated below prior to the first day of chemotherapy for patients having 
started chemotherapy prior to first step registration):  
 
Unstable angina and/or congestive heart failure requiring hospitalization within 
the last 6 months 
 
Transmural myocardial infarction within the 3 months of study registration 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration 
3.2.7 
Pregnant or lactating women   
3.2.8 
Women of childbearing potential and men who are sexually active and not willing/able to 
use medically acceptable forms of contraception; this exclusion is necessary because 
the treatment involved in this study may be significantly teratogenic.  
3.2.9 
If surgical margin status cannot be determined after consultation with the operating 
surgeon and the institutional pathologist, the patient will be ineligible. 
 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT (5/12/16) 
NOTE: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility.  

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28 
4.1 
 Required Evaluations/Management 
See Appendix I; note that failure to perform one or more of these tests may result in 
assessment of a protocol violation. 
4.1.1 
Glucose and Na, K, Cl, CO2, BUN within 21 days of study entry or within 21 days prior 
to day 1 of chemotherapy post-surgery for patients having started chemotherapy prior to 
first step registration  
 
4.2 
Highly Recommended Evaluations/Management 
4.2.1 
If patient consents, a tumor tissue block containing normal tissue and peripheral blood 
that was obtained prior to treatment submitted for correlative studies is highly 
recommended. (NOTE: Tissue block that includes normal tissue is encouraged).   
4.2.2 
If patient consents, urine specimen prior to protocol therapy.  
4.2.3 
If the patient consents to participate in the quality of life (QOL) component of the study, 
sites are required to administer the baseline QOL and functional assessments prior to 
the start of protocol treatment: FACIT-Fatigue and the PROMIS-derived fatigue short 
form  
 
5.0 
REGISTRATION AND STUDY ENTRY PROCEDURES (17-JAN-2024) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified investigators. 
National Cancer Institute (NCI) policy requires all individuals contributing to NCI-sponsored trials 
to register with their qualifications and credentials and to renew their registration annually. To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and 
Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. Investigators and clinical 
site staff who are significant contributors to research must register in the Registration and 
Credential Repository (RCR). The RCR is a self-service online person registration application with 
electronic signature and document submission capability. 
RCR utilizes five person registration types. 
x 
Investigator (IVR) — MD, DO, or international equivalent; 
x 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
x 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, Rave, acting 
as a primary site contact, or with consenting privileges; 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 

RTOG 0848 
 
 
 
 
 
 
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29 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
x 
Addition to a site roster; 
x 
Selection as the treating, credit, or drug shipment  investigator or consenting person in 
OPEN; 
x 
Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval) 
or consenting/treating/drug shipment investigator in OPEN must be rostered at the enrolling site 
with a participating organization.  
 
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov . 
 
5.1 
This study incorporates a two-step registration process and both steps must be 
completed for all patients. (5/12/16) 
 
Step 1 of registration entails OPEN registration as detailed in Section 5.6, at which time 
the patient will be assigned to Arm 1 (gemcitabine alone or combination chemotherapy per 
institutional standard). Note: Chemotherapy may be initiated up to three months prior to 
registration-refer to Sections 3.2.3 and 7.1.1  
 
Step 2 of registration requires a second web registration for all patients. 
Patients that have not progressed and have started the 5th month of the first step 
randomization treatment will then be randomized to either Arm 3 (no radiotherapy) or 
Arm 4 (radiotherapy with fluoropyrimidine sensitization) as described in the schema. 
 
If a patient is not going on to the second randomization, step 2 of registration must 
still be completed via web registration. 
 
5.2  
General Pre-Registration Requirements (4/02/14) 
 
In order to be eligible to enroll patients onto this trial, the center must be credentialed for 
either 3D-CRT or IMRT.   
 
As a first step in the credentialing procedure, a Facility Questionnaire must be completed 
by all institutions entering patients on this protocol. Update your online electronic Facility 
Questionnaire, available on the Imaging and Radiation Oncology Core (IROC) Houston 
web site at http//irochouston.mdanderson.org. 
 
A Credentialing Status inquiry form must be completed. Complete this form on the IROC 
Houston website above to determine if your site has met all of the requirements. This will 
be completed in place of updating the previous Facility Questionnaire. When the 
requirements are met the site and NRG will be notified. NRG will then update the RSS 
database. 
 
 
5.3 
Pre-Registration Requirements for IMRT Treatment Approach (4/02/14) 
As noted above, in order to utilize IMRT on this study, the institution must have met 
specific technology requirements and have provided baseline physics information. 
Instructions for completing these requirements or determining if they already have been 
met are available on the IROC Houston web site at 
http://irochouston.mdanderson.org;select “Credentialing” and “Credentialing Status 
Inquiry”. Instructions for requesting and irradiating this phantom are available on the 
IROC Houston web site at http://irochouston.mdanderson.org; select “Credentialing” and 
“RTOG”. 
 
 

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30 
The institution or investigator must update or complete a Facility Questionnaire  
(available on the IROC Houston web site at http://irochouston.mdanderson.org )  
 
Phantom Irradiation also must be completed for IMRT credentialing. If an institution has 
not previously met credentialing requirements for IMRT in the head and neck region (upper 
aerodigestive tract), an IMRT phantom study with IROC Houston must be successfully 
completed.  Previous credentialing for IMRT with the head & neck PHANTOM will allow 
institutions to enter patients treated with IMRT on this protocol without additional phantom 
irradiation. 
 
IROC Houston QA Center will notify the institution when all requirements have been met 
and the institution is RT credentialed to enter patients onto this study. Subsequently, NRG 
Headquarters will update RSS at CTSU. 
 
5.4 
Digital RT Data Submission Using TRIAD (12-APR-2018) 
TRIAD is the American College of Radiology’s (ACR) image exchange application.  
TRIAD provides sites participating in clinical trials a secure method to transmit DICOM 
RT and other objects. TRIAD anonymizes and validates the images as they are 
transferred. 
 
TRIAD Access Requirements: 
x 
Site physics staff who will submit images through TRIAD will need to be registered with The 
Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and 
Access Management (IAM) account, and be registered as an AP, NPIVR or IVR.  Please refer 
to the CTEP Registration Procedures section for instructions on how to request a CTEP-IAM 
account and complete registration in RCR.  
x 
To submit images, the site physics user must be on the site’s affiliated rosters and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s CTSU 
Administrator or Data Administrator to request assignment of the TRIAD site user role. 
x 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will need to 
have the TRIAD application installed on his/her workstation to be able to submit images. 
TRIAD installation documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/.   
 
This process can be done in parallel to obtaining your CTEP IAM account username and 
password and RCR registration. 
 
If you have any questions regarding this information, please send an email to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
 
5.5 
Regulatory Pre-Registration Requirements (11-APR-2023) 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on the person and site roster assignment housed in the Roster Maintenance application 
and in most cases viewable and manageable via the Roster Update Management System 
(RUMS) on the Cancer Trials Support System  Unit (CTSU) members’ website. 
 
This study is supported by the NCI CTSU. 
 
IRB Approval:  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program (CTEP) 
and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials Network 

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31 
(NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases. In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the site 
after March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to the CTSU 
Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for Local 
Context to the CIRB using IRBManager to indicate their intent to open the study locally. The NCI 
CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory Office, but 
sites are required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to 
establish site preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about establishing site 
preferences can be addressed to the CTSU Regulatory Office by email or calling 1-888-651-CTSU 
(2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
x 
Have an active CTEP status; 
x 
Have an active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
x 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
x 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile;  
x 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
x 
Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
x 
An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
x 
Compliance with all applicable protocol-specific requirements (PSRs). 
 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster. To view/download site registration forms:   
x 
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password or linked ID.me account (ID.me accounts are required for all 
newly created CTEP-IAM accounts and by July 1, 2023 for all users); 
x 
Click on Protocols in the upper left of the screen 
o 
Enter the protocol number in the search field at the top of the protocol tree, or 

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32 
o 
Click on the By Lead Organization folder to expand, then select NRG and protocol 
number RTOG-0848. 
x 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided. (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.)  
 
5.5.2 
Requirements For RTOG 0848 Site Registration: 
 
x 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
x 
For applicable NCTN studies with a radiation and/or imaging (RTI) component, the 
enrolling site must be aligned to a RTI provider.  To manage provider associations 
access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers.  Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. Enrolling sites are responsible for 
ensuring that the appropriate agreements are in place with their RTI provider, and 
that appropriate IRB approvals are in place.   
x 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to 
begin the modality credentialing process.  (Only add if RT modality credentialing is 
part of the study design.) 
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU 
(2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
 
 

RTOG 0848 
 
 
 
 
 
 
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33 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
x 
Click on Regulatory at the top of the screen; 
x 
Click on Site Registration; and 
x 
Enter the site’s 5-character CTEP Institution Code and click on Go: 
o 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Non-English Speaking Canadian and Non-North American Institutions: 
Translation of documents is critical. The institution is responsible for all translation costs. All 
regulatory documents, including the IRB/REB approved consent, must be provided in English and 
in the native language. Certification of the translation is optimal but due to the prohibitive costs 
involved NRG Oncology will accept, at a minimum, a verified translation. A verified translation 
consists of the actual REB approved consent document in English and in the native language, 
along with a cover letter on organizational/letterhead stationery that includes the professional title, 
credentials, and signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
5.5.3 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Prior to clinical trial commencement, Canadian institutions must also complete and 
fax (215-569-0206) or e-mail (CTSURegulatory@ctsu.coccg.org) to the CTSU 
Regulatory Office: 
x 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site 
Information Form,  
x 
Qualified Investigator Undertaking Form, and  
x 
Research Ethics Board Attestation Form.  
5.5.4 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Oncology to receive approval to 
participate in this trial. (For studies involving PMB drug: Prior to granting approval, 
NRG Oncology will contact CTEP regarding drug availability and shipment. If CTEP 
approves, NRG Oncology will provide written approval and at that time the institution 
may seek approval from its local ethics committee). For more details see link below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx 
 
 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to 
enrolling patients to this study. 
 
5.6 
Registration   (12-APR-2018) 
5.6.1 
OPEN Registration Instructions 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://ctep 
core.nci.nih.gov/iam >) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type. 
 

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All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the database.  OPEN can be accessed at https://open.ctsu.org or from the OPEN 
tab on the CTSU members’ web site https://www.ctsu.org.  To assign an IVR or NPIVR as 
the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB 
number used on the site’s IRB approval. 
 
Prior to accessing OPEN site staff should verify the following: 
x 
All eligibility criteria have been met within the protocol stated timeframes.  
x 
All patients have signed an appropriate consent form and HIPPA authorization  
form (if applicable).  
 
NOTE: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' web site OPEN tab or 
within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-
823-5923 or ctsucontact@westat.com.  
 
6.0 
RADIATION THERAPY (5/12/16) 
(NOTE: Ph II-R Erlotinib randomization completed, Arm 2 closed to accrual effective 4/02/14) 
 
NOTE: This trial is not utilizing the services of the ITC for dosimetry digital treatment data 
submission. PRIOR TO ENROLLING PATIENTS, see Section 12.2 for information on 
installing TRIAD for submission of digital RT data  
 
Arm 3 
No RT 
Arm 4 
RT  
 
For ARM 4 ONLY: radiation therapy begins after 2nd step registration and post completion of 
additional adjuvant systemic therapy after RT randomization.  For those patients randomized to 
ARM 4, radiation therapy should begin not sooner than 7 days or later than 21 days post 
completion of additional adjuvant systemic therapy after RT randomization. 
 
 
Overview of Radiotherapy Process 
Be sure to adhere to all of the requirements included in Section 6 in its entirety. 
Due to the complexity of this protocol, the following overview is being provided.   
Note: All patients must be evaluated by radiation oncology prior to registration and enrollment on 
this protocol (see Section 3.1) 
a. 
Patients do not receive radiotherapy on this protocol until the completion of the first step 
adjuvant systemic therapy  
b.  
Only patients who started the 5th month of l adjuvant systemic therapy will be allowed to be 
randomized to Arm 4 and receive radiotherapy on this protocol. 
c.  
After completion of 5 months of adjuvant systemic therapy, (patients are re-imaged and 
evaluated to confirm the absence of progressive disease. If no progressive disease is 
found, patients are randomized to receive an additional month of protocol chemotherapy 
+/- radiotherapy (with fluoropyrimidine sensitization: Arm 3 or Arm 4). CA19-9 levels are 
not used as an indicator of progressive disease. 
d.  
Referral to radiotherapy for re-evaluation and treatment planning should be done within 7 
days of the RT randomization for patients randomized to Arm 4 in order to complete the 
pre-treatment review process as stated below. 
e.  
TIMELY (within 14 to 21 days after RT randomization) digital submission of treatment 
planning data (CT planning showing relevant targets, isodose lines, complete volumetric 
data set DVH)  via TRIAD is mandatory for Arm 4 ONLY. 

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f.  
Patient will not start radiotherapy until the treatment plan is REVIEWED and 
APPROVED. 
g.  
Radiotherapy must be administered by either 3D-CRT or IMRT technique.  
Please Note: The treating institution must be credentialed for the technique chosen 
(either 3D or IMRT) see Section 5. 
h.  
Daily IGRT is not required but is permitted.  
i.  
Motion management is not required, but is permitted. 
j.  
This is a one phase RT treatment. There is no “cone down” or “boost” allowed on this study. 
 
6.1 
Dose Specifications (3D conformal and IMRT) (5/23/11) 
 
The prescribed dose is 50.4 Gy in 28 fractions of 1.80 Gy. Treatment plans must be 
normalized such that 90% of the PTV receives 95% of this prescribed dose and 99% of the 
CTV is to receive 95% of the prescribed dose.  
 
The max and min allowed dose within the PTV are defined in table 6.1:  
 
TABLE 6.1 
Prescribed Dose (PD) 
 
 
Max Dose limit 
(defined for a point 
on DVH curve for 
PTV with a volume 
of 0.03 cm3 
Max Dose limit 
(defined for a point on 
DVH curve for PTV 
with a volume of 5.0 
cm3 
Min Dose limit (defined 
for a point on DVH 
curve for the PTV with 
98% coverage) 
 
50.4 Gy  
 
 
111% of PD = 55.9 
Gy 
 
105% of PD = 52.9 Gy 
 
90% of PD = 45.4 Gy 
Treatment plan normalization must cover 90% of the PTV with 95% of the PD or 47.9 Gy 
 
6.2 
Technical Factors 
A modern linear accelerator with 100cm SAD and > 6MV beam is required. Use of 
Tomotherapy is allowed. 
 
6.3 
Localization, Simulation, and Immobilization (3D Conformal and IMRT) (5/12/16) 
6.3.1 
Treatment Planning Simulation  
Patients will be simulated (and treated) supine with arms up. Immobilization is required. 
This can range from devices to assist in patient comfort up to alpha cradle or vacuum 
bag immobilization. Two leveling marks on the each patient's side (2 on the right and 2 
on the left) are required. 
 
A dedicated planning CT performed with the patient immobilized on a flat, non-curved, 
table and in the selected treatment position is required.   IV contrast for CT planning is 
strongly recommended. If IV contrast is not given at the time of simulation, it is necessary 
to have the images of the contrast enhanced, restaging abdominal CT performed after 
month 5 of chemotherapy readily available (or fused) with the simulation CT in order to 
permit accurate contouring of the portal vein (PV), celiac axis (CA), and superior 
mesenteric artery (SMA). 
 
Planning CT scan slice thickness must be no greater than 3 mm.  
 
6.4 
Treatment Volumes (3D Conformal and IMRT) (5/23/11) 
6.4.1 
GTV 
By definition there is no GTV within the patient at the time of radiotherapy in this study 
(GTV has been resected). However, location of the pancreatic tumor prior to resection 
should be reviewed, noted, and contoured based on the preoperative imaging (please 
see Section 6.4.2 below). 
6.4.2  
CTV 

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Conceptually, this post operative CTV is that area where there is likely to be the highest 
concentration of residual sub-clinical tumor that can be treated with radiotherapy without 
resulting in a treatment volume that encompasses an excessive amount of normal organs 
and normal tissue.  
 
In reviewing the following, please refer to the web based CT atlas which has been 
created for this purpose at www.rtog.org 
 
In order to approach this process logically, it is necessary to review the surgical 
and pathological information at the time of treatment planning and the availability 
of the pre-operative axial imaging is a necessity. Pre and post operative cross-
sectional images will be submitted along with the treatment plan. Please see 
Section 12 for submission link and specifics.  
 
