Clinical trial NCT01196390
Conditions: Esophageal Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Stage IB Esophageal Cancer AJCC v7 Stage IIA Esophageal Cancer AJCC v7 Stage IIB Esophageal Cancer AJCC v7 Stage IIIA Esophageal Cancer AJCC v7 Stage IIIB Esophageal Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2011-02-14; Completion date: 2023-08-15
Enrollment: 203 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer.

Detailed description:
PRIMARY OBJECTIVES:

l. To determine if trastuzumab increases disease-free survival when combined with trimodality treatment (radiation plus chemotherapy followed by surgery) for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing esophageal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To evaluate if the addition of trastuzumab to trimodality treatment increases the pathologic complete response rate and overall survival for patients with HER2-overexpressing esophageal adenocarcinoma.

II. To develop a tissue bank of tumor tissue from patients with non-metastatic esophageal adenocarcinoma.

III. To determine molecular correlates of complete pathologic response, disease-free survival, and overall survival for patients with HER2-overexpressing esophageal adenocarcinoma treated with neoadjuvant and maintenance trastuzumab.

IV. To evaluate predictors of cardiotoxicity in patients with esophageal cancer treated with trastuzumab and chemoradiation.

V. To evaluate adverse events associated with the addition of trastuzumab to trimodality treatment for patients with non-metastatic esophageal adenocarcinoma.

PATIENT-REPORTED QUALITY OF LIFE OBJECTIVES:

I. To determine if the addition of trastuzumab to trimodality treatment improves the patient-reported Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E) Esophageal Cancer Subscale (ECS) score.

II. To determine if an improvement in the FACT-E ECS score at 6-8 weeks post completion of neoadjuvant chemoradiation correlates with pathologic complete response.

III. To determine if pathologic complete response correlates with the FACT-E ECS score at 1 year and/or 2 years from the start of chemoradiation.

IV. To determine if the addition of trastuzumab to trimodality treatment improves the Swallow Index and Eating Index Subscale scores of the FACT-E.

V. To determine if the addition of trastuzumab to paclitaxel, carboplatin, and radiation impacts quality-adjusted survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and 57 and paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Beginning 21-56 days after surgery, patients receive trastuzumab IV over 30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36.

Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery.

After completion of study therapy, patients are followed up every 4 months for 2 years and then yearly thereafter.

Arms: arm 1: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive trastuzumab IV over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and 57 and paclitaxel intravenously IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Beginning 21-56 days after surgery, patients receive trastuzumab IV over 30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36.
Interventions: intervention 1: Carboplatin intervention 2: Laboratory Biomarker Analysis intervention 3: Paclitaxel intervention 4: Quality-of-Life Assessment intervention 5: Radiation Therapy intervention 6: Therapeutic Conventional Surgery intervention 7: Trastuzumab
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given IV intervention 4: Ancillary studies intervention 5: Undergo radiation therapy intervention 6: Undergo surgery intervention 7: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
For Protocol Amendment 6 to: RTOG 1010, A Phase III Trial Evaluating the Addition of Trastuzumab to 
Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma 
 
NCI/Local Protocol #: RTOG 1010 
 
NCI Protocol Version Date: November 15, 2018 
 
Section 
Change 
Global 
• 
Formatting and typographical errors were corrected as needed. 
• 
The protocol version date was updated in the document footer.  
 
Cover pages 
Study Team  
 
Contact information for Lisa Kachnic, Lawrence P. Leichman, Heinz-Joseph Lenz, 
and Kathryn Winter were updated. 
 
Document History Table 
This amendment was added. 
 
CTSU Information 
• 
This table was updated per NCI required language. 
• 
The suite number for NRG Oncology’s office address was updated from 
“1600” to “1720”. 
5.0 
5.3.1 
Revisions to these sections were made to reflect the most updated NCI required 
language. 
 
7.10 
 
Due to CTEP’s migration from CTCAE v 4.0 to CTCAE v 5.0, the protocol was 
revised to reflect the following: 
• 
CTCAE v 4.0 will be utilized for AE reporting until March 31, 2018; 
• 
Beginning April 1, 2018, CTCAE version 5.0 will be utilized for CTEP-AERS 
reporting; 
• 
All study case report forms will continue to use CTCAE version 4.0. 
 
12.0 
The suite number for NRG Oncology’s office address was updated from “1600” to 
“1720”. 


1                
RTOG 1010; version date November 15, 
2018 
NRG ONCOLOGY 
 
RTOG 1010 
 
A PHASE III TRIAL EVALUATING THE ADDITION OF TRASTUZUMAB TO 
TRIMODALITY TREATMENT OF HER2-OVEREXPRESSING ESOPHAGEAL 
ADENOCARCINOMA 
 
This trial is part of the National 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 organizations: the Alliance for Clinical Trials in Oncology; ECOG-ACRIN Medical Group; and 
SWOG. 
 
NRG Oncology Study Team (15-NOV-2018) 
(Study Team continued on next page) 
 
 
 
Principal Investigator/Medical Oncology 
Howard Safran, MD 
The Brown University Oncology Group 
593 Eddy Street 
Providence, RI 02903 
401-444-6217/FAX 401-444-8417 
hsafran@lifespan.org  
 
Radiation Oncology Co-Chair 
Theodore S. Hong, MD  
Massachusetts General Hospital 
100 Blossom St  
Cox 3 
Boston, MA 02114 
617-724-1159/FAX 617-726-2603 
tshong1@partners.org  
 
Radiation Oncology Co-Chair 
Michael Haddock, MD 
Mayo Clinic 
200 First St SW 
Rochester, MN 55905 
507-284-2669/FAX 507-284-0079 
haddock.michael@mayo.edu 
 
Quality of Life Co-Chair 
Lisa Kachnic, MD 
Radiation Oncology, Vanderbilt University Medical 
Center 
2220 Pierce Avenue, B-1034A 
Nashville, TN 37232 
615-343-3523/Fax: 615-343-3075 
lisa.a.kachnic@vumc.org 
 
 
 
Correlative Science Co-Chair 
Chandan Guha, MD, PhD 
Department of Radiation Oncology 
Montefiore Medical Center 
Albert Einstein College of Medicine 
111 East 210 Street 
Bronx, NY 10467 
718-920-2702/FAX 718-231-5064 
cguha@montefiore.org  
 
Translational Co-Chair 
Ulrich Rodeck, MD, PhD 
Thomas Jefferson University 
233 S 10th Street; BLSB 409 
Philadelphia, PA 19107 
215-503-5622/FAX 215-503-5788 
ulrich.rodeck@mail.jci.tju.edu 
 
Pathology Co-Chair 
Murray Resnick, MD, PhD 
The Rhode Island Hospital 
593 Eddy Street 
Providence RI 02930 
401-444-4380/FAX 401-444-8514 
mresnick@lifespan.org  
 
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3198/ FAX 215-928-0153 
winterk@nrgoncology.org 
 


2                
RTOG 1010; version date November 15, 
2018 
RTOG 1010 
 
A PHASE III TRIAL EVALUATING THE ADDITION OF TRASTUZUMAB TO 
TRIMODALITY TREATMENT OF HER2-OVEREXPRESSING ESOPHAGEAL 
ADENOCARCINOMA 
 
Study Team (Continued) (15-NOV-2018) 
 
 
Medical Oncology Co-Chair/SWOG 
Lawrence P. Leichman, MD 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive 
Suite 0698 
La Jolla, CA 92093 US 
760-416-4860 
lleichman@ucsd.edu 
 
Correlative Science Co-Chair/SWOG 
Heinz-Joseph Lenz, MD 
University of Southern California 
Norris Comprehensive Cancer Center 
1441 Eastlake Avenue 
NOR 3456 
Los Angeles, CA 90033  
323-865-3955/FAX 323-865-0061 
lenz@usc.edu  
 
Medical Oncology Co-Chair/ECOG-ACRIN 
Lakshmi Rajdev, MD 
Montefiore Medical Center 
1825 Eastchester Road 
Room 2, South 50 
Bronx, NY 10461 
718-904-2900/FAX:718-904-3892 
lrajdev@montefiore.org 
 
Radiation Oncology Co-Chair/Alliance 
Thomas Dipetrillo, MD 
The Rhode Island Hospital 
593 Eddy Street 
Providence RI, 02903 
401-444-8331/FAX 401-444-5335 
 tdipetrillo@lifespan.org  
 
Thoracic Surgery Co-Chair/Alliance 
Dennis Wigle, MD, PhD. 
Mayo Clinic 
200 First Street, SW 
Rochester, MD 55905 
507-284-8462/FAX 507-284-0058 
Wigle.Dennis@mayo.edu 
 
  
        Medical Oncology Co-Chair/ NRG Oncology (formerly NSABP) 
        Michael J. Guarino, MD 
        NSABP Foundation, Inc.  
        Four Allegheny Center – 5th Floor 
        Pittsburgh, PA 15212-5234 
        412-330-4600/FAX: 412-330-4660 
        mguarino@cbg.org 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
Trastuzumab 
NCI/PMB 
688097 
 
 
 
Participating Sites 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 


3                
RTOG 1010; version date November 15, 
2018 
RTOG 1010 
 
A PHASE III TRIAL EVALUATING THE ADDITION OF TRASTUZUMAB TO 
TRIMODALITY TREATMENT OF HER2-OVEREXPRESSING ESOPHAGEAL 
ADENOCARCINOMA 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 6 
November 15, 2018 
N/A 
Amendment 5 
June 13, 2016 
June 27, 2016 
Closure 
- 
November 9, 2015 
Amendment 4 
November 5, 2014 
January 12, 2015 
Update  
April 17, 2014 
April 17, 2014 
Update 
August 20, 2013 
August 20, 2013 
Amendment 3 
July 16, 2013 
August 20, 2013 
Update 
April 27, 2012 
April 27, 2012 
Amendment 2 
February 22, 2012 
April 10, 2012 
Update 
December 20, 2011 
December 20, 2011 
Update 
August 16, 2011 
August 16, 2011 
Amendment 1 
July 26, 2011 
August 16, 2011 
Update 
February 3, 2011 
February 3, 2011 
Activation 
December 13, 2010 
December 30, 2010 
 
 
 
NRG Oncology 
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. 


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RTOG 1010; version date November 15, 
2018 
RTOG 1010 
 
A PHASE III TRIAL EVALUATING THE ADDITION OF TRASTUZUMAB TO 
TRIMODALITY TREATMENT OF HER2-OVEREXPRESSING ESOPHAGEAL 
ADENOCARCINOMA 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (15-NOV-2018) 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the 
Portal should alert the CTSU 
Regulatory Office immediately 
at 1-866-651-2878 to receive 
further instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at ctsucontact@westat.com 
Submit study data to: 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103  
 
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 Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ web site is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
  
 
 


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RTOG 1010; version date November 15, 
2018 
 