The following should be identified and targeted as specific ROI’s.  
 
The most proximal 1.0-1.5 cm of the celiac artery(CA) and the most proximal 2.5 to 
3.0 cm of the superior mesenteric artery (SMA)  CA should include up to the first 
branching).  
 
Those portions of the portal vein (PV) that run slightly to the right of, in front of 
(anterior) and anteromedial to the inferior vena cava (IVC). These portions are all 
beneath (caudad to) the bifurcation of the PV into right and left branches as it runs 
toward the hepatic hilum and continue down to, but do not include, the PV confluence 
with either the SMV or Splenic Vein (SV). There is substantial anatomical variability 
from patient to patient with respect to the PV. Cephalad, sometimes the PV bifurcation 
occurs quite extrahepatically, and sometimes very close to intrahepatically. Similarly, 
caudally, the PV most often will merge first with the SMV, but may merge with the SV.  
 
The following approach is recommended for contouring the relevant parts of the PV: 
2.0 
Review the anatomical course of the PV from its cephalad extent to its caudal  extent, noting, 
but not including, the slices where it starts to bifurcate into R and L branches at its cephalad 
extent and where it starts to join either the SMV or SV caudally.  
3.0 
Starting from below, contour the PV from just above its junction with the SMV (or SV whichever 
is more cephalad) and proceed in the cephalad and lateral directions until the PV is directly 
anterior to the IVC. Continue contouring cephalad and laterally for approximately one to three 
additional slices (assuming 3 mm slices) until the first slice where the center of the PV width has 
moved past the right lateral edge of the IVC. Contour the PV on this slice and stop.  
 
The preoperative tumor (resected GTV)  
 
The pancreaticojejunostomy (PJ); the PJ usually is readily identified by following the 
pancreatic remnant medially and anteriorly until the junction with the jejunal loop is 
noted. 
 
The aorta from the most cephalad contour of either the celiac axis, PV, or PJ 
(whichever among these 3 is the most cephalad) to the bottom of the L2 vertebral 
body. If the GTV contour extends to or below the bottom of L2 then contour the aorta 
towards the bottom of the L3 vertebral body as needed to cover the region of the 
preoperative tumor location. 
 
Alternatively, there may be a pancreaticogastrostomy (PG). If there is a PG instead 
of a PJ, the PG is not included in defining the CTV. Delineating the PG may still be 
helpful for subsequent reference. 
 
Surgical Clips placed for purposes of delineating areas of concern intraoperatively 
such as close margins, uncinate margin, etc. The significance of surgically placed 
clips can vary quite a bit and in some cases may be irrelevant for treatment planning 
purposes. Surgically placed clips should only be included as an ROI if there is 
documentation in the operative note or other written documentation from the surgeon 
of clips placed for a specific tumor related, or planning related purpose. 
 

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Steps taken with the above to generate the CTV: 
- 
The celiac axis, SMA and PV ROI’s should be expanded by 1.0-1.5 cm in all 
directions. In most cases, 1.0 cm expansions will be sufficient. 
- 
The aortic ROI should be expanded asymmetrically to include the prevertebral 
nodal regions from the top of the PJ, PV, or CA (whichever is most superior) to the 
bottom of L2 (or L3 if GTV location low, see above section).  Suggested 
approximate expansion amounts for the aortic ROI are as follows: 2.5 to 3.0 cm to 
the right, 1.0 cm to the left, 2.0 to 2.5 cm anteriorly, 0.2 cm posteriorly.  The working 
concept for the lateral margins of this ROI is that one needs to cover the 
paravertebral nodes laterally but not include either kidney.  These expansions will  
require the use of clinical judgment. Occasionally,   the PJ or PV expansion may 
extend cephalad to above the level of the celiac axis. In that case the aortic 
expansion should be extended cephalad to the same level as the highest level (CT 
slice) of the PV or PJ expansion (whichever is more cephalad).  
- 
The PJ should be expanded 0.5-1.0 cm in all directions. 
- 
Delineated clips may be expanded by 0.5 – 1.0 cm in all directions or used without 
expansion. 
- 
The CTV should then be created by merging the above ROI/ROI expansions (CA, 
SMA, PV, GTV, Aortic, PJ, , clips) with the following constraints and notes: 
- 
The posterior margin should follow the contour of the anterior aspect of 
the vertebral body without actually including more than 0.10 cm of the 
anterior vertebral body anterior edge. 
- 
If the PJ cannot be identified, the CTV should be generated without it.  
- 
If the surgeon has created a pancreaticogastrostomy, do not include it into 
the CTV. 
- 
If the CTV with the noted expansions protrudes into a dose limited normal 
organ such as the liver or stomach, the CTV should be edited to be 
adjacent (may touch the edge of) the relevant structure. 
6.4.3 
PTV 
The PTV is established by expanding the CTV 0.5 cm in all directions. 
 
6.5 
Normal Organ Dose Volume Considerations (3D Conformal and IMRT) (5/12/16) 
6.5.1  
In addition to the ROI’s already discussed, some of which are also normal structures, the 
normal structures to be contoured are: left and right kidneys, liver, stomach, small 
intestine, and spinal canal.  Contour the kidneys, liver, and stomach in their entireties. 
Contour the small intestine from the jejunum to 2 cm below the lower extent of the CTV. 
Contour the spinal canal within the cranial-caudal extent of the CTV and 
inferiorly/caudally and superiorly/cranially as necessary to identify dose to the spinal cord 
resulting from either entrance dose or exit dose of any (every relevant) treatment beam.  
 
6.5.2 
Normal Tissue Dose-Volume Constraints Per Protocol  
 
Structure 
Constraints 
Kidney 
(L & R) 
D50% <18Gy (no more than 50% of each kidney can receive more than 
18Gy). Mean dose <18Gy.  If only one kidney is present, D15% ≤18Gy 
(no more 15% of the volume of that kidney can receive more than 18 Gy  
Liver 
Mean liver dose must be ≤ 25 Gy  
Stomach and 
Small intestine 
Max dose < 54Gy; D15% < 45Gy (no more than 15% of the organ can 
receive more than 45Gy) 
Spinal canal 
Max dose to a point that is 0.03 cm3 must be ≤ 45Gy 
 
Critical Structures 

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NOTE: All required structures must be labeled for digital RT data submission as 
listed in the table below.  Resubmission of data may be required if labeling of 
structures does not conform to the standard DICOM name listed. 
 
Standard Name 
Description 
 Preop_GTV 
Designation of the preoperative 
location of the GTV 
CVT_5040 
 
PTV_5040 
 
 Kidney_L 
Left Kidney 
 Kidney_R 
Right Kidney 
 Kidneys 
Both Kidneys 
 Liver 
Liver 
 SpinalCord 
Spinal Cord 
 Stomach 
Stomach 
 
 
 External 
External patient contour 
 SmallBowel 
Small Bowel 
 PancJejuno 
Pancreatic jejunostomy (used for 
CTV construction 
 PancJejuno_CTV 
Expansion for inclusion in CTV 
 V_Portal 
 
 V_Portal_CTV 
Expansion of Portal Vein for 
inclusion in CTV 
 A_Aorta 
Portion of Aorta to be included in 
Target 
 A_Aorta_CTV 
Expansion of Aorta for inclusion in 
CTV 
 A_SupMes 
Superior Mesenteric Artery to be 
included in Target 
 A_SupMes_CTV 
Expansion of Superior Mesenteric 
Artery for inclusion in CTV 
 A_Celiac 
Portion of Celiac Artery to be 
included in Target 
 A_Celiac_CTV 
Expansion of Celiac Artery for 
inclusion in CTV 
 
 
6.6 
3D Conformal Beam Arrangements 
Beam arrangement selection for 3D conformal treatment will vary based on the shape, 
size, and location of the CTV and the resulting PTV in relation to normal organs. The 
following sequences are suggested for consideration roughly in order of increasing 
complexity. Other approaches are possible. None of these arrangements has to be used 
exactly as described and appropriate selection of wedges, weighting, and blocking is 
presumed. Wedges should be considered for use in both axial and sagittal views based on 
contour variation, other beams, weighting, etc.  
6.6.1 
Coplanar 
 
AP/PA with Right and Left Lateral beams. 
 
AP/PA with one or both “laterals” slightly angled anteriorly (5-15 degrees to RAO, 
LAO). Although this does increase exit beam to the contralateral kidney in each case, 
the avoidance of entrance beam may result in a dosimetric advantage. 
 
RAO (330-350 deg), LAO (10 – 30), Right Lateral, Left Lateral, PA. This complex 5 
beam arrangement should be reserved for situations where less complex approaches 
do not give adequate kidney or other critical normal organ sparing. This approach can 
be further facilitated by setting the isocenter fairly anteriorly in the CTV. Because of 

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divergence, this minimizes the extent to which the PA field encompasses the kidney 
parenchyma. 
6.6.2 
Non-Coplanar 
Two laterals or very slightly anteriorly angled beams (one or both) with couch angle of 
zero. Inferior-Superior beam with couch angle of 90 degrees (or 270 degrees depending 
on patient orientation) with gantry angle of 20-25 degrees off vertical (warning gantry 
angles more than 25 degrees off vertical may pose a risk of gantry collision with patient 
torso), a lightly weighted posterior beam with a couch angle of 0 or a lightly weighted 
posterior beam with a couch rotation of 90 or 270 degrees and gantry rotation of 5-10 
degrees towards opposing the inferior superior beam may be helpful. 
 
6.7  
IMRT  
6.7.1 
Beam Arrangement (3/4/10) 
 
Using the International Electrotechnical Commission (IEC) coordinate system, the 
following beam arrangement is recommended and should be used as a default starting 
point for linear accelerator based IMRT. This arrangement results in optimal dose 
distribution in the vast majority of patients. The gantry angles are biased towards the 
anterior to limit the dose to the kidneys, while the non-coplanar beams limit the dose to 
the small intestines. Facing the gantry, a 90° couch angle places the patient’s feet 
towards the left of the gantry. 
 
Couch Angle 
Gantry Angle 
0 
350 
0 
90 
0 
30 
0 
310 
90 
20 
90 
330 
 
 
6.8 
Field verification  
6.8.1 
3D Conformal Treatment and IMRT 
As a minimum requirement, institutions are required to obtain verification images at the 
start of treatment and each week thereafter. Prior to the first treatment images that verify 
the position of the isocenter placement must be obtained.  For 3D-CRT this imaging can 
include individual portal views. Weekly imaging can consist of portal views for 3D-CRT 
and isocenter verification images.   For IMRT orthogonal images verifying isocenter 
position are required.  More frequent (daily) imaging is allowed, but is not required. 
 
6.9 
Documentation Requirements (2/19/14) 
6.9.1 
Digital Submission of RT Planning Data 
 
For ARM 4 ONLY: radiation therapy begins after 2nd step registration and post 
completion of additional adjuvant systemic therapy.  For those patients 
randomized to ARM 4, radiation therapy should begin not sooner than 7 days 
or later than 21 days post completion of additional adjuvant systemic therapy 
after RT randomization. 
 Submit via TRIAD (Image Guided Therapy Center) within 14 to 21 days from RT 
randomization for review and APPROVAL prior to start of RT. The treatment planning 
data includes simulation images with isodose lines, structure set, and dose volume 
histograms. (See Section 12.2 for data submission specifics) 
 
All RT plans will be digitally submitted via TRIAD for pre treatment review and 
APPROVAL between 14 to 21 days from RT randomization. Review and feedback to 
institutions will be provided within 3 business days of this submission. Feedback will 
indicate either that the plan is acceptable as submitted or requires specific 

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modification and resubmission as outlined. RT treatment will not be started until RT 
plan is APPROVED. Plans requiring modification will be resubmitted within 4 business 
days for re-review and approval. If a second review is required, approval will be 
provided within 3 business days.   
 
RT plan submission is recommended as early as possible to avoid delays in RT 
treatment start. The following table is provided: 
 
FOR ARM 4 
ONLY:  
Within 14 to 21  
business days 
after RT step 
randomization 
Within 3 
business days  
from receipt at 
IROC 
Philadelphia 
* Within 3-4 
business days 
from RT plan 
review 
* Within  3 
business days of 
resubmission of 
RT plan 
 
 
Submit RT plan 
digitally via TRIAD 
for review 
 
Feedback from 
review for 
resubmission of 
RT plan OR 
APPROVAL of 
RT plan 
 
If required, 
resubmission of 
RT plan 
 
Feedback from 
RT review and 
approval of RT 
plan: begin RT  
 
* These steps will be repeated if necessary for RT plan approval. 
6.9.2 
Treatment Interruptions 
Treatment interruptions should be clearly documented in the patient’s medical record. If 
the sum total exceeds 10 normally scheduled treatment days, the treatment will be 
considered a deviation unacceptable. 1-4 days of scheduled treatment day interruptions 
will be considered per protocol. 5-9 days interruption will be considered a variation 
acceptable. 
 
6.10 
Compliance Criteria for Both IMRT and 3D Conformal (5/23/11) 
It is anticipated that almost all variations will be eliminated by the prospective review 
process. Nevertheless, criteria for judging any variations actually treated are 
provided.  
6.10.1 
Volume Definitions 
 
Variation Acceptable 
Any variation in contouring of the CTV or PTV which in the opinion of the reviewers 
does not result in a deviation unacceptable in dose volume coverage of the correct 
CTV or PTV. 
Any variation in the contouring of a normal organ ROI which in the opinion of the 
reviewers does not result in a deviation unacceptable   in dose volume coverage of 
the correct or actual ROI. 
 
Deviation Unacceptable 
The difficulty that results from an incorrectly delineated CTV, PTV or normal organ 
ROI relates to whether the dose volume criteria (minimal acceptable coverage) for the 
correctly delineated CTV, PTV are still respected and for the normal organ ROI’s 
whether the resulting dose volume relationships are felt to represent an unacceptable 
risk of organ dysfunction. 
6.10.2 
Per Protocol for Target Structures 
 
Doses to PTV and CTV (Per Protocol Limits) 
 
Acceptable PTV and CTV doses:  All plans must be normalized so that 90% of the 
PTV receives at least 95% of the prescription dose and at least 99% of the CTV 
receive  95% of the prescribed dose of 50.4 Gy (= 47.9 Gy). 
 
The Per Protocol statement of the maximum and minimum dose to an additional 
point that is 5 cm in size falling within the PTV is given in Table 6.1 The following 

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Table 6.2 shows the maximum and minimum  dose defining an acceptable deviation 
from the per protocol limits:  
 
TABLE 6.2 -Variation Acceptable Dose Limits 
Prescribed Dose (PD) 
 
 
Max Dose limit 
(defined for a point 
on DVH curve for 
PTV with a volume 
of 0.03 cm3 
Max Dose limit 
(defined for a point on 
DVH curve for PTV 
with a volume of 5.0 
cm3 
Min Dose limit (defined 
for a point on DVH 
curve for the PTV with 
98% coverage) 
 
50.4 Gy  
 
 
115% of PD = 58.0 
Gy 
 
107% of PD = 53.9 Gy 
 
88% of PD = 44.4 Gy 
 
 
Deviation Unacceptable: Any deviation worse than the values for the PTV given in 
table 6.2 above are scored as deviation unacceptable 
 
6.10.3 
Organs at Risk Dose Limits 
Critical Structure Variation Acceptable  
Structure 
Constraints 
Kidney 
(L & R) 
D50% ≤ 20Gy (no more than 50% of each kidney can receive 
more than 20Gy).  Mean dose ≤ 20Gy. If only one kidney is 
present, D15% ≤ 20Gy (no more 15% of the volume of that 
kidney can receive more than 20 Gy 
Liver 
Mean liver dose must be ≤ 30 Gy  
Stomach and 
SmallBowel  
Max dose < 56 Gy; D15% < 50Gy (no more than 15% of the 
organ can receive more than 50Gy) 
SpinalCord  
Max dose to a point that is 0.03 cm3 must be <  50Gy 
 
6.10.4 
Deviation Unacceptable: Any Structure doses which do not meet the constraints listed 
above will be considered a Deviation Unacceptable. 
 
6.11 
R.T. Quality Assurance Reviews (5/12/16) 
Plans requiring modification will be resubmitted within 3 business days for re-review and 
approval. It is expected that with this process no plan utilized will have worse than 
acceptable variation and most plans will meet specified requirements for PTV and normal 
organs and dose maxima. 
 
During this period, radiation treatment plans will be required to be prospectively reviewed 
by senior NRG Oncology radiation oncologists. 
 
 
6.12 
Radiation Therapy Adverse Events 
See Section 7.8.3.   
 
6.13 
Radiation Therapy Adverse Event Reporting  
 
See Sections 7.10 and 7.11 for reporting requirements. 
 
7.0 
DRUG THERAPY  
 
7.1 
First Step: Adjuvant Systemic Treatment (5/12/16) 
7.1.1 
For patients entering on the study who have not received any protocol chemotherapy, 
chemotherapy must start within 7 days after registration and must be administered within 
72 hours (+/- 3 days) of the scheduled date for these therapies.  

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For patients entering on the study who have already received up to 3 months of adjuvant 
chemotherapy, as per the treating institution, with the plan to receive a total of 5 months 
of adjuvant chemotherapy prior to Step 2 randomization, and have received either single-
agent chemotherapy or combination chemotherapy that includes gemcitabine, nab-
paclitaxel, oxaliplatin, fluoropyrimidine, or irinotecan, the subsequent month of 
chemotherapy should begin within 14 days of step 1 registration. (Step 1 registration 
must occur prior to the start of the fourth month of adjuvant therapy.) 
 
ARM 1 
Gemcitabine or allowable 
combination chemotherapy 
Delivered per institutional standard for a total of 
5 months  
 
Note: Chemotherapy may be initiated prior to 
registration- refer to Sections 3.2.3. 
 
 
ARM 2 (NOTE: Ph II-R Erlotinib randomization completed, Arm 2 closed to accrual 
effective 4/02/14). Patients randomized to erlotinib prior to 4/02/14 will continue 
erlotinib treatment per the protocol. 
Gemcitabine 
1000mg/m2/week, IV over 30 minutes,  once a 
week for 3 weeks then off 1 week x 5 cycles 
Erlotinib 
100mg/ po/day X 5 cycles until CT/MRI 
evaluation for progression.  Patients without 
progression will continue erlotinib po daily to 
second randomization treatment. 
 
7.1.2  
Patients must start the 5th month of chemotherapy to be eligible for the RT randomization. 
2nd step registration must be completed for patients with progressive disease by 
radiographic studies after adjuvant systemic treatment is completed; however, these 
patients will not be randomized to further treatment. Elevation of CA19-9 in the absence 
of radiographic progression will not be considered disease progression. 
 
7.2 
Second Step: RT Randomization Treatment: (5/12/16) 
Referral to radiotherapy for re-evaluation and treatment planning should be done within 7 
days of the RT randomization for patients randomized to Arm 4 in order to complete the 
pre-treatment review process as stated in Section 6. 
7.2.1 
Randomization after CT/MRI performed after the 5th month of chemotherapy.  
7.2.2 
Initiation of the 6th month for Arms 3 and 4 (6th month of systemic treatment) must occur 
within 4 weeks of the completion of the 5th month of chemotherapy  and must be 
administered within 72 hours (+/- 3 days) of the scheduled date for these therapies.  
 
ARM 3 
Gemcitabine or allowable  
combination chemotherapy  
1 month identical to the adjuvant systemic 
treatment 
 
    
   ARM 4 
Gemcitabine or allowable  
combination chemotherapy  
1 month identical to the adjuvant systemic 
treatment 
 
Follow with RT and    
 
To start within 21 days after the  last dose of 
chemotherapy  

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43 
5FU or Capecitabine 
Either 5FU 250mg/m2/day, 7 days per week by 
a continuous IV infusion via an outpatient 
infusion pump or  
capecitabine 825mg/m2/po BID M-F  
Both starting on day 1 of RT for 5 ½ weeks or 
until RT completed  
 
  
7.3 
Erlotinib (OSI-774, Tarceva) NSC#718781(5/12/16) 
To supplement the toxicity information contained in this document, investigators must obtain the 
current version of the investigator brochure for comprehensive pharmacologic and safety 
information.  For instructions on obtaining the Investigator Brochure, see Section 7.3.10.  
7.3.1 
Formulation  
Erlotinib is available in 25 mg, 100 mg, and 150 mg white film-coated immediate-release 
tablets packaged in high-density polyethylene (HDPE) bottle. (A 50 mg tablet is not 
available.) Each bottle contains 30 tablets. The tablets are round and convex without 
markings.  The 25 mg tablets are 1/4 inches (6 mm); the 100 mg tablets are 11/32 inches 
(9 mm); and the 150 mg tablets are 13/32 inches (10 mm). OSI-774 excipients include 
lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl 
sulfate, and magnesium stearate. 
7.3.2  
Storage and Stability 
Store the intact HDPE bottles at controlled room temperature, not above 25°C (77°F). 
There is no need to refrigerate the tablets. Current data indicates OSI-774 is stable for 
at least 3 years at room temperature.  
7.3.3 
Administration 
Erlotinib will be taken as a single daily dose on an empty stomach one hour before or 
two hours after meals. Prior to starting treatment, the patient will be provided with and 
instructed in the proper use of a pill diary (see Appendix IX for an example) or a calendar 
to record their daily pill consumption. This record will be checked for compliance by the 
investigator. The diary will be retained in the patient’s record for submission to NRG 
Oncology ONLY upon request; i.e., diaries are not to be submitted but will be retained at 
the site as source documents. Patients who are non-compliant must be re-instructed in 
the use of the diary.  
7.3.4 
Drug Interactions 
Erlotinib is highly protein bound (92% to 95% in humans) and metabolizes primarily via 
CYP3A4 enzymes.  Dose erlotinib cautiously with agents that are highly protein bound 
or potent CYP3A4 inhibitors/inducers enzymes.   
 
Proton Pump Inhibitor 
Erlotinib’s solubility decreases as the pH increases. Co-administration of omeprazole 
with erlotinib will decrease the AUC and Cmax by 46% and 61%, respectively.  
 
H2-antagonist 
Avoid concomitant use of erlotinib with gastric acid reducing agents if possible.  When 
ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax  decrease by 33% and 
54%, respectively.  Increasing the dose of erlotinib will not compensate the loss of 
exposure.  However, if an H2-antagonist receptor is needed, take erlotinib at least 2 
hours before or 10 hours following the H2-antagonist administration.  Dosing such, 
erlotinib loss of exposure is minimized to AUC of 15% and Cmax of 17%. 
 
Anticoagulants 
Concomitant NSAIDs, warfarin or warfarin-derivatives may increase bleeding and PT 
/INR. Dose adjustment may be needed. 
 
Altered coagulation parameters and bleeding have been reported in patients receiving 
erlotinib alone and in combination with other chemotherapeutic agents and 
concomitant warfarin-derivative anticoagulants.  The mechanism for these alterations 
is still unknown.  When warfarin is co-administered with erlotinib (anytime after Day 

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44 
5), international normalized ratio (INR), and prothrombin time should be closely 
monitored and the anticoagulant dose should be adjusted as clinically indicated. 
7.3.5 
Food-Drug Interaction 
Grapefruit juice is a CYP3A4 inhibitor that interferes with the metabolism of erlotinib.  
Therefore, consumption of grapefruit or grapefruit juice should be avoided during 
erlotinib treatment. 
7.3.6 
Smoking 
Advise smokers to stop smoking while on erlotinib.  Smoking induces CYP1A2 enzymes 
and alters erlotinib exposure by 64%.  
7.3.7 
Adverse Events 
 
Gastrointestinal Perforation 
Patients receiving erlotinib are at increased risk of developing gastrointestinal 
perforation, which was observed infrequently.  Some cases had a fatal outcome.  
Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, 
and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or 
diverticular disease, are at increased risk.  Erlotinib should be permanently 
discontinued in patients who develop gastrointestinal perforation. 
 
Bullous and Exfoliative Skin Disorders 
Bullous, blistering and exfoliative skin conditions have been reported, including very 
rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, 
which in some cases were fatal.  Erlotinib treatment should be interrupted or 
discontinued if the patient develops severe bullous, blistering, or exfoliating 
conditions. 
 
Ocular Disorders 
Very rare cases of corneal perforation or ulceration have been reported during use of 
erlotinib. 
 
Other 
ocular 
disorders 
including 
abnormal 
eyelash 
growth, 
keratoconjunctivitis sicca or keratitis have been observed with erlotinib treatment and 
are known risk factors for corneal perforation/ulceration.  Erlotinib therapy should be 
interrupted or discontinued if patients present with acute/worsening ocular disorders 
such as eye pain. 
 
 
Comprehensive Adverse Events and Potential Risks  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
OSI-774 (erlotinib, NSC 718781) 
 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited , July Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 3622 patients.  Below is the CAEPR for OSI-774 (erlotinib). 

RTOG 0848 
 
 
 
 
 
 
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45 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.4, July 24, 20131 
 
 Adverse Events with Possible  
 Relationship to OSI-774 (erlotinib) 
 (CTCAE 4.0 Term) 
[n= 3622] 
 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
(formerly known as ASAEL) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
EYE DISORDERS 
  
 
Conjunctivitis 
 
 Conjunctivitis (Gr 2) 
 
Dry eye 
 
 Dry eye (Gr 2) 
 
Eye disorders - Other (eyelash 
in-growth and/or thickening) 
 
  
 
 
Eye disorders - Other (corneal 
perforation) 
  
 
 
Keratitis 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
 
Gastrointestinal perforation3 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Skin infection4 
 
 Skin infection4 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased 
(Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 

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46 
 
 
Intracranial hemorrhage 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  
 
Pneumonitis 
 
 Pneumonitis (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
Nail loss 
 
 Nail loss (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Includes infection of the skin (folliculitis or cellulitis) as complications of rash. 
 
 
Also reported on OSI-774 (erlotinib) trials but with the relationship to OSI-774 (erlotinib) still 
undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation 
EYE DISORDERS - Blurred vision; Eye disorders - Other (orbital cellulitis); Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Colitis; Constipation; Duodenal ulcer; Dysphagia; Esophagitis; 
Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (pneumatosis intestinalis); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
HEPATOBILIARY DISORDERS - Cholecystitis 
INVESTIGATIONS - Creatinine increased; INR increased (in patients taking Coumadin); Lymphocyte 
count decreased; Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS - Dizziness; Ischemia cerebrovascular; Peripheral sensory 
neuropathy 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 

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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Pharyngolaryngeal pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Urticaria 
VASCULAR DISORDERS - Thromboembolic event 
 
 
Note: OSI-774 (erlotinib) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Note:  OSI-774 (erlotinib)-induced diarrhea and/or vomiting has been associated with dehydration, 
hyperkalemia; hypocalcemia; hypokalemia; hypomagnesemia; hyponatremia; hypophosphatemia, 
increased creatinine, and renal failure. 
 
Note:  Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during 
use of OSI-774 (erlotinib) in patients with baseline hepatic impairment.   
 
7.3.8 
Supply 
Erlotinib will be supplied free of charge for this study by NCI.  
Drug provided free of charge as part of a research protocol must be used only for the 
intended study. It is the responsibility of the Investigator to ensure the 
provided/investigational product is only dispensed to eligible study patients 
7.3.9 
Accountability 
Drug accountability records must be maintained at all sites according to good clinical 
practices and NCI guidelines. 
 
Accountability and Supply 
 
This study will be conducted under an NCI/Pharmaceutical Management Branch 
(PMB) IND. The study agent erlotinib and the associated Investigator Brochure will be 
provided by PMB. 
 
The Principal Investigator (or authorized designee listed by the Investigator on the 
site’s most recent Supplemental Investigator Data Form [IDF] on file with the PMB) at 
each participating institution may request erlotinib from NCI’s Pharmaceutical 
Management Branch (PMB). The updated version (11/10/03) of each institution’s 
Drug Authorization Review and Tracking System (DARTS) will require selecting a 
designee from the individuals listed on the IDF. The information on the IDF is linked 
to the Investigator during the annual Investigator registration process. This process 
must be completed before a drug order can be entered for that investigator. Any 
changes to this information will require updating the first two pages of the IDF, having 
the Investigator sign the revised IDF, and returning it to the PMB via fax at 240-276-
7893. Questions about the process should be directed to the PMB at 240-276-6575. 
Monday through Friday from 8:30 am–4:30 pm Eastern Time. PMB policy requires 
that drug be shipped directly to the institution where the patient is to be treated.   
 
PMB does not permit the transfer of agents between institutions unless prior approval 
from PMB is obtained. Active CTEP-registered investigators and investigator-
designated shipping designees and ordering designees must submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application. Access to the 
OAOP application and the associated training guide is available at the following link: 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account  
< https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an "active" account 
status and a "current" password.  
For questions about drug orders, transfers, returns, or accountability, call  240-276-
6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or e-mail 
PMBAfterHours@mail.nih.gov anytime. 

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48 
7.3.10 
Investigator Brochure 
The Investigator Brochure (IB), if available, for this drug will be supplied by the PMB/NCI. 
All 
requests 
for 
IBs 
should 
be 
e-mailed 
to 
ibcoordinator@mail.nih.gov 
<mailto:ibcoordinator@mail.nih.gov> or the IB Coordinator may be contacted at 240-
276-6575. .  Please refer to the Pharmaceutical Management Branch, CTEP, DCTD, NCI 
“Policy and Guidelines for Investigational Agent Distribution” at the following link:  
http://www.rtog.org/ResearchAssociates/QualityControlSiteAudits/PMBPolicy.aspx. 
NRG Oncology applies these policies to all provided drug. 
 
7.4 
Gemcitabine HCl (5/12/16) 
Please refer to the current FDA-approved package insert provided with each drug and the site-
specific pharmacy for toxicity information and instructions for drug preparation, handling, and 
storage. 
 
Supply 
Gemcitabine is commercially available. The use of drug(s) or combination of drugs in this protocol 
meet the criteria described under Title 21 CFR 312.2(b) for IND exemption 
 
7.5 
Capecitabine (5/12/16) 
Please refer to the current FDA-approved package insert provided with each drug and the site-
specific pharmacy for toxicity information and instructions for drug preparation, handling, and 
storage. 
 
Supply 
Capecitabine is commercially available. The use of drug(s) or combination of drugs in this protocol 
meet the criteria described under Title 21 CFR 312.2(b) for IND exemption 
 
7.6 
Fluorouracil (5/12/16)  
Please refer to the current FDA-approved package insert provided with each drug and the site-
specific pharmacy for toxicity information and instructions for drug preparation, handling, and 
storage.  
 
Supply 
Commercially available. The use of drug(s) or combination of drugs in this protocol meet the criteria 
described under Title 21 CFR 312.2(b) for IND exemption 
 
7.7 
Non-Canadian International Institutions: 
 
Please refer to your LOI Approval Notification. Your institution will be responsible for 
acquiring any drug noted in the protocol as commercially available and not provided for the 
study. Before drug can be provided your institution must comply with all pre-registration 
requirements and certifications and provide all necessary documentation listed in your LOI 
Approval Notification document. 
 

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49 
7.8 
Dose Modifications (5/12/16) 
7.8.1 
Dose Modifications for Erlotinib 
NOTE:(Ph II-R Erlotinib randomization completed, Arm 2 closed to accrual effective  4/02/14) 
 
 
Dose Levels 
 
Full dose     
100 mg/day 
 
Dose level -1 
 75 mg/day 
 
Dose level -2*  50 mg/day 
 
* 
Patients who require more than two dose reductions will be removed permanently from 
erlotinib treatment. 
 