TABLE OF CONTENTS (11/5/14) 
SCHEMA (2/22/12) ....................................................................................................................................... 7 
ELIGIBILITY CHECKLIST—STEP 1 (12/30/10) ........................................................................................... 8 
ELIGIBILITY CHECKLIST—STEP 2 (HER2-POSITIVE PATIENTS ONLY) (7/26/11) ............................... 11 
(PAGE 1 OF 2) ............................................................................................................................................ 11 
1.0 
INTRODUCTION ............................................................................................................................. 13 
1.1  
Trimodality Treatment of Esophageal Cancer ............................................................................ 13 
1.2  
The HER2 Gene .......................................................................................................................... 13 
1.3  
HER2 Expression in Esophageal Adenocarcinoma .................................................................... 13 
1.4  
Trastuzumab Increases Survival in HER2-Overexpressing Esophageal Cancer ....................... 13 
1.5  
Selection of Paclitaxel/Carboplatin/Radiation for the Control Arm .............................................. 14 
1.6  
Decision to Include Esophageal Tumors That Are FISH+ and/or IHC 3+ .................................. 14 
1.7  
Maintenance Trastuzumab .......................................................................................................... 14 
1.8  
Issues Related to Cardiac Toxicity .............................................................................................. 15 
1.9  
Preliminary Data: Trastuzumab with Chemoradiation for Esophageal Cancer .......................... 15 
1.10  
Esophageal Cancer Related Quality of Life ................................................................................ 16 
1.11  
Summary of Study Rationale ...................................................................................................... 19 
2.0 
OBJECTIVES .................................................................................................................................. 19 
2.1 
Primary Objective ........................................................................................................................ 19 
2.2 
Secondary Objectives ................................................................................................................. 20 
3.0 
PATIENT SELECTION  ................................................................................................................... 20 
3.1 
Conditions for Patient Eligibility  .................................................................................................. 20 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 21 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT...................................................................... 22 
4.1 
Required Evaluations/Management  ........................................................................................... 22 
4.2 
Strongly Recommended Evaluations/Management .................................................................... 22 
5.0 
REGISTRATION PROCEDURES  .................................................................................................. 22 
5.1 
Pre-Registration Requirements for 3D-CRT and IMRT Treatment Approaches ........................ 23 
5.2 
Digital RT Data Submission to NRG Oncology Using TRIAD  .................................................... 24 
5.3 
Regulatory Pre-Registration Requirements  ............................................................................... 24 
5.4 
Summary of Patient Registration Procedures ............................................................................. 26 
5.5 
Registration  ................................................................................................................................ 27 
6.0 
RADIATION THERAPY  .................................................................................................................. 27 
6.1 
Dose Specifications  .................................................................................................................... 28 
6.2 
Technical Factors ........................................................................................................................ 28 
6.3 
Localization, Simulation, and Immobilization  ............................................................................. 28 
6.4 
Treatment Planning/Target Volumes  ......................................................................................... 28 
6.5 
Critical Structures  ....................................................................................................................... 29 
6.6 
Documentation Requirements ..................................................................................................... 30 
6.7 
Compliance Criteria  .................................................................................................................... 30 
6.8 
R.T. Quality Assurance Reviews................................................................................................. 31 
6.9 
Radiation Adverse Events ........................................................................................................... 31 
6.10 
Radiation Adverse Event Reporting ............................................................................................ 31 
7.0 
DRUG THERAPY ............................................................................................................................ 33 
7.1 
Treatment  ................................................................................................................................... 33 
7.2 
Details of Chemotherapy  ............................................................................................................ 33 
7.3 
Trastuzumab (Herceptin®) Study Agent Information  ................................................................. 34 
7.4 
Paclitaxel Study Agent Information  ............................................................................................ 40 
7.5 
Carboplatin Study Agent Information  ......................................................................................... 41 
7.6 
Clinical Trials Agreement ............................................................................................................ 42 
7.7 
Dose Modifications: Trastuzumab ............................................................................................... 43 
7.8 
Dose Modifications: Paclitaxel and Carboplatin  ......................................................................... 44 
7.9 
Modality Review .......................................................................................................................... 46 
7.10 
Adverse Events  .......................................................................................................................... 46 


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RTOG 1010; version date November 15, 
2018 
7.11 
CTEP-AERS Expedited Reporting Requirements  ..................................................................... 47 
8.0 
SURGERY  ...................................................................................................................................... 50 
9.0 
OTHER THERAPY .......................................................................................................................... 50 
9.1 
Permitted Therapy ....................................................................................................................... 50 
9.2 
Non-Permitted Therapy ............................................................................................................... 50 
10.0 
TISSUE/SPECIMEN SUBMISSION  ............................................................................................... 50 
10.1 
Tissue/Specimen Submission  .................................................................................................... 50 
10.2 
Tissue Collection for Central Review of HER2 for Eligibility – Mandatory  ................................. 51 
10.3 
Specimen Collection for Banking  Recommended ..................................................................... 53 
10.4 
Reimbursement  .......................................................................................................................... 56 
10.5 
Confidentiality/Storage ................................................................................................................ 56 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 56 
11.1 
Study Parameters: See Appendix I. ............................................................................................ 56 
11.2 
Measurement of Response ......................................................................................................... 56 
11.3 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 56 
11.4 
Quality of Life and Health Utility Assessments ........................................................................... 57 
12.0 
DATA COLLECTION ....................................................................................................................... 57 
12.1 
Summary of Data Submission .................................................................................................... 57 
12.2 
Summary of Dosimetry Digital Data Submission  ....................................................................... 58 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 59 
13.1 
Endpoints .................................................................................................................................... 59 
13.2 
Stratification................................................................................................................................. 59 
13.3 
Sample Size and Power Justification .......................................................................................... 59 
13.4 
Power Information for Health Reported Quality of Life – FACT-E .............................................. 60 
13.5 
Analysis Plan  .............................................................................................................................. 61 
13.6 
Gender and Minorities ................................................................................................................. 65 
REFERENCES ............................................................................................................................................ 66 
APPENDIX I ................................................................................................................................................ 70 
APPENDIX II ............................................................................................................................................... 74 
APPENDIX III .............................................................................................................................................. 75 
APPENDIX IV .............................................................................................................................................. 77 
APPENDIX V  .............................................................................................................................................. 78 
 
 


7                
RTOG 1010; version date November 15, 
2018 
 
RADIATION NRG ONCOLOGY 
 
RTOG 1010 
 
A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-
Overexpressing Esophageal Adenocarcinoma 
 
 
SCHEMA (2/22/12) 
 
STEP 1 REGISTRATION 
↓ 
HER2 Testing 
Mandatory submission of tissue for HER2 testing 
NOTE:  Tumor tissue must be received and patients must have confirmed HER2 positivity before 
randomization can occur. Patients with confirmed HER2 negativity will not be randomized.  
↓ 
STEP 2 REGISTRATION 
 
STRATIFY 
Presence of adenopathy: No vs Yes—celiac absent vs. Yes—celiac present ≤ 2 cm 
 
RANDOMIZE 
↓ 
↓ 
Arm 1  
Radiation (50.4 Gy), paclitaxel, carboplatin, and 
trastuzumab  
 
Followed by surgery 5-8 weeks after completion 
of radiation  
 
Then maintenance trastuzumab, every 3 weeks 
for 13 treatments 
 
Arm 2  
Radiation (50.4 Gy), paclitaxel, and 
carboplatin 
 
Followed by surgery 5-8 weeks after 
completion of radiation 
 
Note: 3D-CRT and IMRT credentialing is required for this protocol; see Section 5.1. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility) (11/5/14) 
Pathologically confirmed HER2 expressing adenocarcinoma of the esophagus, centrally assessed, 
involving the mid (up to 25 cm), distal and/or esophagogastric junction. 
 
Required Sample Size: 197


8                
RTOG 1010; version date November 15, 
2018 
 
ELIGIBILITY CHECKLIST—STEP 1 (12/30/10) 
(page 1 of 3) 
NRG Oncology Institution #   
 
RTOG 1010 
 
 
 
Case #  
  
 
 
_______  (Y)  
1. 
Does the patient have a histologically confirmed primary adenocarcinoma of the 
esophagus that involves the mid (up to 25 cm), distal, or esophagogastric 
junction? (Extension into the stomach, up to 5 cm, is allowed.) 
 
_______  (Y)  
2. 
Did the patient have an endoscopy with biopsy? 
 
_______  (Y)  
3. 
Will the patient’s tissue be submitted for HER2 testing? 
 
_______ (Y/N) 
4. 
Based on the CT scan of the chest/abdomen/pelvis or whole-body PET/CT does 
the patient have regional adenopathy that includes para-esophageal, gastric, 
gastrohepatic, and celiac nodes?  
              (Y/NA)  
If celiac nodes are involved are they ≤ 2 cm?   
 
_______ (Y) 
5. 
Based on the CT scan of the chest/abdomen/pelvis or whole-body PET/CT  and 
endoscopy is the patient’s preliminary cancer stage, according to the AJCC 7th 
edition staging, either T1N1-2, T2-3N0-N2? 
 
_______ (N) 
6. 
Based on the CT scan of the chest/abdomen/pelvis or whole-body PET/CT and 
endoscopy does the patient have distant metastases? 
 
_______(Y) 
7.  Is the patient’s Zubrod performance status 0-2? 
 
_______(Y) 
8. 
Is the patient at least 18 years of age? 
 
_______(Y) 
9. 
Does the patient have adequate bone marrow function as specified in Section 
3.1? 
 
_______(Y) 
10. Do the patient’s other laboratory values meet the criteria in Section 3.1? 
 
             (Y/NA)     11.   For women of childbearing potential, was a serum or urine pregnancy test 
completed within 14 days of registration? 
 
              (Y)  
 
If yes, was the pregnancy test negative? 
 
____(Y/NA) 
12. If a women of childbearing potential or a sexually active male, is the patient willing 
to practice adequate contraception while on study and for at least 60 days after 
the last dose of chemotherapy or trastuzumab? 
 
_______(Y)       
13.  Did the patient provide study specific informed consent prior to study entry? 
 
_______(N) 
14. Does the patient have cervical esophageal carcinoma? 
 
_______(N) 
15. Has the patient had prior chemotherapy for esophageal cancer? 
 
_______(N) 
16. Has the patient had prior radiation for esophageal cancer or prior chest 
radiotherapy? 
 
_______(N) 
17. Has the patient had prior anthracycline or taxane? 
 
_______(N) 
18. Is there evidence of tracheoesophageal fistula or invasion into the trachea or 
major bronchi? 


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RTOG 1010; version date November 15, 
2018 
 
 
 
 
 
 
 
 
 
 
ELIGIBILITY CHECKLIST—STEP 1 (2/22/12) 
(page 2 of 3) 
NRG Oncology Institution #   
 
RTOG 1010 
 
 
 
Case #  
 
 
     
 
  
_______(N/Y) 
19. Has the patient had prior invasive malignancies, except for non-melanomatous 
skin cancers? 
 
 
           _______(Y) If yes, has the patient been disease free for ≥ 2 years? 
 
_______(N) 
20. Has the patient had prior therapy that directly targets the HER1 (EGFR) and/or the 
HER2 pathway? 
 
_______(N) 
21.   Has the patient had prior trastuzumab? 
 
_______(N) 
22. Has the patient had allergic reactions to the study drugs involved in this protocol 
or to a monoclonal antibody? 
 
_______(N) 
23. Does the patient have a history of congestive heart failure? 
 
_______(N) 
24. Does the patient have severe, active co-morbidity, as defined in Section 3.2? 
 
_______(N) 
25. Is the patient pregnant or lactating? 
 
The following questions will be asked at Study Registration for STEP 1:  
 
3D-CRT and IMRT credentialing is required for this protocol. 
 
 
 
1. Institutional person randomizing case 
 
 
(Y) 
2. Has the STEP 1 Eligibility Checklist been completed? 
 
 
(Y) 
3. In the opinion of the investigator, is the patient eligible? 
 
 
 
4. Date informed consent signed 
 
 
 
5. Participant Initials (Last First Middle)  
 
 
 
6. Verifying Physician 
 
 
 
7. Patient ID  
 
 
 
8. Date of Birth 
 
 
 
9. Race 
 
 
  
10. Ethnicity 
 
 
 
11. Gender 
 
 
 
12. Country of Residence 
 
 
 
13. Zip Code (U.S. Residents) 
Continued on next page 
 


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RTOG 1010; version date November 15, 
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ELIGIBILITY CHECKLIST—STEP 1 (2/22/12) 
   
  
 
 (page 3 of 3) 
NRG Oncology Institution #   
 
RTOG 1010 
 
 
Case #  
 
 
 
 
 
14. Method of Payment 
 
 
 
15. Any care at VA or Military Hospital? 
 
 
 
 
16. Calendar Base Date 
 
 
 
 
17. Randomization Date  
 
                   (Y/N) 
 
18. Have you obtained the patient's consent for his or her tissue to be kept for 
use in research to learn about, prevent, treat, or cure cancer?  
 
                   (Y/N) 
 
19. Have you obtained the patient's consent for his or her blood to be kept for   
use in research to learn about, prevent, treat, or cure cancer?  
 
                   (Y/N)            20. Have you obtained the patient's consent for his or her urine to be kept for use 
in research to learn about, prevent, treat, or cure cancer?  
 
                   (Y/N) 
 
21. Have you obtained the patient's consent for his or her tissue to be kept for 
use in research about other health problems (for example: causes of 
diabetes, Alzheimer's disease, and heart disease)?   
 
                   (Y/N) 
 
22. Have you obtained the patient's consent for his or her blood to be kept for 
use in research about other health problems (for example: diabetes, 
Alzheimer's disease, or heart disease)? 
 
                    (Y/N) 
 
23. Have you obtained the patient's consent for his or her urine to be kept for use 
in research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
                      (Y/N)        24.  Have you obtained the patient's consent to allow someone from this 
institution to contact him or her in the future to take part in more research?  
 
                       (Y/N)       25.  Will IMRT be used to treat the patient?


11                
RTOG 1010; version date November 15, 
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ELIGIBILITY CHECKLIST—STEP 2 (HER2-POSITIVE PATIENTS ONLY) (7/26/11) 
(PAGE 1 OF 2) 
NRG Oncology Institution #   
RTOG 1010 
 
Case #  
 
      
 
 
_______ (Y)  
1. 
Is the patient’s esophageal cancer HER2 positive by central testing?  
 
_______ (Y) 
2. 
Has the patient had surgical, medical oncology, and radiation oncology 
consultations per Section 3.1 of the protocol? 
 
_______ (Y) 
3. 
Were the history and physical exam with weight performed within the timeframes 
required in Section 3.1? 
 
_______ (Y) 
4. 
Was the whole-body PET/CT scan performed within the time frame required in 
Section 3.1? 
 
_______(Y) 
5. 
Was and EKG performed within 56 days prior to registration? 
 
_______(Y)      
6.    Did the patient have a LVEF ≥ institutional lower limit of normal by cardiac echo or 
MUGA within 56 days prior to registration? 
 
_______ (Y) 
7. 
Based on the PET scan and endoscopic ultrasound is the patient’s clinical cancer 
stage, according to the AJCC 7th edition staging, either T1N1-2, T2-3N0-N2? 
 
_______(N) 
8. 
Does the patient have T1N0 disease, T4 disease, cervical esophageal carcinoma 
or proximal esophageal cancer? 
 
_______(N) 
9. 
Is there evidence of tracheoesophageal fistula or invasion into the trachea or 
major bronchi? 
 
_______(Y) 
10. Zubrod performance status 0-2? 
 
_______(N) 
11. Has the patient developed any of the comorbidities detailed in Section 3.2.12 
since Step 1 registration? 
 
_______(Y/NA) 
12. For women of childbearing potential was a negative serum pregnancy test 
obtained within 14 days prior to registration? 
 
_______(Y) 
13. Was serum creatinine ≤ 2 x upper limit of normal within 14 days prior to Step 2 
registration? 
 
The following questions will be asked at Study Registration for STEP 2:  
 
3DCRT credentialing is required for this protocol 
 
 
1. Institutional person randomizing case 
 
                      (Y/N) 
2. 
Is the patient going to receive protocol treatment? 
 
 
 
If no, provide reason: 
 
         
 
 
1. HER2 negative 
 
 
 
 
2. Does not meet eligibility requirements, specify: ____________ 
 
 
3. Physician preference  
 
 
 
 
4. Patient refusal  
 
 
 
 
5. Other complicating disease  
 
 
 
 
5. Other, specify: ______________ 
 


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2018 
ELIGIBILITY CHECKLIST—STEP 2 (7/16/13) 
    
 
 
 
 
  
 (page 2 of 2) 
NRG Oncology Institution #   
RTOG 1010 
 
 
 
Case #  
 
 
 
 
 
 
3. Participant Initials (Last, First, Middle)  
 
 
 
4.  Verifying Physician 
 
 
 
5. Patient ID 
 
 
 
6. Calendar Base Date 
 
 
 
7. Randomization Date 
 
 
 (Y) 
8. Has the Step 2 Eligibility Checklist been completed? 
 
 
 (Y) 
9. In the opinion of the investigator, is the patient eligible? 
 
 
        10.  Medical Oncologist’s Name 
 
 
        11.  Surgeon Name 
 
                       (Y/N) 
12. Patient has consented to take part in the quality of life study? 
 
 
 
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: specify_________________ 
 
 
                         
13.  Presence of adenopathy [(1) No or (2) Yes adenopathy, but celiac absent or     
(3) Yes adenopathy and celiac present ≤ 2 cm)] 
 
                          (Y)  
14. Is the patient HER2 positive? 
 
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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1.0 INTRODUCTION 
1.1  
Trimodality Treatment of Esophageal Cancer 
Neoadjuvant chemoradiation followed by esophagectomy has become a standard of care 
for esophageal cancer (Tepper 2008; Kleinberg 2007). Unfortunately, the majority of 
patients will relapse and die of their disease. Therapies that block aberrant growth factor 
pathways have substantial promise as a treatment for human malignancies, including 
esophageal cancer (Mendelsohn 1992; Makuda 1991). An important subset of patients 
with esophageal adenocarcinoma have HER2 overexpression (Safran 2007; Bang 2008; 
Grugan 2008; Brien 2000). Blocking this powerful growth factor signal may improve 
patient outcome.  
 
1.2  
The HER2 Gene 
The HER receptor family consists of 4 transmembrane glycoproteins (HER1-HER4) 
(Makuda 1991). HER2 was the second member of the receptor family to be described. 
Structurally, HER2 is very closely related to HER1; however, it is inactivated more slowly 
than the other HER receptors, and its effects on cell proliferation and growth may last 
longer (Yarden 2001). No natural ligands are known to bind to HER2. Heterodimerization 
with other HER receptors and transactivation is the primary mode for initiating HER2 
regulated signaling (Slamon 1987). HER2 is the preferred dimerization partner of the 
other HER family members (Vogel 2002).  
 
The HER2 gene encodes a transmembrane glycoprotein receptor, p185HER2, that is 
targeted by the humanized anti-p185HER2 monoclonal antibody trastuzumab (Besalga 
2005). Trastuzumab has received FDA approval for treatment of breast cancer. In the 
metastatic setting, trastuzumab increases survival in women with HER2-overexpressing 
breast cancer (Slamon 2001). In the adjuvant setting, trastuzumab dramatically reduces 
disease 
recurrence 
and 
increases 
survival 
for 
HER2-overexpressing 
breast 
adenocarcinoma (Romand 2005; Piccart-Gebhart 2005). 
 
1.3  
HER2 Expression in Esophageal Adenocarcinoma 
Recent studies using modern, established techniques for quantifying HER2 expression 
demonstrate rates of HER2 overexpression in esophageal adenocarcinoma that are 
similar to breast cancer (Safran 2007; Bang 2008; Grugan 2008; Brien 2000). Brien et al 
(2000) reported HER-2/neu gene amplification by fluorescence in situ hybridization 
(FISH) in 19% of patients, and this correlated with poor survival. Similar rates were 
reported by the Brown University Oncology Group (22% FISH+) [Safran 2007]. When 
HER2 positivity was defined as either FISH+ or immunohistochemistry (IHC) 3+, 33% of 
patients with distal esophageal adenocarcinoma overexpressed HER2 (Safran 2007). 
 
The ToGA trial represents the largest phase III trial evaluating the potential role of 
trastuzumab in advanced gastroesophageal cancer.  A total of 3807 patients were 
evaluated, representing the largest dataset to describe the extent of HER2-positive 
disease in advanced esophagogastric cancer (Bang 2008). Formalin-fixed, paraffin-
embedded esophagogastric samples were centrally assayed by both modified 
HercepTest™ (IHC) and pharmDx (FISH) in parallel.  
 
A score of IHC 3+ and/or FISH positive was defined as HER2 positive. The HER2 
positivity was 22.1% for all patients with gastric and esophageal cancer. HER2 positivity 
was significantly associated with tumor location. The HER2 positivity was 19.9% for 
patients with gastric cancer. For patients with adenocarcinoma of the gastroesophageal 
junction and distal esophagus, the HER2 positivity rate was 32.2% in the ToGA trial.  
 
1.4  
Trastuzumab Increases Survival in HER2-Overexpressing Esophageal Cancer 
The ToGA trial evaluated the addition of trastuzumab to cisplatin and a fluoropyrimidine 
(5-FU or capecitabine). Median overall survival was significantly improved with 
trastuzumab and chemotherapy as compared to chemotherapy alone, 13.5 versus 11.1 


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2018 
months, respectively [p = 0.0048, hazard ratio (HR) 0.74; 95% confidence interval (CI) 
0.6-0.91] (Van Cutsem 2009). Overall response rate was 47.3% in patients receiving 
trastuzumab plus chemotherapy, as compared to 35.5% with chemotherapy alone (p = 
0.0017). Safety profiles were similar, with no unexpected adverse events in the 
trastuzumab plus chemotherapy group. There was no difference in symptomatic 
congestive heart failure. Asymptomatic left ventricular ejection fraction (LVEF) decreases 
were reported in 4.6% of the trastuzumab-plus-chemotherapy group as compared to 
1.1% of the chemotherapy group.  
 
1.5  
Selection of Paclitaxel/Carboplatin/Radiation for the Control Arm 
There are many reasonable chemoradiation regimens in esophageal cancer (Herskovic 
1992; Urba 2001; Minsky 1999; Walsh 1996; Kleinberg 2006; Bosset 1997; Burmeister 
2005; Ilson 2009; Ku 2009, Kleinberg 2007). This protocol will utilize the regimen of 
weekly paclitaxel, carboplatin, and radiation following the report of the phase III trial by 
Gaast et al at ASCO 2010. This was a phase III study randomizing 363 patients to 
surgery alone verses trimodality therapy with paclitaxel, carboplatin, and concurrent 
radiation following by surgery. Major toxicities (grade ≥ 3) in the chemoradiation arm 
included leukopenia in 7% of patients.  Nonhematologic toxicities were all below 5%. The 
reported R0 resection rate was 92.3% in the chemoradiation arm versus 64.9% in the 
surgery alone arm. In 132 resected specimens receiving trimodality treatment, the 
pathologic complete response rate was 32.6%. In-hospital mortality was 3.7% in the 
surgery alone arm versus 3.8% in the chemoradiation arm. With a median follow-up of 32 
months, 70 and 97 patients had died in the chemoradiation group versus surgery alone 
group, respectively. The overall survival was significantly better (p = 0.011) in the group 
of patients treated with chemoradiation (HR 0.67 [95% CI 0.50-0.92]). Median survival 
was 49 months in the chemoradiation arm versus 26 months in the surgery alone arm. 
Survival rates of 1, 2, and 3 years are 82%, 67% and 59% in the chemoradiation arm and 
70%, 52% and 48% in the surgery alone arm.  
 
The protocol will utilize the standard preoperative radiation dose of 50.4 Gy used in the 
pilot study of trastuzumab with chemoradiation (Safran 2007) and phase III United States 
preoperative esophageal cancer studies (Tepper 2008). 
 
1.6  
Decision to Include Esophageal Tumors That Are FISH+ and/or IHC 3+ 
Subset analysis in the ToGA trial suggested that patients with HER2-positive esophageal 
cancer who benefited most were those with tumors that were 3+ IHC positive; patients 
with tumors that were FISH+ but had weak IHC staining did not benefit. However, in 
breast cancer, it has been strongly established that all FISH+ patients may benefit from 
adjuvant trastuzumab, with an approximate 50% reduction in recurrence. It is possible 
that interpretation of IHC in esophageal cancer may have been different as compared to 
previous breast cancer studies. This study will use centralized testing by IHC and FISH 
for HER2 positivity and will include all patients that are FISH+ or IHC 3+, since this 
previously has been established as beneficial in the adjuvant setting for patients with 
HER2-positive breast cancer.  
 
1.7  
Maintenance Trastuzumab   
Maintenance trastuzumab will be administered for approximately 1 year based on data 
from 4 seminal adjuvant breast cancer trials: the National Surgical Adjuvant Breast and 
Bowel Project Trial (NSABP) B-31; the North Central Cancer Treatment Group (NCCTG) 
study N-9831; the HERA trial; and the BCIRG 0006 (Romand 2005; Piccart-Gebhart 
2005; Perez 2007; Smith 2007; Untch 2008; Slamon 2006; Mackey 2009; Robert 2007). 
NSABP B-31 and N-9831 were initially designed as separate trials comparing doxorubicin 
plus cyclophosphamide followed by paclitaxel with and without 1 year of adjuvant 
trastuzumab. In the latest combined analysis, there was a 49% reduction in the risk of 
disease recurrence trastuzumab (4-year disease-free survival  86% versus 73% percent; 


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RTOG 1010; version date November 15, 
2018 
HR 0.51), and a 37% reduction in the risk of death (4-year overall survival 93% versus 
89%; HR 0.63) (Perez 2007). 
 