 
Dose Modification Guidelines Table – Erlotinib 
 
Toxicity 
Grade 
Erlotinib dosage 
modification 
Guideline for management 
Keratitis 
1 
None 
No intervention 
2 (if < 14 
days) 
None** 
Preservative-free artificial tears, 
ointments, and/or other therapies as 
clinically indicated, with a follow-up 
examination within 2 weeks 
2 (if >14 
days) 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
> 3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
Diarrhea  
1 
None 
No intervention 
2 
None ** 
Loperamide (4 mg at first onset, 
followed by 2 mg every 2–4 hrs until 
diarrhea free for 12 hrs) 
> 3 
(despite 
optimal 
use of 
loperamid
e) 
Hold until recovery to < 
grade 1  
And then 
Reduce 1 dose level 
Rash 
1 
None 
No intervention 
2 
None ** 
Any of the following: minocycline+, 
topical tetracycline or clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral prednisone 
(short course) 
> 3 
Hold until recovery to < 
grade 1 
And then 
Reduce 1 dose level 
Bilirubin 
 
≥3 x ULN 
 
Hold until grade ≤2  
And then 
Reduce 1 dose level 
 
Liver 
transaminase 
> 5 x 
ULN 
Hold until grade ≤2  
And then 
Reduce 1 dose level 
 

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50 
Signs and symptoms of 
Interstitial Pneumonitis 
Hold pending diagnosis 
Permanently discontinue 
if diagnosis is confirmed 
and considered possibly 
related to OSI-774 
Patient should be thoroughly 
evaluated, closely monitored, and 
supported as clinically indicated. 
Other 
Toxicity 
> 2 prolonged 
clinically 
significant toxicity 
Hold until recovery to 
<grade 1 
And then 
Reduce 1 dose level* 
Treatment as appropriate 
**if dose has been previously held for grade 2 rash or diarrhea, and grade 2 symptoms recur, OR if the 
patient finds the symptoms unacceptable, hold dose until recovery to < grade 1 and then reduce dose one 
level 
+recommended dose: 200mg po bid (loading dose), followed by 100mg po bid for 7-10 days 
 
 
Additional Information for Erlotinib 
GI perforation: In the event of bowel perforation, patient should be removed from erlotinib 
therapy. 
Ocular AEs: Erlotinib should be interrupted for acute/worsening eye pain and should be 
discontinued in patients with persistent inflammation or severe eye surface damage. 
 
7.8.2 
Dose Modifications for Fluorouracil or Capecitabine and Radiation  
 
   
   Hematologic Toxicity 
 
Parameter 
Treatment 
Dose Modification 
ANC > 1000 and  
platelets > 75,000 
Fluorouracil 
Capecitabine 
No dose modification 
ANC 500-999 and/or  
platelets 50,000-75,000 
Fluorouracil 
Capecitabine 
Radiation 
Continue radiation. Hold fluorouracil 
or capecitabine until ANC > 1000 and 
platelets > 75,000, then resume at 
permanent 25% dose reduction.  
ANC < 500 and/or 
Platelets < 50,000 
Fluorouracil 
Capecitabine 
Radiation 
Hold fluorouracil or capecitabine and 
radiation until ANC > 1000 and 
platelets > 75,000 then resume 
radiation and restart fluorouracil or 
capecitabine at permanent 25% 
dose reduction. 
NOTE: Patients who have required two dose reductions and who experience a third episode of 
ANC < 1000 and platelets < 75,000 will complete radiation and but will not receive additional 
fluorouracil or capecitabine  
 
 
Non-Hematologic Toxicity 
 
Only toxicities related to treatment require dose modifications. For patients experiencing adverse 
events unrelated to treatment (such as deep venous thrombosis, pulmonary embolus or non-
neutropenic infection), when treatment is resumed after recovery from these adverse events, no 
dose modifications are required.  
Parameters 
Treatment 
Dose Modification 
Grade 3 or 4 AE,  
1st occurrence 
Fluorouracil 
Capecitabine 
Radiation 
Hold fluorouracil or capecitabine and 
radiation until toxicity has resolved to 
≤ grade 2, then resume radiation and 
fluorouracil or capecitabine with a 
permanent 25% dose reduction  
Grade 3 or 4 AE,  
2nd occurrence 
Fluorouracil 
Capecitabine  
Radiation  
Hold fluorouracil or capecitabine and 
radiation until toxicity has resolved to 
≤ grade 2, then resume radiation and 

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51 
fluorouracil or capecitabine with a 
permanent 25% dose reduction  
Grade 3 or 4 AE,  
3rd occurrence 
Fluorouracil  
Capecitabine 
Radiation 
Hold fluorouracil or capecitabine and 
radiation until toxicity has resolved to 
≤ grade 2, then resume radiation and 
fluorouracil or capecitabine with a 
permanent 25% dose reduction  
Grade 3 or 4 AE,  
4th occurrence  
or Grade 3 or 4 AE that persists 
for > 4weeks 
Fluorouracil  
Capecitabine 
Radiation 
Discontinue 
fluorouracil 
or 
capecitabine 
and 
radiation 
permanently 
Grade 2 Hand/Foot Syndrome 
Capecitabine 
Hold until resolves to ≤ grade 1, then 
resume at permanent 25% dose 
reduction 
Grade 3 Hand/Foot Syndrome 
Capecitabine 
Hold until resolves to ≤ grade 1, then 
resume at permanent 50% dose 
reduction 
 
7.9 
Modality Review (5/12/16) 
 
The medical oncology co-chairs will perform a Chemotherapy Assurance Review of all 
patients who receive or are to receive chemotherapy for the gemcitabine versus 
gemcitabine plus erlotinib research question in this trial.  Drs. Safran and Philip, will perform 
chemotherapy reviews. The goal of the review is to evaluate protocol compliance.  The 
review process is contingent on timely submission of chemotherapy treatment data as 
specified in Section 12.1. The scoring mechanism is: Per Protocol/Acceptable Variation, 
Not Per Protocol, and Not Evaluable.  A report is sent to each institution once per year 
to notify the institution about compliance for each case reviewed in that year. 
   
 
The medical oncology co-chairs will perform a Quality Assurance Review after complete 
data for the first 50 cases enrolled has been received at NRG Oncology. The medical 
oncology co-chairs will perform the next review after complete data for each of the next 
100 cases enrolled has been received at NRG Oncology. The final cases will be reviewed 
within 3 months after this study has reached the target accrual or as soon as complete data 
for all cases enrolled has been received at NRG Oncology, whichever occurs first. Medical 
oncology reviews need to be completed prior to presenting/publishing the primary endpoint 
results. 
 
7.10 
Adverse Events (12-APR-2018) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for 
all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized 
for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will 
continue to use CTCAE version 4.0. All appropriate treatment areas should have access 
to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web 
site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below 
will be reported via the CTEP-AERS (CTEP Adverse Event Reporting System) 
application accessed via the CTEP web site https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613     
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet 
connectivity is restored, an AE report submitted by phone must be entered electronically 
into CTEP-AERS. 
 

RTOG 0848 
 
 
 
 
 
 
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52 
7.10.1 
Adverse Events (AEs)  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product (attribution 
of unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements. February 29, 2012; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.ht
m] 
7.10.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet 
expedited reporting criteria defined in the table in section 7.11 will be reported via CTEP-
AERS.  SAEs that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table in section 7.11.  Contact the CTEP-AERS Help Desk if assistance is 
required 
 
 
Definition of an SAE: Any adverse drug even (experience) occurring at any dose that 
results in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect  
 
Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE, when, based upon medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner  
 
7.10.3 
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system within 30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  

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53 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 
7.11 
CTEP-AERS Expedited Reporting Requirements (5/12/16) 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting table below 
will be reported via CTEP-AERS, the Adverse Event Expedited Reporting System, accessed via 
the CTEP web site  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613     
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 1-
800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, 
an AE report submitted by phone must be entered electronically into CTEP-AERS. 
 
x 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
x 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies an CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to both the NCI at 301-230-0159 and the NRG Oncology 
dedicated SAE FAX, 215-717-0990. 
x 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS System as “expedited reporting NOT required” must still 
be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS System allows submission of all reports regardless 
of the results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 trials as described in the table 
below. Important: All AEs reported via CTEP-AERS also must be reported on the AE section of 
the appropriate case report form (see Section 12.1). 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 (Arm 2) 

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54 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 

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55 
 
 
Any Phase Study Utilizing a Commercial Agent1 (Arms 1 and 3) 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
 
Any Phase Study Utilizing Radiation Therapy (including chemoRT studies)1 (Arm 4) 

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56 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalizatio
n 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 3 adverse events 
 
 
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND: 

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57 
Exceptions to CTEP-AERS Reporting: These events are common and known to be associated 
the protocol regimen, and should not require expedited reporting (in addition to routine reporting 
through case report forms).   
a) Grade 3 N/V/D without or with hospitalization; and 
b) G3-4 myelosuppression with or without hospitalization 
 
7.12 
CRADA  
NCI/DCTD Standard Language for an Agent Covered by a Collaborative Agreement with 
NCI 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of 
Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in 
addition to the provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by 
a patient or patient’s family member participating on the study, the individual should sign 
a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of different 
collaborative agreements , the access to and use of data by each Collaborator shall be 
as follows (data pertaining to such combination use shall hereinafter be referred to as 
"Multi-Party Data.”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order. 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 

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58 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal investigator 
for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual 
property rights, are protected.  Copies of abstracts must be provided to CTEP for 
forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 
8.0 
SURGERY   
8.1  
Surgical Quality Assurance Reviews 
A full surgical quality assurance review is required for this study. The review will be 
performed by the Surgical Oncology Co-Chair, Adam Berger, M.D., after complete data for 
50 cases have been received at NRG Oncology. Dr. Berger will then perform the next 
reviews on a quarterly basis when complete data has been received at NRG Oncology.  
 
8.2 
General Considerations 
In resected pancreatic cancer, the presence of gross or microscopic tumor at the surgical 
margin has been associated with poor survival following pancreaticoduodenectomy. Of 
particular concern is the fact that few studies, including most randomized controlled trials 
have failed to require precise documentation of margin status or information as to how the 
pathologic margins were assessed. Given that adjuvant therapy, chemoradiation in 
particular is designed to impact the risk of local recurrence and that such therapies are less 
effective in the presence of positive margins, the omission of information about surgical 
margin status makes interpretation of treatment efficacy extremely difficult. For the current 
study, documentation of surgical margins will be mandatory. Only patients with negative 
microscopic margins (R0) or those with gross negative and microscopically positive 
margins (R1) will be enrolled. R0 versus R1 status will serve as a stratification criterion.  
 

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59 
In pancreaticoduodenectomy, there are three surgical margins of interest; 1) the common 
bile duct, 2) the pancreatic parenchymal margin and 3) the retroperitoneal margin- or that 
soft tissue abutting the proximal 3-4 cm of the superior mesenteric artery (SMA). It is the 
status of the retroperitoneal margin that is often poorly documented both by the operating 
surgeon and pathologist alike and it is the most commonly positive margin following 
pancreaticoduodenectomy. Only the operating surgeon can differentiate the difference 
between an R1 and an R2 resection as the pathologist cannot determine if gross disease 
has been left attached to the SMA. Therefore, for trial inclusion, it is required that the 
operating surgeon document the presence or absence of gross disease at the SMA. This 
should be documented either as part of the operative note or within the RTOG 0848 
Surgery Document. Finally, statement of the status of all three surgical margins be 
specifically detailed in the pathology report.  
8.2.1 
Specific Requirements 
Either classic (Whipple) or pylorus-preserving pancreaticoduodenectomy should be 
performed. The retroperitoneal dissection along the medial edge of the uncinate process 
and the right lateral border of the superior mesenteric artery (SMA) is an important 
oncologic portion of pancreaticoduodenectomy.  All soft tissue to the right of the SMA 
should be removed (and documented in the operative report).  This requires exposure 
and dissection along the right lateral border of the SMA. 
 
8.3 
Resection Classification and Operative Note Dictation 
The attending surgeon should have dictated the operative note and complete the RTOG 
0848 Surgery Document (Appendix IV). The surgical form should be filled out in 
conjunction with the operating surgeon in order to document the status of the margins 
and whether there was any gross residual disease.  
 
Ideally, the operative report should contain: 
 
A section describing the operative findings including the site and anatomy of the 
primary tumor.   
 
A statement as to whether or not the surgeon believes there is macroscopic 
residual tumor.  
 
Ideally, the results of the final microscopic surgical margins from the finalized pathology 
report should be incorporated into the final dictated and edited operative report. 
 
The definitions for the resection classification that should be utilized in operative notes 
include: 
x 
R0: macroscopically complete removal with negative microscopic margins (bile 
duct, pancreatic parenchyma, and SMA margins). 
x 
R1: macroscopically complete removal with any microscopically positive surgical 
margin (bile duct, pancreatic parenchyma, or SMA margins). 
x 
R2: macroscopically incomplete tumor removal with known or suspected gross 
residual disease.  
 
8.4 
Surgical Pathology 
If resection (R status) and margin status cannot be determined from the operative 
dictation or the pathology report, the patient will be ineligible for this protocol.  
8.4.1 
Pathology Review  
 
Local Pathology Review of the Resected Pancreatic Tumor 
Pathologic examination of the resected pancreatic tumor specimen should be carried 
out by a local surgical pathologist with experience in the diagnosis of pancreatic 
adenocarcinoma.  
 
All relevant margins (SMA, pancreatic, and bile duct) should be identified and inked 
by the surgeon and pathologist at the time of specimen removal.  Any segment of a 
resected vessel should also be identified and marked.  The SMA margin should be 

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60 
separately inked according to the procedures as set out in the 6th edition of the AJCC 
staging system and the College of American Pathologists (CAPS) guidelines for 
reporting of resected exocrine pancreatic cancer (2005—see Appendix IV).  
 
Final Pathology Report  
The pathology report must contain all of the elements as outlined in the CAPS 
guidelines (Appendix IV).  In particular, there should be comment on the following: 
 
Final margin status for the bile duct, pancreatic parenchymal, and SMA margin; 
 
Tumor size; 
 
Degree of differentiation (poor, moderate, well);  
 
Number of lymph nodes examined; 
 
Number of positive lymph nodes; 
 
Local invasion; 
 
Extent of involvement of named vessel(s) if present. 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. These may 
include anti-emetics, anti-diarrheals, red packed cells, platelets, pancreatic enzymes, 
nutritional supplements, and drugs given topically or systemically for the treatment of 
cutaneous toxicities of erlotinib.  Myeloid growth factors are allowed for the treatment of 
neutropenia.   
9.1.1 
Proton Pump Inhibitor 
Erlotinib’s solubility decreases as the pH increases. Co-administration of omeprazole 
with erlotinib will increase the AUC and Cmax by 46% and 61%, respectively.  
9.1.2 
H2-antagonist 
Avoid concomitant use of erlotinib with gastric acid reducing agents if possible.  When 
ranitidine 300 mg is given with erlotinib, erlotinib AUC and Cmax decrease by 33% and 
54%, respectively.  Increasing the dose of erlotinib will not compensate the loss of 
exposure.  However, if an H2-antagonist receptor is needed, take erlotinib at least 2 hours 
before or 10 hours following the H2-antagonist administration.  Dosing such, erlotinib loss 
of exposure is minimized to AUC of 15% and Cmax of 17%.   
9.1.3 
Patients are recommended to wear sun screen protection, hat, long sleeves to avoid sun 
as it can exacerbate skin rash. 
9.1.4 
Patients should be informed that skin toxicity is to be expected during treatment with 
erlotinib.  Skin toxicity may take the form of dry skin, rash, acneiform eruption, or hair or 
nail changes.  Prophylactic treatment of the skin may prevent or reduce skin toxicity.  The 
patient should be encouraged to use an alcohol-free, emollient cream applied twice a 
day to the entire body as soon as the patient starts therapy with erlotinib.  Creams and 
ointments are recommended because they have a greater ability to retain moisture than 
lotions.  Examples of suitable emollient creams include:  Neutrogena® Norwegian 
formula, SARNA® Ultra, Vanicream™, Aveeno® (fragrance-free formulation), and 
Eucerin® cream.  Other over-the-counter aqueous creams or emulsifying ointments may 
also provide symptomatic benefit.  Lotions should be avoided because they often contain 
alcohol, which will dry the skin.  Patients should also be encouraged to use a titanium 
dioxide or zinc oxide-based sunscreen product applied to sun-exposed areas twice per 
day. 
 
9.2 
Non-permitted Supportive Therapy 
Erythroid growth factors are discouraged due to thrombotic potential. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (2/19/14) 
10.1 
General Information  
Tumor block, peripheral blood and urine submission are highly recommended to be 
submitted at study entry. (NOTE: Tissue block that contains normal tissue submission is 

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61 
encouraged). These specimens are to be submitted to the NRG Oncology Biospecimen 
Bank for correlative studies. In addition, at the time of progression, this study encourages 
the submission of peripheral blood and tumor tissue (if a biopsy is performed to 
document progression).  
 
 
The NRG Oncology Biospecimen Bank at the University of California San Francisco 
acquires and maintains high quality specimens from NRG Oncology trials. Tissue from 
each block is preserved through careful block storage and processing. The NRG Oncology 
Biospecimen Bank provides tissue specimens to investigators for translational research 
studies. Translational research studies integrate the newest research findings into current 
protocols to investigate important biologic questions.   
 
10.2 
Specimen Collection for Tissue Banking (Highly Recommended) (12-APR-2018) 
Specimens are to be collected at baseline in all eligible patients who have consented. 
These include the tumor tissue block and peripheral blood (plasma and whole blood) and 
urine. The tumor tissue block will be derived from the material removed at the time of 
surgery and preserved in formalin. Snap freezing is not necessary, as tissue submitted 
will be those preserved in formalin. 
 
10.2.1  Tissue Blocks 
The following must be provided in order for the case to be evaluable for the NRG 
Oncology Biospecimen Bank:    
x 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide 
(block) or can be the diagnostic slide itself.) 
x 
A corresponding paraffin-embedded tissue block of the primary tumor (the block must 
match the H&E being submitted) containing tumor and normal tissue if present 
(NOTE: H&E and tissue block that includes normal tissue is encouraged).   
If the institution is not able to release the block, a 5 mm diameter core of tissue, 
punched from the tissue block containing the tumor with a punch tool and submitted 
in a plastic tube labeled “tumor” with the surgical pathology number, as well as 25 
unstained sections on plus slides that are to be cut at 5 microns taken from the block 
after it has been punched. These must come from the same block as the H&E being 
submitted. NOTE: A kit with the punch tool, specimen tube, and instructions can be 
obtained from the Biospecimen Bank with frozen specimen kids. To request a kit, 
contact the Biospecimen Bank at NRGBB@ucsf.edu or 415-476-7864. Block or core 
must be clearly labeled with the pathology identification number and block ID that 
corresponds to the submitted Pathology Report. 
See Appendix V for specimen punch tool kit and instructions. 
x 
A Pathology Report documenting that the submitted block or core contains tumor and 
the clinical status. The report must include the NRG Oncology protocol number and 
patient’s case number. The patient’s name and/or other identifying information should 
be removed from the report. The date of procedure and surgical pathology report 
numbers and information must NOT be removed from the report. 
x 
A Specimen Transmittal Form (ST) clearly stating that tissue is being submitted for the 
NRG Oncology Biospecimen Bank; if for translational research, this should be stated 
on the form. The form must include the NRG Oncology protocol number and patient’s 
NRG Oncology case number.  
10.2.2 
Whole Blood, Plasma, and Urine  (Highly Recommended) 
x 
5 cc of whole blood, and 7-10cc of blood to be separated for plasma are required.  
See Appendix V for blood collection kit, processing and shipping instructions. 
x 
10mL urine to be collected at study entry.  
See Appendix V for urine collection kit, processing and shipping instructions. 
x 
A Specimen Transmittal Form (ST) documenting the date of collection of the whole 
blood, plasma, and urine; the NRG Oncology protocol number, the patient’s NRG 

RTOG 0848 
 
 
 
 
 
 
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62 
Oncology case number, time point of study, and method of storage, for example, 
stored at -80° C, must be included. 
 
NOTE: At the time of progression, if a biopsy is obtained to document progression, it 
is highly recommended that an H&E and a block of the tumor tissue be sent to NRG 
Oncology Biospecimen Bank. In addition peripheral blood (10 cc) is also requested at 
the time of progression. See Section 10.4 (Specimen Collection Summary table) 
 
10.3 
Storage Conditions (6/8/10) 
 
Store at –80q C (-70qC to -90qC) until ready to ship. If a -80qC Freezer is not available:  
x Samples can be stored short term in a -20q C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only). 
OR: 
x Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship 
out Monday-Wednesday only). 
OR: 
x Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday 
only). 
 
Please indicate on the ST Form the storage conditions used and time stored. 
 
10.4 
Specimen Collection Summary (12-APR-2018) 
Highly Recommended Specimens 
Specimens taken from patient: 
Collected 
When: 
Submitted as: 
 
Shipped: 
Representative H&E stained slides of 
the primary tumor  
Removed at 
time of surgery 
H&E Slide (slide can be a duplicate 
cut stained H&E or the diagnostic 
slide.) 
Ambient to 
NRGBB-SF 
1 corresponding block primary tumor 
containing normal tissue (NOTE:  A 
tissue block containing normal tissue is 
not mandatory but is encouraged) OR 
5mm 
punch of tumor tissue block with 25 
unstained sections on plus slides. 
Removed at 
time of surgery 
Preserved in formalin; paraffin 
embedded. Note: The block, punch 
and unstained must be taken from 
same block as the H&E slide being 
submitted 
 
Ambient. (A 
cold pack is 
recommende
d during 
warmer 
months) to 
NRGBB-SF 
PLASMA: 5-10 mL of anticoagulated 
whole blood in EDTA tube #1 
(purple/lavender top) and centrifuge 
Prior to 
chemotherapy 
start, if 
possible, 
otherwise, at 
study entry 
Frozen plasma samples containing 
minimum of 0.5 mL per aliquot in 1 
mL cryovials (five ) 
Store frozen at -80qC 
Plasma sent 
frozen on dry 
ice via 
overnight 
carrier to 
NRGBB-SF 
 
Whole blood for DNA: 5-10 mL of 
anticoagulated whole blood in EDTA 
tube #2 , (purple/lavender top tube) 
and mix 
Prior to 
chemotherapy 
start, if 
possible, 
otherwise, at 
study entry .  
 
Note: If site 
missed this 
collection time 
point they may 
collect whole 
blood for DNA 
at a later time 
point instead 
but must note 
Frozen whole blood samples 
containing of 1.5 mL per aliquot in 2 
mL cryovials (three) 
Whole blood 
sent frozen 
on dry ice via 
overnight 
carrier to 
NRGBB-SF 
 

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63 
this on the ST 
Form.  
 
10-25 mL clean-catch urine 
Prior to 
chemotherapy 
start, if 
possible, 
otherwise, at 
study entry 
One 10 mL urine aliquot in one 
sterile 15 ml polypropylene 
centrifuge tubes.  Store frozen at -
20qC (short term only) or 80q C 
Urine sent 
frozen on dry 
ice via 
overnight 
carrier to 
NRGBB-SF 
Representative H&E stained slides of 
the progression tumor 
Disease 
progression 
H&E Slide (slide can be a duplicate 
cut stained H&E, or the diagnostic 
slide.) 
Ambient to 
NRGBB-SF 
1 block progression tumor OR 
punch of block plus 25 unstained 
sections on plus slides. 
Disease 
progression 
Preserved in formalin; paraffin 
embedded. Block or 
punch/unstained must come from 
same block as H&E being submitted 
Ambient. (A 
cold pack is 
recommende
d during 
warmer 
months to 
NRGBB-SF 
 
PLASMA: 5-10 mL of anticoagulated 
whole blood in EDTA tube #1 
(purple/lavender top) and centrifuge  
Disease 
progression 
Frozen plasma samples containing 
of 0.5 mL per aliquot in 1 mL 
cryovials (five-ten) 
Plasma sent 
frozen on dry 
ice via 
overnight 
carrier to 
NRGBB-SF 
 
Whole blood for DNA: 5-10 mL of 
anticoagulated whole blood in EDTA 
tube#2, (purple/lavender top) and mix 
Disease 
progression 
Frozen whole blood samples 
containing 1.5 mL per aliquot in 2 
mL cryovials (three) 
Whole blood 
sent frozen 
on dry ice via 
overnight 
carrier to 
NRGBB-SF 
 
10.5 
Submit materials as follows:  (12-APR-2018) 
 
US Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco-Box 1800 
2340 Sutter Street, Room S341   
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens and Trackable 
FFPEs 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341   
San Francisco, CA 94115 
 
Questions: 415-476- 7864/FAX 415-476-5271;  
NRGBB@ucsf.edu 
 
10.6 
Reimbursement  (2/19/14) 
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) 
Program, NCI funds for reimbursement for protocol-specified biospecimen materials will be 
distributed per the requirements/methods specified by the new NCTN Program. This 
information will be made available with the other registration materials in the Oncology 
Patient Enrollment Network (OPEN) portal system. OPEN will serve as the registration 
system for all patient enrollments onto NCI-sponsored NCTN trials, including this study, 

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64 
which will be transitioned into the new Program from the NCI-sponsored Cooperative 
Group Clinical Trials Program. 
 
10.7 
Confidentiality/Storage (4/02/14) 
 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.asp
x for further details.) 
10.7.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank database only 
includes the following information: the number of specimens received, the date the 
specimens were received, documentation of material sent to a qualified investigator, type 
of material sent, and the date the specimens were sent to the investigator. No clinical 
information is kept in the database. 
10.7.2 
Specimens for tissue banking will be stored for an indefinite period of time. Specimens 
for the translational research component of this protocol will be retained until the study 
is terminated, unless the patient has consented to storage for future studies. If at any 
time the patient withdraws consent to store and use specimens, the material will be 
returned to the institution that submitted it. 
 
 
11.0 
PATIENT ASSESSMENTS (2/19/14) 
11.1 
Study Parameters: See Appendix I. 
 
 
11.2 
Evaluation for Progression following Adjuvant Systemic Therapy 
Patients must be evaluated for progression by IV contrast CT (or MRI, if allergic), and start 2nd 
step systemic treatment within 4 weeks of completing step 1 systemic treatment. CA19-9 levels 
are not used as an indicator of progressive disease. 
 
11.3 
Quality of Life Assessments 
Patients should complete the FACIT-Fatigue and the PROMIS-derived fatigue short form at 
baseline before systemic therapy initiation, after completion of 1st step adjuvant systemic therapy 
but prior to clinical evaluation for progression, as well as at 9, 12, and 24 months from start of 1st 
step adjuvant systemic therapy. 
 
FACIT-Fatigue, version 4, is a 13-item questionnaire that assesses self-reported tiredness, 
weakness, and difficulty conducting usual activities due to fatigue (SB Yellen, 1997). A 5-point 
intensity type of rating scale (from “not at all” to “very much”) is used. The FACIT-Fatigue is a 
psychometrically sound instrument and has been widely used to measure fatigue for patients with 
various chronic illnesses including cancer and pancreatic cancer (SB Yellen, 1997; DW 
Robinson, 2008). This questionnaire can be completed by patients in approximately 5 minutes. 
The site research nurse or CRA is encouraged to be sensitive to each patient's demeanor. If 
patients appear particularly uncomfortable answering a question, they will be informed that they 
can skip that question. Similarly, interviewers will give patients a short break if the patient appears 
fatigued or otherwise in need of a few minutes break. Note: The FACIT-Fatigue has been 
translated into 49 languages and is available free of charge to institutions with the completion of 
an agreement to share data, accessible at http://www.facit.org/translation/licensure.aspx.   
 
PROMIS-fatigue, A Novel Short Form Fatigue Scale is a 7-item questionnaire that assesses self-
reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. This 
questionnaire was developed to minimize patient burden and for ease of use in oncology 
populations. While the psychometric properties of this 7-question short fatigue scale have been 
validated in the general population (SF Garcia, 2007; J-S Lai, 2008), validation in patients with 
cancer is underway. A “cross-walk” has been successfully developed between the PROMIS 
fatigue item bank and the PROMIS-Cancer fatigue item bank that produced the short form 
measure. These two item banks, sharing 54 common items, were linked by equating item 
parameters using items that held stable psychometric properties between the cancer and general 

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65 
population populations in which they were tested. Results showed that cancer patients reported 
more severe fatigue (1/3 standard deviation more severe, but the same scale characteristic curve 
slope) than the general population, which matches clinical expectations (D Cella, 2007). This 
questionnaire can be completed by patients in less than 5 minutes. The site research nurse or 
CRA is encouraged to be sensitive to each patient's demeanor. If patients appear particularly 
uncomfortable answering a question, they will be informed that they can skip that question. 
Similarly, interviewers will give patients a short break if the patient appears fatigued or otherwise 
in need of a few minutes break. Note: The PROMIS-fatigue is available in validated English and 
Spanish language formats, and is currently being translated into German and Dutch; is accessible 
through the PROMIS Assessment Center website: http://www.assessmentcenter.net/ac1/.  
 
11.4 
Criteria for Discontinuation of Protocol Treatment 
 
Progression of disease; 
 
A delay in protocol treatment, as specified in Sections 6.0 and/or 7.0. 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
 

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12.0 
DATA COLLECTION 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1600 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will 
be used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
12.1 
Summary of Data Submission  (5/12/16) 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks of 1st step 
registration 
Initial Evaluation Form (I1) (for patients who have not 
received chemotherapy prior to registration 
Initial Evaluation Form (I2) (for patients having started 
chemotherapy prior to first step registration) 
 
 
 
Slides/Blocks (P2)  
 
Surgery Form(S1) 
Surgical Operative Report(S2) 
Surgical Pathology Report(S5) 
Specimen Transmittal Form(ST) 
 
FACIT-Fatigue QOL(FA) 
PROMIS Fatigue QOL (PR) 
 
 
 
 
 
FACIT-Fatigue QOL(FA) 
PROMIS Fatigue QOL (PR) 
 
After completion of 1st step  
adjuvant systemic therapy 
but prior to clinical 
evaluation for progression, 
and then at 9, 12, and 24 
months from the START 
OF  1st step adjuvant 
systemic therapy 
 
Post Adjuvant Systemic Treatment tumor status form (F3) 
1 week after evaluation for 
disease progress post 1st 
step adjuvant systemic 
treatment 
 
Adjuvant Systemic  Treatment Form (TF) 
(For patients registered prior to amendment 6 only) 
 
1 week after completion of 
1st step adjuvant systemic 
treatment 
 
 
Arm 3 or 4 1st cycle Treatment Form (AT) 
(For patients registered prior to amendment 6 only) 
1 week after completion of 
1st cycle  Arm 3 or 4 
treatment 
 
Systemic Treatment Summary Form (TC) 
 
1 week after completion of 
month 5 treatment 

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67 
(For patients registered to amendment 6 version of the 
protocol) 
 
Additional Systemic Treatment Form (AX) 
(For patients registered to amendment 6 version of the 
protocol)  
 
 
 
 
 
Arm 4 Concurrent Treatment Form (SF) 
 
 
1 week after completion of 
month 6 treatment 
 
 
 
 
 
 
1 week after completion of 
concurrent Arm 4 treatment 
(chemo/RT) 
 
Preoperative cross-sectional images 
(access  
http://www.rtog.org/CoreLab/RTQASubmissionInformation.aspx 
for submission specifics) 
 
1 week after completion of 
RT Arm 4 treatment  
Follow-up Form (F1)  
FOR PATIENTS WHO DO NOT RECEIVE ARM 3 OR 4 
TREATMENT 
 
FOR PATIENTS WHO DO RECEIVE ARM 3 OR 4 
TREATMENT 
Every 6mo x 2 then 
annually 
 
 
 
Every 3mo x 2 yrs then 
every 6mo x 3yrs then 
annually(from the start of 
arm 1 or 2 treatment) 
 
 *NOTE: Copies of simulation and port films and the complete RT daily treatment record for the (site) will 
be submitted to NRG Oncology ONLY if specifically requested.  
 
 
12.2 
Summary of Dosimetry Digital Data Submission  
(Submit to TRIAD; see Section  5.4 for account access and installation instructions) ARM 4 
ONLY (5/12/16) 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan along with pre and post-operative CT 
scans submitted to  TRIAD exported from treatment planning machine by Physicist 
Within 7-14 
days post 1st 
chemo month 
after  
RT 
randomization 
Digital data submission includes the following and must be submitted for plan 
approval pre-RT start: 
x 
CT data, critical normal structures, all GTV, CTV, and PTV contours  
x 
Digital beam geometry for RT fields 
x 
Dose distribution 
x 
Digital DVH data for all required critical normal structures, GTV, CTV, and 
PTVs for total dose plan  
x 
All required structures MUST be labeled per the table in Section 6.5. 
x 
The “RTOG 0848Datasheet” is available in the Forms section of the of the 
NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0848 
Submit via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, complete an online digital 
data transmission form (DDSI) located in the Core Lab Tab at    
http://www.rtog.org/CoreLab/TRIAD.asp  
 

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68 
 
 
NOTE: All simulation and portal films and/or digital film images will be kept by the 
institution and only submitted if requested. 
 