The HERA trial, in which 5090 women received standard chemotherapy with or without 1 
or 2 years of adjuvant trastuzumab had similar findings following 1 year of trastuzumab. 
There was a 36% reduction in disease recurrence as well as an improvement in overall 
survival (Piccart-Gebhart 2005; Smith 2007; Untch 2008). Data have not been reported 
for the 2-year group. The BCIRG 006 trial evaluated the efficacy of 2 anthracycline 
containing regiments (AC followed by docetaxel) to a non-anthracycline containing 
regimen (carboplatin and docetaxel) with and without 1 year of adjuvant trastuzumab 
(Slamon 2006; Mackey 2009; Robert 2007). In an initial analysis, the disease-free 
survival favored the trastuzumab-containing regimens and the safety profile favored TCH 
[Taxotere 
(docetaxel)/carboplatin/Herceptin 
(trastuzumab)]. 
There 
were 
fewer 
symptomatic cardiac events and a lower incidence of asymptomatic decline in LVEF with 
TCH compared to either anthracycline group. Furthermore, there were 4 leukemias in the 
anthracycline-containing arms versus none in the TCH-treated women. 
 
All of the previously described trials studied at least 1 year of adjuvant trastuzumab. 
Almost 10,000 patients with HER2-positive breast cancer are included in these 4 trials. 
The FInHER trial evaluated the use of 9 weekly trastuzumab treatments after 
chemotherapy (Joensuu 2006; Joensuu 2009). In this trial, which included 232 patients 
with HER2-positive breast cancer, a benefit of trastuzumab was demonstrated. However, 
it is not known whether short-course trastuzumab would have the same benefit as 1 year 
of maintenance treatment.   
 
1.8  
Issues Related to Cardiac Toxicity 
In the 4 large adjuvant breast cancer trastuzumab trials (NSABP B32, N-9831, HERA, 
and BCIRG), the incidence of severe heart failure (NYHA class III/IV) has ranged from 
0.6% to 4.1%, while the incidence of an asymptomatic decrease in LVEF was between 
7.4% and 17.3% (Telli 2007; Tan-Chiu 2005). Risk factors for cardiotoxicity included the 
use of anthracyclines, advanced age, and a previous risk of cardiac disease. In the 
proposed adjuvant esophageal cancer trial, patients will not receive an anthracycline, and 
all patients will be required to have a normal pretreatment LVEF (Perez 2004). Any 
patient with a history of heart failure will be excluded from this study. 
 
Current evidence suggests that the risk of radiation with concurrent trastuzumab does not 
substantially increase the risk of cardiac dysfunction. Halyard et al (2009) retrospectively 
examined adverse events data from the NCCTG phase III trial, N9831, and directly 
evaluated the effect of trastuzumab on radiation-induced cardiac toxicity. At a median 
follow up of 3.7 years, radiotherapy concurrently with trastuzumab did not increase 
relative frequency of cardiac events, regardless of treatment side, suggesting that 
concurrent adjuvant radiation therapy and trastuzumab was not associated with 
increased acute adverse events.  
 
To carefully monitor for cardiac toxicity, all patients will be required to have physical 
examinations at least every 6 weeks while on maintenance trastuzumab. Furthermore, 
determination of LVEF will be performed at completion of chemoradiation, then at month 
3, 6, 9 and 12. A standard dose modification scheme, which has been applied to adjuvant 
trastuzumab in breast cancer, will be utilized in this study. 
 
1.9  
Preliminary Data: Trastuzumab with Chemoradiation for Esophageal Cancer 
The Brown University Oncology Group performed a pilot trial evaluating the addition of 
trastuzumab to chemoradiation for patients with locally advanced, HER2-overexpressing, 
esophageal adenocarcinoma (Safran 2004; Safran 2007). The goals of this study were to 
establish the safety of trastuzumab both with chemoradiation and continued for 1 year as 
maintenance. Secondary goals were to obtain preliminary survival data. Patients with 


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2018 
adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 
overexpression by IHC were eligible. FISH was performed to determine HER2 gene copy 
number on tumor tissue from all patients. 
 
All patients received cisplatin, 25 mg/m2, and paclitaxel, 50 mg/m2, weekly for 6 weeks 
with radiation, 50.4 Gy. The first and second cohorts of 3 patients received trastuzumab, 
2 mg/kg, and 3 mg/kg bolus followed by weekly x 5 week dosing of 1 mg/kg and 1.5 
mg/kg with chemoradiation. The final 13 patients received trastuzumab, 4 mg/kg, on 
week 1, followed by 2mg/kg for 5 weeks. Maintenance trastuzumab was 6 mg/kg every 
21 days for a total of 1 year of trastuzumab. Attempted surgical resection was not 
required if patients had medical comorbidities or distant adenopathy that precluded 
surgery. Echocardiogram was performed every 4 months. Nineteen patients were 
entered; 7 (37%) had celiac adenopathy and 7 (37%) had retroperitoneal, portal 
adenopathy or scalene adenopathy.   
 
There were no increases in adverse events from the addition of trastuzumab. Acute 
toxicities for all patients are listed in the table below. Multiple toxicities in the same patient 
are scored as separate events. There was only 1 incidence of grade 4 esophagitis and 1 
of grade 3 esophagitis. There were no cardiac toxicities. Prophylactic feeding tubes were 
not used. Other grade 3/4 adverse events included nausea (3), dehydration (1), 
neutropenia (4), hypersensitivity to paclitaxel (1), and infection (1). There were no 
complications from maintenance treatment.  
 
Highest Adverse Event Grade for Each Patient (N=19) 
 
Adverse Event 
Grade 2 
Grade 3 
Grade 4 
Esophagitis 
1 
1 
1 
Nausea 
4 
3 
0 
Dehydration 
1 
1 
0 
Diarrhea 
1 
0 
0 
Neutropenia 
2 
3 
1 
Allergy 
0 
0 
1 
Infection  
1 
1 
0 
Cardiac 
0 
0 
0 
 
The 3-year survival of all 19 patients was 47%, which includes patients not candidates for 
surgical resection due to medical comorbidities or distant adenopathy.  
 
1.10  
Esophageal Cancer Related Quality of Life  
The quality of survival, in addition to the length of survival, is now accepted by 
oncologists as an important clinical endpoint in phase III trial design for patients with 
locally advanced cancers (Burris 1997; ASCO 1996). To date, there has been limited 
available literature using formal health-related quality of life (QOL) measures for patients 
with esophageal cancer receiving definitive chemoradiation on prospective trials. 
However, RTOG has evaluated QOL for patients with localized esophageal cancer on a 
large randomized phase III effort (Kachnic 2001). RTOG 94-05 (Intergroup 0123) 
compared the QOL outcomes for patients with esophageal cancer receiving 
chemoradiation with conventional dose radiation (50.4 Gy) versus high-dose radiation 
(64.8 Gy). QOL was assessed using the Functional Assessment of Cancer Therapy 
(FACT) Head & Neck (version 2) (Cella 1993) at baseline, after chemoradiation, at 8 
months after therapy, and at 1 year. Two-year outcome analysis showed no survival or 
local control benefit for the 64.8 Gy arm (Kachnic 2001). In terms of QOL, functional and 
swallowing scores were decreased after chemoradiation in both treatment arms, with 
total QOL scores significantly poorer than baseline in the 64.8 Gy arm.  
 


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One factor associated with the paucity of QOL data to assess treatment efficacy for 
esophageal cancer has been the lack of a validated QOL instrument tailored to this 
patient population. More recently, the FACT-Esophageal (FACT-E) questionnaire has 
been developed, used prospectively (Brooks 2002), and undergone validation (Darling 
2006) for adult patients with esophageal cancer. 
 
Scores on the FACT-E correlate well with several important clinical factors and were 
found to be responsive to change in patients treated with esophagectomy alone and in 
those treated with neoadjuvant chemoradiotherapy (Darling 2006). 
 
In trimodality therapy for locally advanced esophageal cancer, it is difficult to predict 
which patients will benefit from surgical resection following neoadjuvant chemoradiation. 
To this end, several methods to predict response to neoadjuvant chemoradiation are 
under investigation. Repeated computed tomography scanning, endoscopy, and 
endoscopic ultrasound have not been particularly helpful in predicting early response to 
chemoradiation therapy (Beseth 2000; Swisher 2004). The use of therapy-induced 
metabolic changes in the tumor glucose metabolism by positron emission tomography 
(PET) has shown some reliability in adenocarcinoma of the gastroesophageal junction 
(Ott 2006; Weber 2001). Yet, this method has not shown enough accuracy at predicting 
nonresponders in squamous cell carcinoma or in patients receiving chemoradiation. An 
improvement of the leading symptoms (in this case, dysphagia) early in the treatment 
course also may prove useful as a predictor of chemoradiation response (Darling 2006). 
In patients treated with neoadjuvant chemoradiotherapy, a significant improvement was 
reported in the esophageal cancer swallowing subscale (Swallowing Index Subscale 
Score) and eating subscale (Eating Index Subscale Score) of the FACT-E at 6 to 8 weeks 
following chemoradiation (Darling 2006). It is therefore hypothesized, for the primary QOL 
question in this study, that an improvement in patient-reported QOL (specifically, the 
Esophageal Cancer Subscale, or ECS, of the FACT-E) at 6 weeks post-completion of 
neoadjuvant chemoradiation is predictive of pathologic complete response.   
1.10.1  
The Functional Assessment of Cancer Therapy-Esophageal (FACT-E)  
This QOL instrument has been specifically designed for adults with esophageal cancer. 
The FACT-E questionnaire has been used prospectively (Brooks 2002) and undergone 
validation (Darling 2006). The FACT-E self-reporting scale is comprised of the validated 
FACT-General core (27 general items including the 4 domains of physical well-being, 
social and family well-being, emotional well-being, and functional well-being, which had 
been developed for adults with various cancer diagnosis) (Cella 1993; Overcash 2001), 
combined with the new FACT-E subscale (the ECS), which includes 17 additional items 
specific for symptoms and problems related to esophageal cancer, such as eating, 
appetite, swallowing, pain, talking/communicating, mouth dryness, breathing difficulty, 
coughing, and weight loss. The total FACT-E score is the sum of the esophageal-
specific questions and the FACT-G scores. 
 
Each FACT-E question has a possible 5-point response of 0-4 (i.e., not at all to very 
much). Negatively worded items are reverse scored so that higher scores always 
represent better QOL or less severe symptoms. The total questionnaire takes the 
patient approximately 10 minutes to complete. As with the FACT-G, higher scores 
indicate a better health-related QOL or functioning. The FACT-E 44-item questionnaire 
has undergone psychometric testing in patients with esophageal cancer (Darling 2006). 
The FACT-E had good construct validity (convergence and divergence) when 
compared with the EORTC QLQ 30 and its specific esophageal module. It had very 
good to excellent internal consistency and reliability. FACT-E scores correlated well 
with several important clinical factors and were found to be responsive to change in 
patients treated with esophagectomy alone and in those treated with neoadjuvant 
chemoradiotherapy. 
In 
the 
subset 
of 
patients 
treated 
with 
neoadjuvant 
chemoradiotherapy, a significant improvement was reported in the ECS swallowing 
subscale (Swallowing Index Subscale Score) and eating subscale (Eating Index 


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2018 
Subscale Score) at 6 to 8 weeks following chemoradiation (Darling 2006). The FACT-E, 
version 4, will be used to measure QOL, with the focus on the ECS. Patients will 
complete the FACT-E at the following time points: pretreatment (baseline), 6 weeks 
following chemoradiation plus trastuzumab at the time of restaging prior to surgical 
resection, at 1 year from the start of treatment, and at 2 years from the start of 
treatment. 
 
There are no published data to date demonstrating how QOL is affected by the addition 
of trastuzumab to standard chemoradiation regimens for the treatment of 
gastrointestinal malignancies. Based on the impressive local response rates associated 
with the use of trastuzumab and on data from Darling and colleagues (2006), we also 
hypothesize that the addition of trastuzumab to standard chemoradiation for HER2-
positive locally advanced esophageal cancer will improve the FACT-E ECS score by at 
least 5 points. Further QOL endpoints will determine if the addition of trastuzumab to 
standard chemoradiation improves the Swallowing Index Subscale Score and the 
Eating Index Subscale Score of the FACT-E ECS by at least 2 points and if pathologic 
complete response correlates with the ECS Score at 1 year and/or 2 years from the 
start of treatment. 
1.10.2  
The EuroQol (EQ-5D)  
Patient-reported outcomes (PROs) are increasingly being incorporated into clinical 
trials for documentation of effects of treatment not measured by traditional endpoints, 
such as overall and disease-free survival (Safran 2008). This is important with 
interventions that may increase treatment-related side effects without positively 
impacting survival. Quality-adjusted survival is an endpoint that incorporates a patient’s 
utility or preference of the health state that is combined with the time spent in that 
health state. The resultant is a quality-adjusted life-year (QALY).  Utility can be 
measured by different methods including Standard Gamble, Time Trade-Off, and 
Health Utilities Index III. The EuroQol (EQ-5D) is another instrument for measuring 
utilities. It is a 2-part questionnaire that takes the patient approximately 5 minutes to 
complete (Schulz 2002). The first part consists of 5 items covering 5 dimensions, 
including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension can be graded on 3 levels including: 1-no problem, 2-moderate 
problems, and 3-extreme problems. There are 243 potential health states.  The second 
part is a visual analogue scale (VAS) valuing current health state, measured on a 20 
cm, 10 point-interval scale.  Either the index score or the VAS score can be used in the 
quality-adjusted survival analysis (Wu 2002). The benefit of measuring quality-adjusted 
survival is that the product, quality-adjusted survival, can be compared to the outcomes 
of other interventions across disease sites and can be used by health policy makers to 
rank interventions. 
 