 
 
Final Dosimetry Information 
Within 1 week 
of RT end 
Radiotherapy Form (T1) [copy to HQ] 
Daily Treatment Record (T5) [copy to HQ] 
 
 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES 
WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
 
 
 
 
 
13.0 
STATISTICAL CONSIDERATIONS (2/19/14) 
13.1 
Endpoint(s) 
13.1.1 
Primary Endpoints 
 
Ph II-R: For the erlotinib question (first randomization closed to accrual 4/02/14): 
Overall survival (OS) (failure: death due to any cause) 
 
Ph III: For the chemoradiation question (second randomization): Overall survival (OS) 
(failure: death due to any cause) 
13.1.2 
Secondary Endpoints 
For both the erlotinib question (Ph II-R) and the chemoradiation question (Ph III) unless 
otherwise noted 
x 
Disease-free survival (failure: local or regional disease progression, distant 
metastases, second primary, or death due to any cause)  
x 
Adverse events 
x 
Pre-op imaging to determine frequency of objective criteria of resectability 
x 
Quality of Life: fatigue as measured by the FACIT-F (primary) and the PROMIS derived 
short form (exploratory) 
 
13.2 
Stratification (5/12/16) 
 
13.2.1  Current Stratification 
Prior to the chemoradiation randomization, patients will be stratified with respect to the 
following stratification variables: nodal status (involved vs. uninvolved), serum CA19-9 (≤ 
90 vs. > 90-180), and surgical margins (positive vs. negative). Patients entered prior to the 
closure of the erlotinib randomization (4/02/14) will also be stratified by their first treatment 
(gemcitabine vs. gemcitabine + erlotinib). As of the amendment to allow induction 
chemotherapy regimens beyond single-agent gemcitabine (Amendment 6), patients are 
also 
stratified 
by 
chemotherapy 
(single-agent 
gemcitabine 
vs 
gemcitabine 
combination).Patients must start the 5th month of chemotherapy to be eligible for the 
chemoradiation randomization.  The treatment allocation scheme described by Zelen will 
be used because it balances patient factors other than institution. [Zelen, 1974] 
 
13.2.2 Previous Stratification 
During the period when there was an erlotinib randomization in addition to the  
chemoradiation randomization, patients were stratified as follows. Prior to the erlotinib 
randomization, patients were stratified with respect to the following stratification variables: 
nodal status (involved vs. uninvolved), serum CA19-9 (≤ 90 vs. > 90-180), and 
chemotherapy (single agent gemcitabine versus combination chemotherapy at any time), 
and surgical margins (positive vs. negative). Prior to the chemoradiation randomization, 
patients were stratified with respect to the following stratification variable: first treatment 
(gemcitabine vs. gemcitabine + erlotinib). Patients had to start the 5th cycle of 
chemotherapy to be eligible for the chemoradiation randomization.  The treatment 

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69 
allocation scheme described by Zelen was used because it balances patient factors other 
than institution. [Zelen, 1974] 
 
13.3 
Sample Size and Power Justification (17-JAN-2024) 
13.3.1 
The sample size calculation for this trial begins with the primary endpoint question in the 
second randomization and the corresponding hypothesis that the use of concurrent 
fluoropyrimidine and radiotherapy following adjuvant chemotherapy improves overall 
survival for patients who are without evidence of progressive disease after 5 months of 
chemotherapy.  The primary endpoint of overall survival for patients who do not progress 
after adjuvant chemotherapy will be measured from the date of the second randomization 
(chemotherapy vs. chemotherapy followed by chemoradiation) to the date of death.  
However, by the time these patients are randomized to the chemoradiation question, 
they will already have been on the trial for approximately 6 months.  The median survival 
time (MST) for the gemcitabine alone arm from the CONKO-1 trial [Neuhaus, 2008] was 
22 months from study entry.  Since patients randomized to the chemoradiation question 
will be those who did not progress following adjuvant chemotherapy, it is projected that 
the control arm will have a MST of 23 months from study entry.  Adjusting for the 6 
months that patients will have already been on trial, the sample size for the primary 
hypothesis for the second randomization (i.e., that chemotherapy followed by 
chemoradiation will improve overall survival for patients who are disease free following 
adjuvant chemotherapy) will be based on improving MST from 17 months to 22.5 months.  
 
The required sample size for the primary endpoint of overall survival for the 
chemoradiation question is based on the following conditions: 
 
 
Survival times are exponentially distributed with (at least approximately) 
proportional hazards between the chemotherapy and chemoradiation treatment 
arms 
 
The control arm will have a MST of 17 months from the second randomization 
(monthly hazard of 0.0408) 
 
The experimental arm will have a MST of 22.5 months from the second 
randomization (monthly hazard of 0.0308) 
 
One-sided test at D = 0.05 
 
80% power 
 
3.5 years of follow-up post accrual completion 
 
Two interim significance tests and a final test are planned 
 
Using the group sequential design method [Pocock, 1977] with 2 interim analyses, 354 
randomized patients are required to detect an increase in MST from 17 to 22.5 months 
[measured from the date of RT randomization (chemotherapy vs. chemotherapy followed 
by chemoradiation) to the date of death], translating into a hazard ratio 
(experimental/control) of 0.76.  Based on the number of patients that will not proceed to 
the RT randomization due to progression, death without progression, not starting the 5th 
month of adjuvant chemotherapy treatment, or refusal, 545 patients will be entered.   
 
Redesign 
The redesign was done in accordance with the NCI Policy for Major Design Amendments 
for Ongoing Randomized Clinical Trials and redesign specifics performed by a statistician 
independent from the trial. 
Due to a lower than expected event rate throughout the trial, and a decreased event 
rate for the primary endpoint in post 5-year follow-up, definitive analysis based on the 
requisite events defined in Section 13.4.3 (n= 316 OS events) is projected to occur in 
2029 or later. Consequently, the analysis plan is modified to specify conduct of the 
primary endpoint analysis at the earlier of either a) the requisite events are observed or 

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70 
b) all patients have achieved a minimum of 5 years of potential follow-up time from 
enrollment, which will occur in the fourth quarter of 2023. 
In the original design, observation of 316 OS events provided statistical power of 80% 
for testing the specified alternative (34% reduction in failure rate, or HR=0.76) at one-
sided alpha 0.05. At the current event rate, it is projected that 316 OS events may not 
be reached before 2029. By October 1, 2023, it is anticipated that at least 265 events 
will have been observed.  Undertaking analysis at this fixed calendar time will result in 
a modest decrease of statistical power for the primary endpoint as follows: 
 
# Events 
Statistical Power 
 
 
265 
0.72 
 
 
295 
0.76 
 
 
 
13.3.2 
(4/02/14). The study design for the erlotinib research question has been revised to a Ph 
II-R design. The primary hypothesis for the Ph II-R portion is that the addition of erlotinib 
to standard adjuvant gemcitabine will show a signal for an increase in overall survival for 
patients with resected head of the pancreas adenocarcinoma.  A total of 200 events 
(deaths) between the gem and gem/erlotinib treatment arms will provide 80% power to 
detect a signal for an increase in median overall survival from 22 to 28.8 months and 
90% power to detect a signal for an increase in median overall survival from 22 to 30.6 
months (HRs of 1.31 and 1.39 respectively, in favor of the erlotinib arm) with the addition 
of erlotinib and a 1-sided alpha of 0.15.   The number of patients accrued prior to this 
amendment is sufficient to obtain the 200 required events with a projected analysis 
timeline of ~ 2.5 years from the amendment. 
13.3.3 
Power Calculations for QoL: Health Related Quality of Life (HRQOL) FACIT-Fatigue 
(FACIT-F) and PROMIS-Fatigue 
The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) and National 
Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System 
(PROMIS) Fatigue will be used to measure HRQOL.  The primary HRQOL endpoint will 
be to determine if baseline FACIT-F scores are correlated with overall survival.  The 
FACIT-F and PROMIS Fatigue tools are described in Sections 1.7.2 and 1.7.3 
respectively, as well as Section 11.3. Based on work done by Robinson (details in 
Section 1.7.2), FACIT-F scores predicted survival when a baseline FACIT–F score of 30 
was used as the cut-point for defining high (≤30) and low (> 30) fatigue.  Four hundred 
evaluable patients will provide at least 90% power to detect a HR of 0.70 between low 
and high fatigue using a baseline FACIT-F cut-point of 30, with a 1-sided alpha of 
0.05.   The FACIT-F and PROMIS will be collected on all cases participating in this 
portion of the trial and will be collected at five time points: pretreatment (baseline), at the 
time of evaluation for progression following the first-step randomization treatment, 9, 12, 
and 24 months from start of first-step registration treatment. Secondary endpoints 
include change in FACIT-F from baseline, PROMIS fatigue scores correlating with overall 
survival, and change in PROMIS fatigue scores from baseline Protocol-eligible patients 
providing a baseline FACIT-F score will be included in the HRQOL primary endpoint 
analysis.  To allow for patients agreeing to participate in the HRQOL portion of the trial, 
not completing FACIT-F at baseline and/or attrition following start of treatment, a total of 
500 patients will be recruited. 
13.3.4  
Patient Accrual 
Patient accrual is projected to be 14 cases per month, with a ramp-up period in the first 
6 months. The expected monthly accrual in months 1-3 and months 4-6 following 
activation are 0 and 3, respectively.  
 
This study will use a stricter rule than the CTEP early stopping guidelines for   
slow accruing trials: 

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71 
 
If the average monthly accrual rate by 2 years following activation is below 10 
cases per month (< 75% of projected), the study team will discuss potential 
amendments with CTEP and the NCI GI Steering Committee to determine what 
study questions will be able to be answered in a timely fashion. 
 
13.4 
Interim Analysis (11-APR-2023) 
(4/02/14) Overall and disease-free survival will be estimated by the Kaplan-Meier method 
[Kaplan, 1958]. The distribution of overall survival estimates between the two arms for both 
primary endpoint questions will be compared using the log rank test.[Mantel, 1966]  
Survival time for the erlotinib question will be measured from the date of first randomization 
(gemcitabine vs. gemcitabine/erlotinib) to the date of death or last follow-up.  Survival time 
for the chemoradiation question will be measured from the date of second randomization 
(chemotherapy vs. chemotherapy followed by chemoradiation) to the date of death or last 
follow-up. The Cox proportional hazard regression model will be used to analyze the effects 
of factors, in addition to treatment, that may be associated with overall survival.  
13.4.1 
Interim Analysis to Monitor the Study Progress 
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published. In general, the interim reports will 
contain the following information: 
 
patient accrual rate with a projected completion date (while the study is still 
accruing) 
 
total patients accrued  
 
distributions of important pretreatment and prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm. 
 
compliance rates of treatment delivery 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoints, overall survival, or any secondary endpoints, with the 
exception of reporting of adverse events. 
13.4.2 
Significance Testing for Early Termination and/or Reporting 
 
Chemoradiation Question Primary Endpoint: Overall Survival 
Two interim significance tests of treatment difference are planned. The timing of the 
interim analyses will be based on primary endpoint events, deaths. Under the 
alternative hypothesis that chemotherapy followed by adjuvant radiation and 
concurrent capecitabine will increase overall survival (MST from 17 months to 22.5 
months from the second randomization) for patients with resected head of pancreas 
adenocarcinoma who are disease free after adjuvant chemotherapy, the number of 
events needed and the nominal significance levels for rejecting the H0 (efficacy) or 
the H1 (futility) for each of these interim analyses are shown in the table below:  
 
 
 
 
 
Table 2: Nominal Significance Levels for Interim Analyses 
 
Interim 
Analysis 
Efficacy: 
Reject H0 if 
p (H0) ≤ 
Futility: 
Reject H1 if 
p (H1) ≤ 
 
# Events 
 
#1 
0.001 
0.005 
113 
#2 
0.001 
0.005 
225 
 
At each planned interim analysis, the one-sided p-value from the log-rank test 
assessing treatment efficacy with respect to overall survival will be compared to the 
nominal significance levels in Table 1. The levels for testing the null hypothesis are 
based on the Haybittle-Peto method.  If the computed p-value for efficacy is less than 
or equal to the nominal significance level boundary for rejecting the H0 (efficacy), then 

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72 
accrual will be stopped (if applicable), it will be concluded that the overall survival rate 
of the chemoradiation arm is higher than that of the non-chemoradiation arm and  the 
results will be reported.  For futility, the alternative hypothesis will be tested using rule 
C from Freidlin and Korn at a significance level of 0.005. [Freidlin, 2002] If the p-value 
is less than or equal to the nominal significance level boundary for rejecting the H1 
(futility), then accrual will be stopped (if applicable) and it will be reported that it cannot 
be concluded that the overall survival rate of the chemoradiation arm is higher than 
that of the non-chemoradiation arm.  If neither of these boundaries is crossed, accrual 
(if applicable) and follow-up will continue until the next interim or final analysis.  
 
Following the required number of deaths for each planned interim analysis, the 
blinded efficacy/futility results will be reported to the NRG Oncology DMC, in addition 
to accrual, distributions of pretreatment characteristics, frequency and severity of 
adverse events, and compliance with protocol treatment.   
 
13.4.3  
Analysis for Reporting the Initial Treatment Results 
 
Erlotinib Question (First Randomization) Primary Endpoint: Overall Survival 
The primary hypothesis of the erlotinib question is whether the addition of erlotinib will 
show a signal for an increase in overall survival (potential effect sizes as described in 
Section 13.3.2) for patients with resected head of pancreas adenocarcinoma.  This 
major analysis will occur after a total of 200 events (deaths) have occurred between 
the gem and gem/erlotinib treatment arms. It will include:   
 
 
tabulation of all cases entered and those excluded from the analyses with the 
reasons for exclusion given 
 
distributions of important prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm 
 
compliance rate of treatment delivery 
 
observed results with respect to the primary and secondary endpoints applicable 
to the erlotinib question 
 
All eligible patients randomized, regardless of the amount of erlotinib received, will be 
included in the comparison and will be grouped in the analysis by assigned treatment 
from the erlotinib randomization (gemcitabine vs. gemcitabine/erlotinib). The primary 
hypothesis of treatment benefit will be tested using the log-rank statistic with a 
significance level of 0.15. Additionally, analyses of treatment effect will be performed 
using the Cox proportional hazard model with the three stratification factors included 
as fixed covariates, as well as any factors that show an imbalance between the arms. 
Where feasible, treatment comparisons with respect to the primary endpoint (overall 
survival) will be compared within gender, ethnic and racial categories. 
 
Chemoradiation Question (Second Randomization) Primary Endpoint: Overall 
Survival 
The primary hypothesis of the chemoradiation question is whether chemotherapy 
followed by adjuvant radiation and concurrent capecitabine will increase median 
survival for patients with resected head of pancreas adenocarcinoma who are disease 
free after adjuvant chemotherapy.  This major analysis will occur at the earlier of either 
a) the requisite events are observed [316 OS events] or b) all patients have achieved a 
minimum of 5 years of potential follow-up time from RT randomization - which will occur 
in the fourth quarter of 2023.  It will include:  
 
tabulation of all cases entered and those excluded from the analyses with the 
reasons for exclusion given 
 
distributions of important prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm 

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73 
 
compliance rate of treatment delivery 
 
observed results with respect to the primary and secondary endpoints applicable 
to the chemoradiation question 
 
All patients randomized to the chemoradiation portion of the trial will be included in 
the comparison and will be grouped in the analysis by assigned treatment from the 
second 
randomization 
(chemotherapy 
vs. 
chemotherapy 
followed 
by 
chemoradiation). The primary hypothesis of treatment benefit will be tested using the 
log-rank statistic with a significance level of 0.05, given that the three interim analyses 
were carried out per Section13.4.2. Additionally, analyses of treatment effect will be 
performed using the Cox proportional hazard model with the four stratification factors 
included as fixed covariates, as well as any factors that show an imbalance between 
the arms). Where feasible, treatment comparisons with respect to the primary 
endpoint (overall survival) will be compared within ethnic and racial categories. 
13.4.4 
Analysis of HRQoL Endpoints 
 
FACIT-F Scoring and Analysis 
 
The FACIT-F will be scored per the FACIT-F Scoring Guidelines (Version 4 
www.facit.org), with higher scores indicating less fatigue. 
 
The primary objective in the HRQoL analysis is determine if baseline FACIT-F  
scores are correlated with overall survival; specifically if patients with baseline 
FACIT-F scores > 30 (low fatigue) have better overall survival than patients with 
baseline FACIT-F scores ≤ 30 (high fatigue). 
 
The primary HRQoL hypothesis will be tested using the log-rank statistic with a 
significance level of 0.05. Additionally, analyses of fatigue effect will be performed 
using the Cox proportional hazard model with first step-randomization treatment, 
nodal status (involved vs. uninvolved), serum CA19-9 (≤ 90 vs. > 90-180), and 
surgical margins (positive vs. negative) included as fixed covariates, as well as any 
factors that show an imbalance between patients with low and high FACIT-F scores. 
 
Analysis for Secondary Endpoints Related to HRQoL  
 
Missing Data 
The distributions of HRQoL data collection patterns over all collection points.  To 
inspect the missing data mechanism for each tool, we will use at least a graphical 
method.  A missing completely at random (MCAR) mechanism exists when missing 
values are randomly distributed across all observations. A missing at random (MAR) 
mechanism exists when values are not randomly distributed across all observations, 
rather than one or more sub-samples.  
 
If the cause of missing data is MCAR, listwise deletion (complete case analysis) will 
be done. If the MAR assumption is supported by the data, then an imputation 
method such as multiple imputation will be applied to impute missing data.  
 
If the MAR assumption is not supported by the data, then adjusting for covariates 
(such as the baseline QOL score) might reduce the conditional association between 
outcomes and missing values. If missing data patterns look similar when stratified 
by such covariate(s), then an analysis that adjusts for such covariate(s) will be 
conducted and an imputation method such as multiple imputation will be applied.  If 
approximate conditional independence cannot be obtained with any set of 
covariates, then MNAR (missing not at random) must be addressed by an explicit 
model for the missing data mechanism [Donaldson, 2005] and then an imputation 
method such as multiple imputation will be applied. All results from the imputed 
analysis using the multiple imputation will be compared to the complete case 
analysis results to assess any potential biases.  
 
The PROMIS Fatigue will be scored per the PROMIS Fatigue Scoring Guidelines 
(Version 1 www.nihpromis.org). 
 
Exploratory Analyses 

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The baseline PROMIS Fatigue scores will be analyzed to determine if there is a cut-
point (adjusting for multiple comparisons) that correlates with overall survival using 
the log-rank statistic.  If a cutpoint is determined, addition analyses of fatigue effect 
will be performed using the Cox proportional hazard model with first step-
randomization treatment, nodal status (involved vs. uninvolved), serum CA19-9 (≤ 
90 vs. > 90-180), surgical margins (positive vs. negative) and chemotherapy (single 
agent gemcitabine versus combination) and timing of study entry (prior to any 
chemotherapy versus after up to 3 months) included as fixed covariates, as well as 
any factors that show an imbalance between patients with low and high PROMIS 
Fatigue scores. 
13.4.5 
Data and Safety Monitoring 
This study will be reviewed by the NRG Oncology Data Monitoring Committee on a 
semi-annual basis for accrual (while applicable) and adverse events; as well as for 
efficacy/futility as specified in Section 13.4.2.    
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
 
13.5 
Statistical Methods Analysis for Laboratory Correlative Section (2/19/14) 
The primary erlotinib analysis is planned with 200 deaths. Taking into account a 90% 
submission rate (accounting for some inability to obtain specimens and for some 
specimens to be inadequate to obtain marker data), it is projected that there will be 180 
deaths for these correlative studies.   
13.5.1 
There are two primary aims for this study:  
 
To assess whether patients with EMT phenotype fail to benefit from the addition of 
erlotinib, while those without this phenotype experience improved clinical outcome 
when erlotinib is combined with gemcitabine therapy.  
 
To determine the influence of K-Ras mutations on benefit from erlotinib 
13.5.2 
Analysis Plan 
 
The primary clinical endpoint of this study is overall survival, defined from the date of 
study registration to the date of death or to the date the patient was last known to be 
alive (censored observation).  Analyses will be done using the Cox proportional hazards 
model[Cox, 1972]. This technique will allow us to assess marker effects while adjusting 
for treatment assignment, and the effect of other known prognostic factors such as nodal 
status, margin status, and tumor diameter. The primary aims of the trial translate 
statistically into a test of marker by treatment interaction, which can be assessed using 
this model.   
 
 
Traditional descriptive statistics and summary tables will be generated for all data from 
this study. The frequencies of various markers are not well known in adjuvant pancreatic 
cancer.   
 
13.5.3 
Power Assessments 
 
The primary aims of interest are to assess the relationship between EMT phenotype and 
treatment with respect to overall survival, and between EGFR loop activation and 
treatment with respect to overall survival.  
 
 
Power estimates are influenced in part by the frequency of the marker of interest in this 
population.  Because these frequencies are not well known in this population, we provide 
estimates based on either a relatively equal split, and under the more extreme 
assumption of 10% EMT phenotype and 90% EGFR. 
 
 
Because there are two primary objectives, power calculations have been based on one-
sided .025 tests of the interactions to preserve an overall type-I error rate of 5%. For 
purposes of assessing EMT, the hypothesis is that there will be no benefit to treatment 

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in the presence of the EMT phenotype.  This translates into a hazard ratio of 1 between 
the chemotherapy treatment arms in this subset.  Among patients without the EMT 
phenotype, it is assumed that there will be improvement in the erlotinib arm.  In this 
situation, the hazard ratio for the interaction can be interpreted as the hazard ratio 
between the ‘standard’ arm and the erlotinib arm.   
 
 
Similarly, for the EGFR loop activation, it is assumed that those without activated EGFR 
will fail to benefit from the addition of erlotinib, while those with activated EGFR will show 
benefit.  In this case, the hazard ratio for the interaction would be the same as the hazard 
ratio for the treated arms in the subset with EGFR activation. 
 
 
Table 1 provides power estimates for selected levels of assessing either the EMT or 
EGFR endpoint, under three ranges of splits for the frequency of presence/absence of 
the marker.  Because the treatment trial is powered for an overall hazard ratio (under the 
proportional hazards assumption) of at least 1.3 (control/experiment), this implies that 
we would expect a much higher hazard ratio, since the treatment effect is hypothesized 
to occur only in subsets of the population.  It should also be noted that these calculations 
assume independence between these markers, when in fact there may be some 
correlation between them. 
 
Table 1:  Power to detect selected levels of an interaction between EMT phenotype, 
EGFR loop activation, or kRAS status and treatment assignment with respect to overall 
survival, assuming a 0.025 one-sided test and 180 deaths.   
 
Interaction HR 
Power 
50:50 split 
Power 
25:75 split 
Power 
10:90 split 
1.6 
0.88 
0.77 
0.47 
1.7 
0.94 
0.86 
0.56 
1.8 
0.97 
0.92 
0.65 
1.9 
0.99 
0.96 
0.73 
 
Note that these splits can be read as follows; as an example, the 25:75 split gives the 
resulting power for either 25% EMT present, or 25% inactive EGFR.  Similarly, in 
parenthesis, the 75:25 split gives the power for kRAS, under the assumption that 25% of 
the patients are kRAS WT, and is the subset which predicts response to erlotinib.  
 
13.5.4 
Secondary Objectives 
 
We will also assess whether overexpression of c-Met and RON are correlated with 
treatment outcome, using IHC for RON, C-met and matriptase-1, and QPRC to quantify 
HGF and HGFL. These markers will initially be analyzed as either positive/negative or 
by categorizing into high/low for measures of expression. This is due to the fact that the 
distributions of these continuous measures often do not lend themselves to a linear term 
in the Cox model.  An initial categorization at the median is one approach; alternatives 
to be explored will be to select the split that maximizes the logrank statistic comparison 
of survival between the two levels. It should be emphasized that there is no single ‘best’ 
way to dichotomize gene expression for a single marker, and thus we will need to be 
cautious in the way we generalize these data. 
 
 
Another aim will be to compare the frequency of markers between baseline pre-treatment 
samples and characteristics of the tumor at recurrence.   
 
 
We will also assess the relationship of the markers noted above to disease-free survival. 
 
13.6 
Gender and Minorities (12-APR-2018) 
Both men and women of all races and ethnic groups are eligible for this study.  In 
conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with 
regard to inclusion of women and minorities in clinical research, we have also considered 

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the possible interaction between race/ethnicity and treatment. Based on RTOG 9704, it is 
projected that 57% of the patients will be men and 43% women; 2% will be of Hispanic or 
Latino ethnicity; racial distribution will be 90% white, 7% black or African American, and 
1% each of American Indian or Alaskan Native, Asian, and Native Hawaiian or other 
Pacific Islander.  The following table lists the projected accrual by ethnic and racial 
categories.  Assuming no differences between the ethnicities, or among the races, the 
statistical power for detecting the hypothesized treatment difference is 0.78 for males and 
0.68 for females for the erlotinib question and 0.49 for males and 0.40 for females for the 
chemoradiation question. The statistical power for non-whites, and Hispanic/Latino is too 
low for any meaningful treatment comparisons. 
  
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
4 
5 
9 
Not Hispanic or Latino 
230 
306 
536 
Ethnic Category: Total of all subjects 
234 
311 
545 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
3 
3 
6 
Asian 
3 
3 
6 
Black or African American 
20 
15 
35 
Native Hawaiian or other Pacific Islander 
3 
3 
6 
White 
205 
287 
492 
Racial Category: Total of all subjects 
234 
311 
545 
 
  
 
 

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APPENDIX I (5/12/16) 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS 
 
(NOTE: Ph II-R, ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 
CLOSED TO ACCRUAL EFFECTIVE 4/02/14) 
 
Assessments 
31 days prior to 
registration for patients 
who have not started 
chemotherapy or 31 days 
prior to day 1 of 
chemotherapy post 
surgery 
21 days prior to 
registration for patients 
who have not started 
chemotherapy or 21 
days prior to day 1 of 
chemotherapy post 
surgery 
14 days prior to registration 
for patients who have not 
started chemotherapy or 14 
days prior to day 1 of 
chemotherapy post surgery 
History 
X 
 
 
Physical with weight 
and vital signs 
X 
 
 
Performance Status 
 
 
X 
CT/MRI of 
abdomen/pelvis 
X 
(See Section 3.1) 
 
 
Chest CT or x-ray 
X 
 
 
CBC w/ diff; platelets 
& ANC 
 
X 
 
SGOT; total bilirubin 
creatinine 
 
X 
 
Na, K, Cl, CO2 , 
glucose, BUN 
 
X 
 
Post-op CA19-9 
 
X 
 
Serum pregnancy 
test (if applicable) 
 
 
X 
Quality of Life 
Evaluation ( if patient 
consents) 
 
Prior to 1st step registration 
 
 
Urine submission  
(if patient consents) 
Obtained prior to start of chemotherapy if possible, otherwise at study entry 
Tissue and blood,  
submission ( if patient 
consents) 
Obtained prior to start of chemotherapy if possible, otherwise at study entry  
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX I (5/12/16) 
 
STUDY PARAMETER TABLE: DURING TREATMENT ASSESSMENTS 
 
(NOTE: PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 
CLOSED TO ACCRUAL EFFECTIVE 4/02/14) 
 
Assessments 
During 
1st step adjuvant systemic 
therapy per institutional 
standard 
 
Within 3 weeks after 
completing the 5th 
month of 1st step 
adjuvant systemic 
therapy 
Post 2nd step 
randomization:  
Wkly during 
chemo/RT 
 
Physical with 
weight and vital 
signs 
X 
X 
X 
Performance 
Status 
X 
X 
 
CT/MRI of 
abdomen/pelvis 
 
X 
 
Chest CT or x-
ray 
 
X 
 
CBC w/ diff; 
platelets & ANC 
X 
 
X 
per institutional 
standard 
X 
SGOT; total 
bilirubin 
creatinine 
 
X 
per institutional 
standard 
 
Na, K, Cl, CO2 , 
glucose, BUN 
 
X 
per institutional 
standard 
 
 
Quality of Life 
Evaluation ( if 
patient consents) 
After completion of  1st step adjuvant systemic therapy but prior to CLINICAL 
EVALUATION FOR PROGRESSION 
Adverse event 
eval (and as 
needed based 
on reporting 
requirement) 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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              APPENDIX I (5/12/16) 
STUDY PARAMETER TABLE: FOLLOW UP ASSESSMENTS 
 
(NOTE: PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 CLOSED TO ACCRUAL 
EFFECTIVE 4/02/14) 
 
 
 
Assessments 
Following completion of all 
treatment for patients on Arms 1 
and 2 ONLY 
Every 6mos x 4yrs, then annually 
Following completion of all 
treatment for patients on 
Arms 3 or 4 
Every 3mos x 2yrs,  
Every 6mos x 3yrs, then annually 
Physical with weight 
and vital signs 
X 
X 
Performance Status 
X 
X 
CT/MRI of 
abdomen/pelvis 
X 
X 
Chest CT or x-ray 
X 
X 
Quality of Life 
Evaluation ( if patient 
consents) 
9, 12, and 24 months from the start of 1st 
step adjuvant systemic therapy 
 
CA19-9 
X 
X 
Adverse event eval 
(and as needed based 
on reporting 
requirement) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX II 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair 50% or 
more of waking hours. 
4 
Completely disabled. Cannot carry on self-care. Totally confined to 
bed or chair (. 
5 
Death. 
 
 
 
 
 
 

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APPENDIX III 
 
STAGING FOR PANCREAS 
AJCC, 6th Edition 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ* 
T1 
Tumor limited to the pancreas, 2 cm or less in greatest dimension 
T2 
Tumor limited to the pancreas, more than 2 cm in greatest dimension 
T3 
Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior 
mesenteric artery 
T4 
Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor) 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
 
 
Distant Metastasis (M) 
 
MX 
Presence of distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
*This also includes the “PanInIII” classification 
 
Stage Grouping 
 
Stage 0 
Tis 
N0 
M0 
Stage IA 
T1 
N0 
M0 
Stage IB 
T2 
N0 
M0 
Stage IIA 
T3 
N0 
M0 
Stage IIB 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
Stage III 
T4 
Any N 
M0 
Stage IV 
Any T 
Any N 
M1 
 
 
 
 

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APPENDIX IV 
 
Example of Surgical Pathology Reporting Form  
(www.cap.org/apps   accessed January 8, 2009) 
 
 
 
Pancreas (Exocrine) 
Protocol applies to all carcinomas 
of the exocrine pancreas. 
Protocol revision date: January 2005 
Based on AJCC/UICC TNM, 6th edition 
Procedures 
• Cytology (No Accompanying Checklist) 
• Incisional Biopsy (No Accompanying Checklist) 
• Partial Pancreatectomy 
• Pancreaticoduodenectomy (Whipple Resection) 
Author 
Carolyn C. Compton, MD, PhD 
Department of Pathology, McGill University, Montreal, Quebec, Canada 
For the Members of the Cancer Committee, College of American Pathologists 
Previous contributors: Donald E. Henson, MD; Carlos Fernandez-del Castillo, MD; 
Andrew L. Warshaw, MD; Christopher Willett, MD 
Pancreas (Exocrine) • Digestive System CAP Approved 
2 
© 2005. College of American Pathologists. All rights reserved. 
The College does not permit reproduction of any substantial portion of these protocols 
without its written authorization. The College hereby authorizes use of these protocols by 
physicians and other health care providers in reporting on surgical specimens, in 
teaching, and in carrying out medical research for nonprofit purposes. This authorization 
does not extend to reproduction or other use of any substantial portion of these protocols 
for commercial purposes without the written consent of the College. 
The College of American Pathologists offers these protocols to assist pathologists in 
providing clinically useful and relevant information when reporting results of surgical 
specimen examinations of surgical specimens. The College regards the reporting 
elements in the “Surgical Pathology Cancer Case Summary (Checklist)” portion of the 
protocols as essential elements of the pathology report. However, the manner in which 
these elements are reported is at the discretion of each specific pathologist, taking into 
account clinician preferences, institutional policies, and individual practice. 
The College developed these protocols as an educational tool to assist pathologists in the 
useful reporting of relevant information. It did not issue the protocols for use in litigation, 
reimbursement, or other contexts. Nevertheless, the College recognizes that the 
protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective 
January 1, 2004, the Commission on Cancer of the American College of Surgeons 
mandated the use of the checklist elements of the protocols as part of its Cancer Program 
Standards for Approved Cancer Programs. Therefore, it becomes even more important 
for pathologists to familiarize themselves with the document. At the same time, the 
College cautions that use of the protocols other than for their intended educational 
purpose may involve additional considerations that are beyond the scope of this 
document. 