The EQ-5D has been used to evaluate interventions in patients with esophageal 
cancer.  Williams et al (2006) found a baseline utility of .676 and .663 in patients 
undergoing esophageal endoscopy by a physician and nurse, respectively, in the Multi-
Institution Nurse Endoscopy Trial (MINuET). A utility is a patient preference for a 
certain health state, with 0 being death and 1 being perfect health. There are some 
health states with a utility of < 1. At 1 year, patient utility increased to .725 and .703 for 
endoscopy by a physician and nurse, respectively. Jones et al (2003) used the EQ-5D 
to assess heartburn in patients with gastroesophageal reflux disease in Germany and 
Sweden. They found a reduction in health-related QOL in patients with heartburn, with 
patients with more severe heartburn symptoms having reduced quality-adjusted 
survival. Of note, they did not find a relationship between the findings at endoscopy and 
the severity of symptoms as measured by the Gastrointestinal Symptom Rating Scale 
(GSRS) or the EQ-5D.   
 
The EQ-5D will be used to assess quality-adjusted survival. Protocol-eligible patients 
will be included in the quality-adjusted survival analysis only if they have provided 


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2018 
baseline and at least 1 subsequent measurement. Patients will complete the EQ-5D at 
the following time points: pretreatment (baseline), at 1 year from the start of treatment, 
and at 2 years from the start of treatment.  Quality-adjusted survival is then calculated 
as the weighted sum of different time in different health states added up to a total 
quality-adjusted survival time [U=sum of quality (qi) of health states K times the 
duration (si) spent in each health state]. (Glasziou 1990). 
 
The FACT-E and EQ-5D questionnaires are being completed in the currently active 
phase III study, RTOG 0436, evaluating the addition of cetuximab to non-operative 
treatment of esophageal cancer in patients. 
 
For this trial, all protocol eligible-patients (those that are HER2 positive) will be asked to 
participate in the QOL component of this study. In this study, as well as other NRG 
Oncology studies, baseline QOL is not mandated as part of the pretreatment 
evaluation. NRG Oncology feels that this allows patients who want to participate in a 
clinical trial, but who do not want to participate in the QOL portion, to still have access 
to the trial and its potential benefits. However, we have found that on our ongoing 
RTOG 0436 study,  91% of all eligible patients consented to baseline QOL, and of 
these, 93% participated in baseline FACT-E and EQ-5D assessments.  
Patients will be included in the QOL analysis only if they have provided both baseline 
and at least 1 subsequent measurement. This is done because of the attrition of QOL 
completion over time, a challenge that affects the majority of QOL studies. We have 
found on RTOG 0436, that at 6 to 8 weeks following chemoradiation, QOL participation 
was 65.5% and 62% for FACT-E and EQ-5D, respectively; no participation was 
reported in 12.7% and 13.9% for FACT-E and EQ-5D, respectively; and completed 
assessments have not yet been received by NRG Oncology in 21.8% and 24.2% for 
FACT-E and EQ-5D, respectively. This attrition is demonstrated despite robust efforts 
on the part of NRG Oncology to minimize missing data. As such, due to the potential 
attrition of QOL participation all HER2-eligible patients will be allowed to consent to 
QOL in this trial. 
 
1.11  
Summary of Study Rationale 
HER2 is fundamentally overexpressed, as measured by gene amplification by FISH and 
IHC, in a similar rate in esophageal and breast adenocarcinoma. In North America, 
HER2-expressing esophageal adenocarcinoma is associated with advanced locoregional 
adenopathy and a poor prognosis. Trastuzumab increases survival in metastatic breast 
cancer that overexpresses HER2 and dramatically reduces recurrence and increases 
survival in adjuvant breast cancer. Similarly, a large international phase III trial 
demonstrates that trastuzumab increases survival in metastatic gastroesophageal 
cancer. Neoadjuvant 
trastuzumab combined with chemoradiation 
followed 
by 
maintenance chemotherapy is safe in esophageal cancer. A phase III trial evaluating the 
addition of trastuzumab to trimodality treatment of esophageal cancer will be performed 
to determine if trastuzumab increases disease-free and overall survival and improves 
quality-adjusted 
survival 
for 
patients 
with 
HER2-overexpressing 
esophageal 
adenocarcinoma.  
 
2.0 OBJECTIVES 
2.1 
Primary Objective 
2.1.1    To determine if trastuzumab increases disease-free survival when combined with 
trimodality treatment (radiation plus chemotherapy followed by surgery) for patients 
with HER2-overexpressing esophageal adenocarcinoma   
 


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RTOG 1010; version date November 15, 
2018 
2.2 
Secondary Objectives 
2.2.1  
To evaluate if the addition of trastuzumab to trimodality treatment increases the 
pathologic complete response rate and overall survival for patients with HER2-
overexpressing esophageal adenocarcinoma; 
2.2.2 
To develop a tissue bank of tumor tissue from patients with non-metastatic esophageal 
adenocarcinoma; 
2.2.3       To determine molecular correlates of complete pathologic response, disease-free 
survival, and overall survival for patients with HER2-overexpressing esophageal 
adenocarcinoma treated with neoadjuvant and maintenance trastuzumab; 
2.2.4     
To evaluate predictors of cardiotoxicity in patients with esophageal cancer treated with 
trastuzumab and chemoradiation;  
2.2.5 
To evaluate adverse events associated with the addition of trastuzumab to trimodality 
treatment for patients with non-metastatic esophageal adenocarcinoma; 
2.2.6     
Patient-Reported Quality of Life Objectives 
▪ 
To determine if the addition of trastuzumab to trimodality treatment improves the 
patient-reported Functional Assessment of Cancer Therapy for Esophageal Cancer 
(FACT-E) Esophageal Cancer Subscale (ECS) score; 
▪ 
To determine if an improvement in the FACT-E ECS score at 6-8 weeks post 
completion of neoadjuvant chemoradiation correlates with pathologic complete 
response; 
▪ 
To determine if pathologic complete response correlates with the FACT-E ECS 
score at 1 year and/or 2 years from the start of chemoradiation; 
▪ 
To determine if the addition of trastuzumab to trimodality treatment improves the 
Swallow Index and Eating Index Subscale scores of the FACT-E; 
▪ 
To determine if the addition of trastuzumab to paclitaxel, carboplatin, and radiation 
impacts quality-adjusted survival. 
 
3.0 PATIENT SELECTION (11/5/14) 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED. For questions 
concerning eligibility, please contact the study data manager. 
 
3.1 
Conditions for Patient Eligibility (7/16/13) 
3.1.1 
Pathologically confirmed primary adenocarcinoma of the esophagus that involves 
the mid (up to 25 cm), distal, or esophagogastric junction. The cancer may involve 
the stomach up to 5 cm 
3.1.2 
Endoscopy with biopsy  
PRIOR TO STEP 1 REGISTRATION BUT WITHIN 56 DAYS PRIOR TO STEP 2 
REGISTRATION 
3.1.3. 
Intent to submit tissue for central HER2 testing per Sections 10.2.2 and 10.2.3 
3.1.4 
Stage T1N1-2, T2-3N0-2, according to the American Joint Committee on Cancer 
(AJCC) 7th edition staging, based upon the following minimum diagnostic work-up: 
▪ 
Chest/abdominal/pelvic CT or whole-body PET/CT (NOTE: if CT is performed at 
this time point, whole-body PET/CT will be required prior to Step 2 registration; 
PET/CT of skull base to mid-thigh is acceptable) (NOTE: if adenopathy is noted 
on CT or whole-body PET/CT scan, an endoscopic ultrasound is not required 
prior to STEP 2 registration as long as adequate tissue has been obtained for 
central HER2 testing, see 3.1.14 
▪ 
Patients may have regional adenopathy including para-esophageal, gastric, 
gastrohepatic and celiac nodes. If celiac adenopathy is present, it must be < 2 
cm.  
▪ 
Patients with tumors at the level of the carina or above must undergo 
bronchoscopy to exclude fistula  
3.1.5 
Age ≥ 18  
3.1.61 
Zubrod performance status 0-2 
3.1.7 
CBC/differential obtained, with adequate bone marrow function defined as follows: 
▪ 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 


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RTOG 1010; version date November 15, 
2018 
▪ 
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) 
3.1.8 
Additional laboratory studies  
▪ 
Creatinine ≤ 2 x the upper limit of normal 
▪ 
Bilirubin ≤ 1.5 x upper limit of normal 
▪ 
AST ≤ 3 x upper limit of normal 
▪ 
For women of childbearing potential, a negative serum or urine pregnancy 
test 
3.1.9 
Patients must sign study-specific informed consent prior to study entry 
 
 
Conditions for Patient Eligibility PRIOR TO STEP 2 REGISTRATION (HER2-
positive patients only) 
3.1.10 
HER2 expressing adenocarcinoma of the esophagus centrally 
3.1.11 
Surgical consultation to confirm that patient will be able to undergo curative 
resection after completion of chemoradiation within 56 days prior to Step 2 
registration 
3.112 
Radiation oncology consultation to confirm that disease can be encompassed in a 
radiotherapy field within 56 days prior to Step 2 registration 
3.1.13 
Consultation with a medical oncologist within 56 days prior to Step 2 registration 
3.1.14 
Stage T1N1-2, T2-3N0-2, according to the AJCC 7th edition staging, based upon the 
following minimum diagnostic work-up: 
▪ 
History/physical examination, with documentation of the patient’s weight, 
within 14 days prior to Step 2 registration 
▪ 
Whole-body PET/CT scan within 56 days prior to Step 2 registration (if only 
CT performed prior to Step 1 registration) 
▪ 
Endoscopic ultrasound within 56 days prior to Step 2 registration, unless the 
patient is found to have adenopathy per CT or whole-body PET/CT scan 
▪ 
EKG within 56 days prior to Step 2 registration 
▪ 
Serum creatinine ≤ 2 x the upper limit of normal within 14 days prior to step 2 
registration 
3.1.15 
Zubrod performance status 0-2 within 14 days prior to Step 2 registration 
3.1.16 
For women of childbearing potential, a negative serum pregnancy test within 14 
days prior to Step 2 registration 
3.1.17 
LVEF ≥ institutional lower limit of normal by cardiac echo or MUGA scan within 56 
days prior to Step 2 registration 
3.1.18 
Women of childbearing potential and sexually active male participants must agree to 
practice adequate contraception while on study and for at least 60 days following the 
last dose of chemotherapy or trastuzumab 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Patients with cervical esophageal carcinoma 
3.2.2 
Patients with T1N0 disease, T4 disease, and proximal esophageal cancers (15-24 cm)  
3.2.3 
Prior systemic chemotherapy for esophageal cancer; note that prior chemotherapy for a 
different cancer is allowable 
3.2.4 
Prior radiation for esophageal cancer or prior chest radiotherapy 
3.2.5 
Prior anthracycline or taxane 
3.2.6 
Evidence of tracheoesophageal fistula or invasion into the trachea or major bronchi 
3.2.7 
Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free 
for a minimum of 2 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix are 
permissible)  
3.2.8 
Medical contraindications to esophagectomy 
3.2.9 
Prior therapy with any agent targeting the HER2 pathway or HER1 (EGFR)pathway 
3.2.10 
Prior therapy with trastuzumab 
3.2.11 
Prior allergic reaction to the study drugs involved in this protocol or to a monoclonal 
antibody 


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RTOG 1010; version date November 15, 
2018 
3.2.12 
Previous history of congestive heart failure 
3.2.13 
Severe, active comorbidity, defined as follows: 
▪ 
Unstable angina in the last 6 months 
▪ 
Transmural myocardial infarction within the last 6 months 
▪ 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time 
of registration 
▪ 
Acquired immune deficiency syndrome (AIDS) based upon current CDC 
definition; note, however, that HIV testing is not required for entry into this 
protocol. The need to exclude patients with AIDS from this protocol is 
necessary because the treatments involved in this protocol may be 
significantly immunosuppressive.  Protocol-specific requirements may also 
exclude immunocompromised patients. 
3.2.14 
Pregnant or nursing women or 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.  
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
Note: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility.   
 
4.1 
Required Evaluations/Management (2/22/12) 
4.1.1 
PFTs (including routine spirometry and DLCO) within 56 days prior to Step 2 
registration  
4.1.2. 
Na, K, BUN, glucose within 14 days prior to Step 1 registration. 
 
4.2 
Strongly Recommended Evaluations/Management 
4.2.1 
Arterial blood gas within 56 days prior to Step 2 registration 
 
5.0 REGISTRATION PROCEDURES (15-NOV-2018) 
CTEP Registration Procedures: 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require 
all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 


23                
RTOG 1010; version date November 15, 
2018 
Documentation Required 
IVR 
NPIVR 
AP 
A 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 
1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
Access requirements for OPEN and TRIAD: 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity 
and Access Management (IAM) account. This is the same account (user id and password) 
used for the CTSU members' web site. To obtain an active CTEP-IAM account, go to 
https://eapps-ctep.nci.nih.gov/iam. 
 
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients 
 
5.1 
Pre-Registration Requirements for 3D-CRT and IMRT Treatment Approaches 
Institutions intending to use IMRT to treat any patients registered to this study must 
complete the IMRT credentialing requirements.  Institutions credentialed for IMRT will 
automatically be credentialed for the use of 3D-CRT. 
 
5.1.1 
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 Imaging and Radiation Oncology Core (IROC) Houston web site. Visit 
http://irochouston.mdanderson.org and select “Credentialing” and “Credentialing Status 
Inquiry”. 
 
 An IMRT phantom study with the IROC Houston must be successfully completed (if 
the institution has not previously met this IMRT credentialing requirement). Instructions 
for requesting and irradiating the phantom are available on the IROC Houston web site 
at http://irochouston.mdanderson.org; select “Credentialing”. Upon review and 
successful completion of the phantom irradiation, IROC Houston will notify both the 
registering institution and IROC Philadelphia that the institution has completed this 
requirement. Subsequently, NRG Oncology Headquarters will notify the institution that 
the IMRT credentialing requirement has been met. If either gating or target tracking 
techniques are used for motion management when treating some patients from a 
particular institution on this protocol, IROC Houston will send a pre-programmed 
moving table with the lung phantom. This moving table will simulate respiratory motion. 


24                
RTOG 1010; version date November 15, 
2018 
If the institution used abdominal compression or the target motion stay with the stated 
PTV margins, the institution can use previous credentialing using the IROC Houston 
head-and-neck phantom in lieu of irradiating the lung phantom. 
5.1.2 
The institution or investigator must update an existing or complete a new IMRT Facility 
Questionnaire and a Credentialing Status Inquiry Form (available on the IROC Houston 
web site, http://irochouston.mdanderson.org) and send it to NRG Oncology for review 
prior to entering any cases. NRG Oncology will notify the institution when all 
requirements have been met and the institution is RT credentialed to enter patients 
onto this study. 
 
5.2 
Digital RT Data Submission to NRG Oncology Using TRIAD (11/5/14) 
TRIAD is the American College of Radiology’s (ACR) image exchange application and it is used 
by the Radiation Therapy Oncology Group (RTOG). TRIAD provides sites participating in RTOG 
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: 
• 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. Please refer to Section 5.0 of the protocol for 
instructions on how to request a CTEP-IAM account. 
• To submit images, the site physics user must have been assigned the 'TRIAD site user' 
role on the relevant Group or CTSU roster. RTOG users should contact your site Lead RA 
to be added to your site roster.  Users from other cooperative groups should follow their 
procedures for assignment of roster roles. 
• 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 on the RTOG web site Core Lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD Support 
mailbox at TRIAD-Support@acr.org. 
5.3 
Regulatory Pre-Registration Requirements (15-NOV-2018) 
 
5.3.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 


25                
RTOG 1010; version date November 15, 
2018 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied 
to the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent 
to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the RTOG 1010 protocol page located 
on the CTSU members’ website.   
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Either enter the protocol # in the search field at the top of the protocol tree, or 
▪ 
Click on the By Lead Organization folder to expand 
▪ 
Click on the RTOG link to expand, then select trial protocol #RTOG 1010 
▪ 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
 
Requirements for RTOG 1010 site registration: 
• CTSU IRB Certification (for sites not participating via the NCI CIRB); 
• CTSU IRB/Regulatory Approval Transmittal Sheet(for sites not participating via 
the NCI CIRB) ; 
• CTSU RT Facilities Inventory Form (if applicable) 
• IRB/REB approval letter  
• IRB/REB approved consent (English and native language versions*)  
*Note: Institutions must provide certification of consent translation to NRG 
Oncology 
• IRB/REB assurance number renewal information, as appropriate 
 
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. 
 


26                
RTOG 1010; version date November 15, 
2018 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Regulatory tab  
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
5.3.2 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
In addition to the requirements above, Canadian institutions must also complete and 
fax to the CTSU Regulatory Office (215-569-0206) Health Canada’s Therapeutic 
Products Directorates’ Clinical Trial Site Information Form, Qualified Investigator 
Undertaking Form, and Research Ethics Board Attestation Form.  
5.4 
Summary of Patient Registration Procedures  
Once the site has met pre-registration requirements, this study incorporates a 2-step 
registration process.  
 
Step 1 of registration entails an initial registration for HER2 testing and to document that 
the patient meets Step 1 eligibility criteria (See Section 3.1) 
▪ 
The site will register the patient and will then submit tissue for HER2 testing per 
Section 10.2. 
 
Step 2 of registration entails a second web registration, after which the patient will either 
be randomized to treatment or it will be documented that the patient will not receive 
protocol treatment. 
▪ 
If the patient is determined to be HER2 negative, the site will not proceed to 
Step 2 registration. 
▪ 
If the patient is determined to be HER2 positive and the patient will not receive 
protocol treatment for any reason, the site will proceed to Step 2 registration to 
document the reason. The patient will not be randomized. 
▪ 
If the patient is determined to be HER2 positive and the patient will receive 
protocol treatment, the site will proceed to Step 2 registration and the patient will 
be randomized to Arm 1 or Arm 2.  


27                
RTOG 1010; version date November 15, 
2018 
▪ 
See Section 5.4 for online registration procedures. 
5.5 
Registration (11/5/14) 
5.5.1 
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
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. All site 
staff will use OPEN to enroll patients to this study.  OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
• 
All 
patients 
have 
signed 
an 
appropriate 
consent 
form 
and 
HIPAA 
authorization form (if applicable).  
 
Access requirements for OPEN: 
• 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group roster.  
• 
To perform registrations on protocols for which you are a member of NRG 
Oncology, you must have an equivalent 'Registrar' role on the NRG Oncology 
roster.  Role assignments are handled through the Groups in which you are a 
member.  
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the relevant 
Group roster. Site and/or Data Administrators can manage CTSU roster roles via 
the new Site Roles maintenance feature under RSS on the CTSU members' web 
site. This will allow them to assign staff the "Registrar" role. 
 
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. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact 
web support for assistance with web registration: websupport@acr.org or call the 
Registration Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. 
ET. The registrar will ask the site to fax in the eligibility checklist and will need the 
registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration 
system (e.g. drug shipment and confirmation of registration) will occur.  
 
 
6.0 RADIATION THERAPY (11/5/14) 
NOTE: Intensity Modulated RT (IMRT) Is Allowed. Using IMRT requires a phantom 
irradiation, as described in Section 5.1.1. 
 
Radiation therapy must begin within 10 days after STEP 2 registration, on a Monday or 
Tuesday if possible. 
 


28                
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See Section 5.2 for information on installing TRIAD for submission of digital RT data PRIOR to 
enrolling patients. 
 
6.1 
Dose Specifications (11/5/14) 
NOTE: ICRU-50 and ICRU-62 prescription methods and nomenclature shall be 
utilized for this study. 
6.1.1 
The prescription volume is the PTV. The dose providing the PTV coverage stated in 
Section 6.1.3 will be specified in cGy to muscle. 
6.1.2 
Tissue Heterogeneity   
CT-based treatment planning is required.  Calculations that take into account tissue 
heterogeneity shall be used. Acceptable calculation algorithms such as the 
superposition/convolution and not pencil-beam or Clarkson algorithms should be used. 
6.1.3 
The total dose for both arms will be 50.4 Gy in 28 fractions. The initial phase will be 45 
Gy in 25 fractions.  A minimum of 95% of the planning target volume (PTV) will receive 
45 Gy.  No more than 10% of the PTV shall receive greater than 50 Gy. The final boost 
will be for an additional 5.4 Gy in 3 fractions. For this phase, a minimum of 95% of the 
boost PTV will receive 5.4 Gy. No more than 10% of the boost PTV will receive more 
than 6 Gy for the boost phase. 
 
6.2 
Technical Factors  
Megavoltage equipment with effective photon energies ≥ 6MV is required. 
 
6.3 
Localization, Simulation, and Immobilization (11/5/14) 
6.3.1 
CT-based treatment planning is required for this study. The planning CT should 
encompass the entire thoracic cavity and the abdomen to a level below the bottom of 
the kidneys.  A maximum slice thickness of 3-5 mm is required through regions of the 
gross tumor volume (GTV) and a maximum of 8-10 mm is required elsewhere.  A 
uniform 5 mm thickness may be utilized. 
6.3.2 
The patient is to be positioned in an individualized immobilization device in the 
treatment position on a flat hard table.  The patient may be in the supine or prone 
position. 
6.3.3 
Esophageal contrast may be used during simulation but is optional if a diagnostic CT 
scan with contrast was performed. 
 
6.4 
Treatment Planning/Target Volumes (2/22/12) 
6.4.1 
ICRU-50 and ICRU-62 prescription and nomenclature shall be utilized for this study.  
All available information shall be utilized to define target volumes including endoscopic 
ultrasound, esophagram, CT or other imaging findings including PET/CT. 
6.4.2 
Gross Tumor Volume (GTV) 
The GTVp is defined as the primary tumor in the esophagus.  The GTVn is defined as 
any grossly involved regional lymph nodes. 
6.4.3 
Clinical Target Volume (CTV) 
The CTV is defined as the GTVp with a 4 cm expansion superiorly and inferiorly along 
the length of the esophagus and cardia and a 1.0-1.5 radial expansion plus the GTVn 
with a 1.0-1.5 expansion in all dimensions.  This volume should be expanded if needed 
to cover the para-esophageal and celiac lymph node regions.  The 4 cm superior and 
inferior expansion should follow the contour of the esophagus and proximal stomach.  
The intent is to extend the margin along the length of the esophagus and proximal 
stomach to provide a margin for coverage of submucosal extension of tumor. The 
celiac axis should be covered for tumors of the distal esophagus or gastroesophageal 
junction. 
6.4.4 
Planning Target Volume (PTV) 
Additional margin shall be added to the CTV for set up error and movement.  This 
expansion should be 0.5 to 1.0 cm and does not need to be uniform in all dimensions.  
4DCT data is allowed to customize PTV expansion. 
6.4.5 
Boost PTV 


29                
RTOG 1010; version date November 15, 
2018 
 
The boost PTV is defined as the GTVp along the length of the esophagus and GTVn 
with an expansion of 0.5 to 1.0 cm. The expansion does not need to be uniform in all 
dimensions. 4D-CT data is allowed to customize PTV expansion. 
6.4.6 
IMRT Planning 
IMRT plans will optimize the initial treatment of 45 Gy and the boost treatment of 5.4 
Gy separately. A simultaneous boost technique is NOT allowed for this protocol. 
Submitting a composite plan is required. 
 