RTOG 0848 
 
 
 
 
 
 
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87 
 
 
 
 
Pancreas (Exocrine) • Digestive System CAP Approved 
* Data elements with asterisks are not required for accreditation purposes for 
the Commission on Cancer. These elements may be clinically important, 
but are not yet validated or regularly used in patient management. 
Alternatively, the necessary data may not be available to the pathologist 
at the time of pathologic assessment of this specimen. 
 
Surgical Pathology Cancer Case Summary (Checklist) 
Protocol revision date: January 2005 
Applies to invasive carcinomas only 
Based on AJCC/UICC TNM, 6th edition 
PANCREAS (EXOCRINE): Resection 
Patient name: 
Surgical pathology number: 
Note: Check 1 response unless otherwise indicated. 
MACROSCOPIC 
Specimen Type 
___ Pancreaticoduodenectomy (Whipple resection), partial pancreatectomy 
___ Pancreaticoduodenectomy (Whipple resection), total pancreatectomy 
___ Pylorus sparing pancreaticoduodenectomy, partial pancreatectomy 
___ Pylorus sparing pancreaticoduodenectomy, total pancreatectomy 
___ Partial pancreatectomy, pancreatic body 
___ Partial pancreatectomy, pancreatic tail 
___ Other (specify): ____________________________ 
___ Not specified 
Tumor Site (check all that apply) 
___ Pancreatic head 
___ Uncinate process 
___ Pancreatic body 
___ Pancreatic tail 
___ Not specified 
Tumor Size 
Greatest dimension: ___ cm 
*Additional dimensions: ___ x ___ cm 
___ Cannot be determined (see Comment) 
*Other Organs Resected 
*___ None 
*___ Spleen 
*___ Gallbladder 
*___ Other(s) (specify): _________________________ 
 
 
MICROSCOPIC 
Histologic Type 
___ Ductal adenocarcinoma 
___ Mucinous noncystic carcinoma 
___ Signet-ring cell carcinoma 

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88 
___ Adenosquamous carcinoma 
___ Undifferentiated (anaplastic) carcinoma 
___ Undifferentiated carcinoma with osteoclast-like giant cells 
___ Mixed ductal-endocrine carcinoma 
___ Serous cystadenocarcinoma 
___ Mucinous cystadenocarcinoma – invasive 
___ Invasive papillary-mucinous carcinoma 
___ Acinar cell carcinoma 
___ Acinar cell cystadenocarcinoma 
___ Mixed acinar-endocrine carcinoma 
___ Other (specify): ____________________________ 
___ Carcinoma, type cannot be determined 
Histologic Grade (ductal carcinoma only) 
___ Not applicable 
___ GX: Cannot be assessed 
___ G1: Well differentiated 
___ G2: Moderately differentiated 
___ G3: Poorly differentiated 
___ G4: Undifferentiated 
___ Other (specify): ____________________________ 
Pathologic Staging (pTNM) 
Primary Tumor (pT) 
___ pTX: Cannot be assessed 
___ pT0: No evidence of primary tumor 
___ pTis: Carcinoma in situ 
___ pT1: Tumor limited to the pancreas, 2 cm or less in greatest dimension 
___ pT2: Tumor limited to the pancreas, more than 2 cm in greatest dimension 
___ pT3: Tumor extends beyond the pancreas but without involvement of the celiac 
axis or the superior mesenteric artery 
___ pT4: Tumor involves the celiac axis or the superior mesenteric artery 
Regional Lymph Nodes (pN) 
___ pNX: Cannot be assessed 
___ pN0: No regional lymph node metastasis 
___ pN1: Regional lymph node metastasis 
*___ N1a: Metastasis in single regional lymph node 
*___ N1b: Metastasis in multiple regional lymph nodes 
Specify: Number examined ___ 
Number involved: ___ 
 
Distant Metastasis (pM) 
___ pMX: Cannot be assessed 
___ pM1: Distant metastasis 
*Specify site(s), if known: ____________________________ 
Margins (check all that apply) 
___ Cannot be assessed 
___ Margins uninvolved by invasive carcinoma 
Distance of invasive carcinoma from closest margin: ___ mm 
*Specify margin (if possible): ____________________________ 
___ Carcinoma in situ absent at ductal margins 
___ Carcinoma in situ present at common bile duct margin 
___ Carcinoma in situ present at pancreatic parenchymal margin 

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89 
___ Margin(s) involved by invasive carcinoma 
___ Posterior retroperitoneal (radial) margin: posterior surface of pancreas 
___ Uncinate process margin (non-peritonealized surface of the 
uncinate process) 
___ Distal pancreatic margin 
___ Common bile duct margin 
___ Proximal pancreatic margin 
___ Other (specify): ____________________________ 
*Venous/Lymphatic (Large/Small Vessel) Invasion (V/L) 
*___ Absent 
*___ Present 
*___ Indeterminate 
*Perineural Invasion 
*___ Absent 
*___ Present 
*Additional Pathologic Findings (check all that apply) 
*___ None identified 
*___ Pancreatic intraepithelial neoplasia (highest grade: PanIN ___) 
*___ Chronic pancreatitis 
*___ Acute pancreatitis 
*___ Other (specify): ____________________________ 
*Comment(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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90 
APPENDIX V (5/12/16) 
 
 
Appendices for NRG Oncology Biospecimen Collection  
 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Blood Collection Kit Instructions 
NRG Oncology Urine Collection Kit Instructions 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341   
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341   
San Francisco, CA 94115 
 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal Form (ST) has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. Slides, Blocks, or Plugs can be shipped 
ambient or with a cold pack either by United States Postal Service (USPS) to the USPS 
address (94143) or by Courier to the Street Address (94115).  
 Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens via overnight courier to the address above. Specimens should only be 
shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to 
delivery delays. Saturday or holiday deliveries cannot be accepted. Samples can be stored 
frozen at -80q C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by e-mail: NRGBB@ucsf.edu or phone: 415-4767864 or Fax: 415-476-
5271. 

RTOG 0848 
 
 
 
 
 
 
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91 
 
 
 
 
APPENDIX V (5/12/16) 
NRG Oncology FFPE SPECIMEN PLUG KIT INSTRUCTIONS  
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen Bank. 
The plug kit contains a shipping tube and a punch tool.   
 
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area.  (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block.  Twist the punch tool 
once around to separate the plug from the block.  Then pull the 
punch tool out of the block.  The punch should be filled with tissue 
sample. 
 
 
 
 
Step 2 
Label punch tool with proper specimen ID. Include pathology 
accession number and block ID.  
DON’T remove specimen from the punch. 
 
Use a separate punch tool for every specimen. Call or email us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
 
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block 
and return the remaining block to your facility.  Please indicate on the submission form the request to 
perform the plug procedure and return of the block. 
Ship:  Specimen plug kit, specimen in punch tool, and all paperwork to the address below: 
 
 
 
 
 

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92 
US Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only  
NRG Oncology Biospecimen Bank 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341   
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.): For Frozen specimens or Trackable FFPE 
shipments 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341   
San Francisco, CA 94115 
Questions: 415-476- 7864/FAX 415-476-5271; NRGBB@ucsf.edu 

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93 
APPENDIX V (5/12/16) 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS   
 
This Kit is for collection, processing, storage, and shipping of plasma, or blood (as specified by 
protocol): 
 
Kit contents: Sites are required to provide their own blood draw tubes. 
x 
) 
x 
Ten (10) 1 ml cryovials 
x 
Biohazard bags (2) and Absorbent shipping material (2) 
x 
One Styrofoam container (inner)  and Cardboard shipping (outer) box per case 
x 
UN1845 DRY Ice and UN3373 Biological Substance Category B Stickers 
x 
Specimen Transmittal Form and Kit Instructions 
 
Preparation and Processing Plasma and Whole Blood: 
 
(A) Plasma: Purple Top EDTA tube #1 (two 5 ml or one 10 ml EDTA tube) 
 
Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with 
the NRG Oncology study and case number, collection date, time, and time point, and clearly 
mark cryovials “plasma”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4qC (preferred).  If sites are unable to process samples at 4qC then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST form. 
3. If the interval between specimen collection and processing is anticipated to be greater than 
one hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into up to 5 cryovials as are 
necessary for the plasma collected  labeled with NRG Oncology study and case numbers, 
collection date/time, time point collected and clearly mark specimen as “plasma”.  Avoid 
pipetting up the buffy coat layer 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90qC 
6. Store frozen plasma -70 to -90q C until ready to ship on dry ice 
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection timepoint 
on ST. 
 
(B) Whole Blood For DNA: Purple Top EDTA tube #2 (one 5 ml or one 10ml EDTA tube) 
                          
 
Label as many 1 ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date and time, and time point, and clearly 
mark cryovials“blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials labeled “blood” as are 
necessary for the blood collected (3 to 5) labeled with NRG Oncology study and case 
numbers,  collection date/time, time point collected and clearly mark specimen as “blood” 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80q Celsius. 
4. Store blood samples frozen until ready to ship on dry ice. 
5. See below for storage conditions. 
 

RTOG 0848 
 
 
 
 
 
 
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94 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED 
 
and includes collection time point on ST 
 
Storage and Shipping 
 
Freezing and Storage:  
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80qC (-70qC to -90qC) until ready to ship.  
If a -80qC Freezer is not available,  
 
Samples can be stored short term in a -20q C Freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only- Canada Mon-Tues). 
- OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only- Canada Mon-Tues). 
- OR: 
 
Samples can be stored in liq. nitrogen vapor phase (ship out Monday-Wednesday only- 
Canada Mon-Tues). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic and tape to the outside top of the 
Styrofoam box. 
 
Wrap frozen specimens of same type (i.e., all plasma together and whole bloods together) in 
absorbent shipping material and place each specimen type in a separate biohazard bag.  Place 
specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please Email 
NRGBB@ucsf.edu or call (415)476-7864  
Shipping Address : 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341   
San Francisco, CA 94115 
415-476-7864 
 
 
 

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95 
 
APPENDIX V (5/12/16) 
NRG Oncology URINE COLLECTION KIT/INSTRUCTIONS  
 
This Kit is for collection, processing, storage, and shipping of urine specimens. 
 
This Kit contains: 
x 
One (1) Sterile Urine collection cup 
x Two 15 ml polypropylene centrifuge 
tubes 
x 
Two 7 ml disposable pipettes 
x Biohazard bags 
x 
Absorbent paper towel 
x Parafilm for sealing outside of tubes 
 
Preparation and Processing of Urine Specimens: 
Process 
A clean catch urine specimen will be collected. To collect the specimen, use the following 
instructions: 
o 
Males should wipe clean the head of the penis and females need to wipe between the 
labia with soapy water/cleansing wipes to remove any contaminants.  
o 
After urinating a small amount into the toilet bowl to clear the urethra of contaminants, 
collect a sample of urine in the collection cup. 
o 
After 10-25 mL urine has been collected, remove the container from the urine stream 
without stopping the flow of urine. 
o 
Finish voiding the bladder into the toilet bowl 
x 
Aliquot 5-10 mls of urine into each of two 15 ml polypropylene centrifuge tubes (disposable 
pipets are provided in the kit). Do not fill with more than 10 mls to avoid cracking of tubes due 
to expansion during freezing. Replace the cap and tighten on the tubes. Make sure the cap is 
not cross-threaded or placed on incorrectly or leaking will occur.  
x 
Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
x 
Discard remaining Urine and collection cup. 
x 
Label the specimen with the NRG Oncology study and case number, collection date and 
time, time point of collection, and clearly mark specimens as “urine”. 
x 
Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and 
seal the bag. Freeze and store Urine samples in a -20qC or -80qC freezer until ready to ship. 
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with NRG Oncology study and case 
numbers, collection date/time, and time point collected (e.g. pretreatment, post-treatment). 
 
Storage and Shipping: 
 Freezing and Storage: 
 
Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days 
of collection. Store at -20qC or -80qC (-70qC to -90qC) until ready to ship. If a -80qC Freezer is not 
available:  
 
Samples can be stored short term in a -20q C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time 
stored. 
 
 
 
 
 

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96 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 
lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal 
Investigator and Clinical Research Assistant of the submitting institution. The institution should send a 
subsequent sample, collected as close as possible to the original planned collection date. 
 
For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please 
e-mail NRGBB@ucsf.edu or call (415)476-7864 or fax (415) 476-5271. 
 
 
Shipping Address: FedEx/UPS/Courier address (For all frozen samples) 
NRG Oncology Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341   
San Francisco, CA 94115 
Contact Phone: (415) 476- 7864 
 
 

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97 
APPENDIX VI (2/19/14) 
(NOTE: PH II-R ERLOTINIB RANDOMIZATION COMPLETED, ARM 2 CLOSED TO ACCRUAL 
EFFECTIVE 4/02/14) 
 
RTOG 0848 
PATIENT’S PILL DIARY- ERLOTINIB 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month of treatment 
2. Record the date, the number of pills taken, and the total dose  
3. Please bring the forms to your Research Nurse/Physician weekly during treatment. 
 
Date 
 # of pills 
taken 
Total Dose 
Date 
 # of pills 
taken 
Total Dose 
1. 
 
 
 
 
17. 
 
 
 
2. 
 
 
 
18. 
 
 
 
3. 
 
 
 
19. 
 
 
 
4. 
 
 
 
20. 
 
 
 
5. 
 
 
 
21. 
 
 
 
6. 
 
 
 
22. 
 
 
 
7. 
 
 
 
23. 
 
 
 
8. 
 
 
 
24. 
 
 
 
9. 
 
 
 
25. 
 
 
 
10. 
 
 
 
26. 
 
 
 
11. 
 
 
 
27. 
 
 
 
12. 
 
 
 
28. 
 
 
 
13. 
 
 
 
29. 
 
 
 
14. 
 
 
 
30. 
 
 
 
15. 
 
 
 
31. 
 
 
 
16. 
 
 
 
 
 
 
 
 
Patient’s Signature:_____________________________________          Date:___-____-____ 
 
 
 

RTOG 0848 
 
 
 
 
 
 
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98 
APPENDIX VII 
RTOG 0848 
PATIENT’S PILL DIARY- CAPECITABINE 
INSTRUCTIONS TO THE PATIENT: 
1.Complete one form for each month of treatment 
2.Record the date and number of pills each time you take them in the morning and in the evening. 
3.Please return the forms to your Research Nurse/Physician weekly during treatment. 
 
Date 
AM: # of pills 
taken 
PM: # of pills 
taken 
Date 
AM: # of pills 
taken 
PM: # of pills 
taken 
1. 
 
 
 
 
17. 
 
 
 
2. 
 
 
 
18. 
 
 
 
3. 
 
 
 
19. 
 
 
 
4. 
 
 
 
20. 
 
 
 
5. 
 
 
 
21. 
 
 
 
6. 
 
 
 
22. 
 
 
 
7. 
 
 
 
23. 
 
 
 
8. 
 
 
 
24. 
 
 
 
9. 
 
 
 
25. 
 
 
 
10. 
 
 
 
26. 
 
 
 
11. 
 
 
 
27. 
 
 
 
12. 
 
 
 
28. 
 
 
 
13. 
 
 
 
29. 
 
 
 
14. 
 
 
 
30. 
 
 
 
15. 
 
 
 
31. 
 
 
 
16. 
 
 
 
 
 
 
 
 
Patient’s Signature:_____________________________________          
Date:________________________ 
 
 
 
 

RTOG 0848 
 
 
 
 
 
 
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99 
APPENDIX VIII: RETIRED STUDY CHAIR (11-APR-2023) 
 
Dr. Ross Abrams retired from Rush University Medical Center after the recruitment and treatment phase 
of this trial.  Dr. Abrams continues to serve as the Principal Investigator of this study during the post 
treatment phase.  
 
Principal Investigator/Radiation Oncology  
Ross A. Abrams, MD 
Rush University Medical Center 
Chicago IL