 
6.4.7 
IMRT Beam Arrangement 
A five-field beam arrangement is preferred to minimize the low dose distributed to the 
lungs. Suggested beam arrangements are: 
a. For distal esophagus the following beam arrangement (using IEC coordinate 
system) is useful for minimizing dose to the heart and lungs: LPO (155), 
LAO(70-80), AP(0), RAO(280-290), RPO(205). Note that the range of gantry 
angles for the LAO and RAO fields is due to the fact that one needs to find the 
best compromise between the amount of heart and lung in the field. 
b. For GE-junction esophagus, the following beam arrangement (using the IEC 
coordinate system) may be substituted if it is better for minimizing dose to the 
kidney: PA (180º), close to LL (90º+/-10º), LAO (30-35º), RAO (325-330º),  
close to RL (270º+/-10º). These recommended beam arrangements may be 
changed to one more fitting for the patient’s particular anatomy.  
 
Field verification: 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 and saved by the institution, but these images will not submitted.  
 
For 3D-CRT this imaging can include individual portal views. Twice 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, particularly for patients treated with motion 
management techniques, but is not required. 
 
6.5 
Critical Structures (7/16/13) 
NOTE: All required structures must be labeled per DICOM Standard Name as listed in 
Section 6.5.3 for submission to TRIAD.  Resubmission may be required if labeling of 
structures does not conform to the list provided. 
 
6.5.1 
Organs at risk to be contoured include both lungs, liver, kidneys, heart, and spinal cord.  
The left ventricle should also be contoured.  A contrast-enhanced CT scan should be 
available for contouring the left ventricle. 
6.5.2 
Dose to the organs at risk must meet constraints in the Section 6.7 table.  
6.5.3 
Standard Structure Names for TRIAD Submission (11/5/14) 
Standard Names 
Description 
Required or not 
GTV 
Gross Tumor Volume: Includes 
primary and nodes 
Required 
CTV_4500 
Clinical Target Volume for initial 
fraction group 
Required 
CTV_5040 
Clinical 
Target 
Volume 
for 
boost/cone down fraction group 
Required 
PTV_4500 
Planning Target Volume for initial 
fraction group 
Required 


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RTOG 1010; version date November 15, 
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PTV_5040 
Planning 
Target 
Volume 
for 
boost/cone down fraction group 
Required 
Esophagus 
Esophagus 
Optional 
Heart 
Heart 
Required 
Liver 
Liver 
Required 
Lung_L 
Left Lung 
Required 
Lung_R 
Right Lung 
Required 
Lungs 
Total Lung 
Required 
Kidney_L 
Left Kidney 
Required 
Kidney_R 
Right Kidney 
Required 
Kidneys 
Total Kidneys 
Required 
External 
External patient contour 
Required 
SpinalCord 
Spinal Cord 
Required 
 
6.6 
Documentation Requirements 
First day port films or portal images of each field must be obtained and kept by the 
treating institution and must be available for review upon request. Twice weekly (at least 
48 hours apart) verification films or images of orthogonal views (anterior to posterior and 
lateral projection) must be reviewed by the treating physician. Daily image guidance is 
encouraged but not required.  If daily image guidance is utilized, it must be documented. 
 
6.7 
Compliance Criteria (11/5/14) 
Dose constraints must follow the guidelines in the table below. The treating physician must 
carefully consider the tolerance dose/volume to each critical normal structure. When all 
constraints are met, the physician is encouraged to reduce lung dose as much as possible.  
 
Structure 
Description 
Metric 
Per Protocol 
Variation 
Acceptable 
Variation 
Unacceptable 
Initial Plan 
PTV_4500 
PTV 45 
Max Dose (Gy, 
0.03 cc) 
≤ 110% Rx 
Dose 
≤ 113 % Rx 
Dose 
> 113 % Rx Dose 
 
 
% PTV receiving 
45 Gy 
>95% 
>90% 
<90% 
 
 
V50Gy(%) 
<10% 
 
>10% 
Heart 
Heart & 
Pericardium 
Max Dose (Gy, 
0.03 cc) 
≤ 50Gy 
≤ 52 Gy 
> 52 Gy 
 
 
Mean Dose (Gy) 
≤ 30 Gy 
≤ 31 Gy 
> 31 Gy 
 
 
V40 
≤ 50% 
≤ 55% 
> 55% 
Boost Plan 
PTV_5040 
 
% PTV receiving 
5.4 Gy 
>95% 
>90% 
<90% 
 
 
V6Gy(%) 
<10% 
 
>10% 
Composite Plan 
Lungs 
Lungs - PTV 
Max Dose (Gy, 
0.03 cc) 
≤ 110% Rx 
Dose 
≤ 113% Rx 
Dose 
> 113% Rx Dose 
 
 
Mean Dose (Gy) 
≤ 20 Gy 
≤ 21 Gy 
> 21 Gy 
 
 
V30 
≤ 20% 
≤ 25% 
> 25% 
 
 
V20 
≤ 25% 
≤ 30% 
> 30% 
 
 
V10 
≤ 40% 
≤ 50% 
> 50% 


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2018 
 
 
V5 
≤ 50% 
≤ 55% 
> 55% 
Heart   
Heart & 
Pericardium 
Max Dose(Gy, 
0.03cc) 
≤ 52Gy 
≤ 54Gy 
> 54Gy 
 
 
Mean Dose (Gy) 
≤ 32Gy 
≤ 34Gy 
>34Gy 
 
 
V40 
≤ 50% 
≤ 55% 
>55% 
Kidneys 
Combined 
Kidneys 
Max Dose (Gy, 
0.03 cc) 
≤ 45 Gy 
≤ 50 Gy 
> 50 Gy 
 
 
V20 
≤ 30% 
≤ 40% 
> 40% 
SpinalCord 
Spinal Cord 
Max Dose (Gy, 
0.03 cc) 
≤ 45 Gy 
≤ 50 Gy 
> 50 Gy 
Liver 
Liver 
Mean Dose (Gy) 
≤ 21 Gy 
≤ 25 Gy 
> 25 Gy 
 
 
V30 
≤ 30% 
≤ 40% 
> 40% 
 
6.7.1 
Elapsed Days/Therapy Interruptions 
Elapsed Days 
• 
Per Protocol: 38 – 44 total elapsed days; 
• 
Variation Acceptable: 45-51 total elapsed days; 
• 
Deviation Unacceptable: ≥ 50 total elapsed days  
 
Therapy Interruptions 
Interruption of radiation is permitted only on the basis of toxicity.  When radiation is 
interrupted for toxicity, systemic therapy with paclitaxel, carboplatin, and 
trastuzumab also should be interrupted. Therapy will be interrupted for absolute 
granulocyte counts ≤ 500; platelet count ≤ 50,000; and > grade 3 radiation-related, 
non-hematologic toxicity. If the patient develops ≥ grade 3 radiation-related toxicity, 
radiation therapy and chemotherapy should be withheld. Interruption of therapy may 
continue until the toxicity has regressed to ≤ grade 2 to allow resumption of therapy; 
however, every effort should be made to limit treatment interruptions to 1-2 weeks. If 
a patient develops grade 3 esophagitis in the last week of treatment, radiation 
therapy and trastuzumab (but not chemotherapy) may continue at the discretion of 
the treating physician. 
 
Dose Modifications 
Every effort must be made to deliver the full 50.4 Gy to all patients.  Toxicity may be 
encountered that is sufficiently severe to require treatment interruption. Once the 
toxicity has resolved, the patient’s therapy should resume and full protocol radiation 
dose should be delivered. The toxicity that forced any dose reduction must be 
documented. Total number of fractions and elapsed days should be carefully 
reported. If an interruption of more than 2 weeks is necessary, resumption of 
treatment is at the discretion of the radiation oncology chairs. The patient’s 
treatment plan will be considered a deviation unacceptable, but follow up will be 
continued. 
 
6.8 
R.T. Quality Assurance Reviews 
One of the Radiation Oncology Co-Chairs, Dr. Ted Hong, Dr. Michael Haddock, or Dr. Thomas 
Dipetrillo, will perform an RT Quality Assurance Review after complete RT data is received.   
These reviews will be ongoing. 
 
6.9 
Radiation Adverse Events 
Adverse effects related to radiation therapy include nausea/vomiting, diarrhea, weight loss, 
fatigue, myelosuppression, skin erythema, subcutaneous fibrosis, esophagitis, carditis, myelitis, 
acute radiation pneumonitis and late pulmonary fibrosis, and esophageal stricture.  
 
6.10 
Radiation Adverse Event Reporting 
See Section 7.10. 


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2018 
7.0 DRUG THERAPY  
Protocol treatment must begin within 10 days after STEP 2 registration.  
 
7.1 
Treatment (7/16/13) 
Note: Trastuzumab, paclitaxel, carboplatin must be administered within 48 hours (+/- 2 days) of 
the scheduled date for these therapies. 
 
7.1.1 
Arm 1: Trastuzumab, Paclitaxel, and Carboplatin with Concurrent Radiation  
Agent 
Dose* 
Schedule 
Trastuzumab 
4 mg/kg IV 
Day 1 
Trastuzumab 
2 mg/kg IV 
Day 8, 15, 22, 29, 36 
Trastuzumab 
6 mg/kg IV 
On day 57  
Paclitaxel 
50 mg/m2 IV 
Day 1, 8, 15, 22, 29, 36 
Carboplatin 
AUC = 2 
Day 1, 8, 15, 22, 29, 36 
Radiation 
50.4 
Gy, 
at 
180 
cGy/fx  
Day 1-5, 8-12, 15-19, 22-26, 29-33, 36-38  
 
Maintenance 
trastuzumab 
6 mg/kg IV 
 
Once every 3 weeks x 13 treatments beginning as 
soon as the patient has recovered from surgery, at a 
minimum of 21 days and a maximum of 56 days 
*Based on actual body weight. 
Paclitaxel and carboplatin and trastuzumab may be administered before or after radiation. 
Paclitaxel, carboplatin and trastuzumab doses do not need to be recalculated for change in body 
weight as long as the weight change is < 10% of the patients total body weight. However, post-
surgery it is recommended that the trastuzumab dose be recalculated based on the body weight 
at initiation of trastuzumab post-surgery.  
 
7.1.2 
Arm 2: Paclitaxel and Carboplatin with Concurrent Radiation  
 
Agent 
Dose* 
Schedule 
Paclitaxel 
50 mg/m2 IV 
Day 1, 8, 15, 22, 29, 36 
Carboplatin 
AUC = 2 
Day 1, 8, 15, 22, 29, 36 
Radiation 
50.4 
Gy, 
at 
180 
cGy/fx  
Day 1-5, 8-12, 15-19, 22-26, 29-33, 36-38  
*Based on actual body weight. 
 
Paclitaxel and carboplatin may be administered before or after radiation. Paclitaxel, carboplatin 
and doses do not need to be recalculated for change in body weight as long as the weight 
change is < 10% of the patients total body weight.  
 
7.2 
Details of Chemotherapy (7/16/13) 
7.2.1 
Trastuzumab 
Trastuzumab will be administered prior to paclitaxel and carboplatin. The initial dose of 
trastuzumab is 4 mg/kg intravenously administered over 90 minutes on day 1, followed 
by weekly infusions of 2 mg/kg intravenously over 30-60 minutes on days 8, 15, 22, 29, 
and 36 (+/-2 days). Trastuzumab, 6 mg/kg IV will be given on day 57(+/- 2 days) over 
30-90 minutes. As soon as the patient has recovered from surgery, at a minimum of 21 
days and a maximum of 56 days, patients will receive trastuzumab, 6 mg/kg IV once 
every 3 weeks, over 30-90 minutes x 13 doses. 
Note: It is recommended that maintenance trastuzumab be administered within 1 day 
of the scheduled treatment. However, maintenance trastuzumab may be administered 
+/- 3 days of the scheduled treatment.  
7.2.2  
Paclitaxel 
Paclitaxel 50 mg/m2 will be administered as an intravenous infusion over 1 hour on 
days 1, 8, 15, 22, 29, and 36. 


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RTOG 1010; version date November 15, 
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Prior to the first dosage of paclitaxel, patients will be premedicated with 
dexamethasone 20 mg (or an equivalent agent per institutional guidelines) orally the 
night before and 20 mg either orally or intravenously on the morning of paclitaxel 
administration. On the morning of the first paclitaxel administration: if dexamethasone 
is given intravenously, administer 30 minutes prior to paclitaxel administration; if 
dexamethasone is given orally, administer 1-3 hours prior to paclitaxel administration. 
Also prior to the first dosage of paclitaxel, patients will be premedicated with 
diphenhydramine, 50 mg intravenously, and ranitidine (or other H2 blocker), 50 mg 
intravenously. If no allergic reactions occur, then subsequent dosages of 
premedications with dexamethasone, diphenhydramine, and H2 blockers may be 
reduced at the investigator’s discretion.  
 
Patients must be attended by medical personnel for the first 15 minutes of infusion and 
then have blood pressure checked every 15 minutes for 1 hour, then as needed (or per 
institutional guidelines). Medications for acute management of anaphylaxis should be 
readily available in the location where the patient is being treated. 
7.2.3  
Carboplatin 
The dose of carboplatin is area under the curve (AUC) = 2 over 1 hour on days 1, 8, 
15, 22, 29, and 36. The dose of carboplatin is calculated as follows, using the Calvert 
formula based on creatinine clearance: Total dose (mg) = Target AUC (in mg/mL per 
min) x (Estimated GFR + 25).  
 
The GFR should not exceed 125 ml/min. If the calculated GFR based on the Calvert 
formula is greater than 125 ml/min, a GFR of 125 ml/min should be used. The 
maximum carboplatin dose for an AUC = 2 should not exceed 300 mg 
 
Carboplatin will be administered after paclitaxel. Patients will receive appropriate 
antiemetics and supplemental hydration as per their institutional protocol. 
 
7.3 
Trastuzumab (Herceptin®) Study Agent Information [NSC 688097; IND] (8/20/13) 
7.3.1 
Investigator Brochure 
To supplement the toxicity information contained in this document, all investigators 
who receive a copy of the protocol also should obtain the current version  of the 
Investigator’s Brochure (IB) for comprehensive pharmacologic and safety 
information. 
Investigator’s Brochures are available from the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI and may be obtained by e-mailing the IB Coordinator 
(ibcoordinator@mail.nih.gov) or by calling the IB Coordinator 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. 
7.3.2 
Formulation 
Trastuzumab is supplied as a lyophilized powder in multidose vials, containing 440 
mg of trastuzumab, and one 20 mL vial of Bacteriostatic Water for Injection (BWFI), 
USP (containing 1.1% benzyl alcohol), for reconstitution.  The drug is formulated in 
histidine, trehalose, and polysorbate 20.  Each vial is reconstituted with only 20 mL 
of BWFI.  The reconstituted solution contains 21 mg/mL trastuzumab and will be 
added to an infusion bag containing 250 mL of 0.9% Sodium Chloride for Injection, 
USP (Dextrose solutions should not be used) and the bag gently inverted to mix the 
solution.  For patients with a known hypersensitivity to benzyl alcohol (the 
preservative in Bacteriostatic Water for Injection) reconstitute trastuzumab with 
Sterile Water for Injection (SWFI), USP.  Trastuzumab reconstituted with SWFI must 
be used immediately. Discard the SWFI-reconstituted trastuzumab vial following a 
single use.  Do not mix or dilute trastuzumab with other drugs. 


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RTOG 1010; version date November 15, 
2018 
7.3.3 
Administration 
 
The initial dose of trastuzumab will be administered over a 90-minute period. If this 
dose is well tolerated, subsequent infusion periods may be shortened to 30 minutes. 
If the initial or subsequent doses are not well tolerated, (e.g., the patient experiences 
fever or chills), subsequent infusions may be shortened only after a dose is well 
tolerated. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  
7.3.4 
Storage and Stability 
Trastuzumab must be stored in a refrigerator (2°C-8°C) immediately upon receipt to 
ensure optimal retention of physical and biochemical integrity. DO NOT FREEZE. 
The reconstituted formulation (440-mg vial) is designed for multiple uses.  Unused 
drug may be stored for 28 days at 2°C-8°C (36°F-46°F).  Discard any remaining 
reconstituted solution after 28 days.  Reconstituted Trastuzumab should be a 
colorless to pale yellow, transparent solution. 
7.3.5 
Accountability and Supply 
Drug accountability records must be maintained at all sites according to good clinical 
practices and NCI guidelines. 
 
Genentech will supply trastuzumab free of charge to patients on study, and it will be 
distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy 
Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), 
National Cancer Institute (NCI). 
 
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 trastuzumab 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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RTOG 1010; version date November 15, 
2018 
7.3.6 
Adverse Events (6/13/16) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Trastuzumab (Herceptin, NSC 688097) 
 
The Comprehensive Adverse Events 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 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 (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 4621 patients. Below is the CAEPR for 
trastuzumab (Herceptin). 
 
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, April 14, 20161 
 
 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 4.0 Term) 
[n= 4621] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
Febrile neutropenia2 
 
  
CARDIAC DISORDERS 
  
 
Cardiac disorders - Other 
(cardiomyopathy) 
 
  
 
Heart failure 
 
  
 
Left ventricular systolic dysfunction  
 Left ventricular systolic dysfunction 
(Gr 3) 
 
Pericardial effusion 
 
  
 
Pericarditis 
 
  
 
Sinus tachycardia3 
 
 Sinus tachycardia3 (Gr 2) 
 
Supraventricular tachycardia3 
 
  
EYE DISORDERS 
  
 
Conjunctivitis 
 
  
 
Watering eyes 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
 
Nausea 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills3 
 
 Chills3 (Gr 2) 
 
Edema limbs 
 
  


37                
RTOG 1010; version date November 15, 
2018 
 
 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 4.0 Term) 
[n= 4621] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever3 
 
 Fever3 (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction4 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 3) 
INVESTIGATIONS 
  
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
Cardiac troponin I increased 
 
  
 
Ejection fraction decreased 
 
 Ejection fraction decreased (Gr 3) 
 
GGT increased 
 
 GGT increased (Gr 2) 
 
Neutrophil count decreased2 
 
 Neutrophil count decreased2 (Gr 4) 
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
 Bone pain (Gr 2) 
 
Musculoskeletal and connective 
tissue disorder - Other (muscle 
spasms) 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
 Tumor pain (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
Peripheral sensory neuropathy 
 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Adult respiratory distress 
syndrome3, 4 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 2) 
 
 
Bronchospasm3, 4 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea3, 4 
 
 Dyspnea3,4 (Gr 3) 


38                
RTOG 1010; version date November 15, 
2018 
 
 Adverse Events with Possible  
 Relationship to Trastuzumab (Herceptin) 
 (CTCAE 4.0 Term) 
[n= 4621] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Hypoxia4 
 
 Hypoxia4 (Gr 2) 
 
 
Pneumonitis4 
  
 
 
Pulmonary edema4 
  
 
 
Pulmonary fibrosis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Nail loss 
 
  
 
Rash acneiform 
 
 Rash acneiform (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria3 
 
 Urticaria3 (Gr 2) 
VASCULAR DISORDERS 
  
 
Hot flashes 
 
  
 
Hypertension3 
 
  
 
Hypotension3 
 
  
 
Lymphedema 
 
  
 
Vascular disorders - Other 
(vasodilation) 
 
  
 
 
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. 
 
2Fatal event when given in combination with Xeloda® (capecitabine) and Taxotere® (docetaxel). 
 
3Associated with infusion-related reactions or administration-related reactions (ARRs).  
 
4Severe hypersensitivity reactions including angioedema and pulmonary adverse events (e.g., hypoxia, 
dyspnea, pulmonary infiltrates, pleural effusion, intersitial lung disease, wheezing, and acute respiratory 
distress syndrome) have been reported. 
 
5Infection may include any of the 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on trastuzumab (Herceptin) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that trastuzumab (Herceptin) caused 
the adverse event: 
 
CARDIAC DISORDERS - Asystole; Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (edema); 
Chest pain - cardiac; Myocardial infarction; Myocarditis; Palpitations; Sinus bradycardia; Ventricular 
arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
EYE DISORDERS - Dry eye; Extraocular muscle paresis 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dyspepsia; Enterocolitis; Esophagitis; 
Gastritis; Gastrointestinal disorders - Other (ischemic bowel); Small intestinal perforation; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Injection site reaction; Malaise; 
Multi-organ failure; Sudden death NOS 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 


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RTOG 1010; version date November 15, 
2018 
INVESTIGATIONS - Alanine aminotransferase increased; Blood bilirubin increased; Creatinine increased; 
Platelet count decreased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperkalemia; Hypoalbuminemia; 
Hypokalemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; Flank pain; 
Generalized muscle weakness; Muscle weakness left-sided; Neck pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Depressed level of consciousness; Dizziness; 
Encephalopathy; Leukoencephalopathy; Paresthesia; Seizure; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis; Nasal congestion; 
Pharyngolaryngeal pain; Pleural effusion4; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (oropharyngeal pain); Wheezing4 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Erythema multiforme; Hyperhidrosis; 
Palmar-plantar erythrodysesthesia syndrome; Pruritus; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hematoma; Thromboembolic event 
 
 
Note: Trastuzumab (Herceptin) 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. 
 
 


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7.4 
Paclitaxel Study Agent Information (7/16/13) 
Refer to the package insert for comprehensive pharmacologic and safety information. 
7.4.1  
Formulation 
Paclitaxel is a poorly soluble plant product from the western yew, Taxus brevifolia. 
Improved solubility requires a mixed solvent system with further dilutions of either 
0.9% sodium chloride or 5% dextrose in water. Vials will be labeled with shelf-life. All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the 
concentration of drug and the time elapsed after preparation, although when 
prepared as described below, solutions of paclitaxel (0.3-1.2 mg/ml) are physically 
and chemically stable for 27 hours at ambient temperature (270 C).  
7.4.2  
Preparation 
A sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial) in polyoxyethylated 
castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. The contents of 
the vial must be diluted just prior to clinical use. Paclitaxel will be diluted to a final 
concentration of 0.3 to 1.2 mg/ml in D5W, USP, in glass or polyolefin containers due 
to leaching of diethylhexphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) 
bags and intravenous tubing by the Cremophor vehicle in which paclitaxel is 
solubilized. Each bag/bottle should be prepared immediately before administration. 
NOTE: Formation of a small number of fibers in solution (NOTE: acceptable limits 
established by the USP Particular Matter Test for LVPs) have been observed after 
preparation of paclitaxel. Therefore, in-line filtration is necessary for administration 
of paclitaxel solutions. In-line filtration should be accomplished by incorporating a 
hydrophilic, microporous filter of pore size not greater than 0.22 microns (e.g.: 
Millex-GV Millipore Products) into the intravenous fluid pathway distal to the infusion 
pump. Although particulate formation does not indicate loss of drug potency, 
solutions exhibiting excessive particulate matter formation should not be used. 
7.4.3  
Administration 
Paclitaxel, at the appropriate dose and dilution, will be given as a 1-hour infusion. 
The paclitaxel is mixed in D5W or NS with 0.22 m in-line filter. Paclitaxel will be 
administered via an infusion control device (pump) using non-PVC tubing and 
connectors, such as the intravenous administration sets (polyethylene or polyolefin) 
that are used to infuse parenteral nitroglycerin. Nothing else is to be infused through 
the line through which paclitaxel is administered.  
 
Caution is warranted when paclitaxel is concomitantly administered with known 
substrate or inhibitors of CYP2C8 and CYP3A4.   
7.4.4 
Storage 
Paclitaxel vials should be stored between 20-25C (68°-77°F).  
7.4.5 
Adverse Effects 
• Hematologic: Myelosuppression 
• Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain 
• Heart: Arrhythmias, heart block, hypertension 
• Neurological: Sensory and peripheral neuropathy 
• Allergy: Severe anaphylactic reactions 
• Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, 
induration, tenderness, rarely ulceration), hypotension, irritation to the injection 
site, mucositis 
7.4.6 
Supply 
Commercially available.  


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7.5 
Carboplatin Study Agent Information (7/16/13) 
Refer to the package insert for comprehensive pharmacologic and safety information. 
7.5.1 
Formulation 
Carboplatin is available as a sterile lyophilized powder in single-dose vials 
containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial contains equal parts 
by weight of carboplatin and mannitol.  
7.5.2 
Administration  
Carboplatin can be infused intravenously over 30-60 minutes. The dose of 
carboplatin is area under the curve (AUC) = 2.  The dose of carboplatin is calculated 
as follows, using the Calvert formula based on creatinine clearance: Total dose (mg) 
= Target AUC (in mg/mL per min) x (Estimated GFR + 25) 
 
The GFR should not exceed 125 ml/min. If the calculated GFR based on the Calvert 
formula is greater than 125 ml/min, a GFR of 125 ml/min should be used. The 
maximum carboplatin dose for an AUC = 2 should not exceed 300 mg. 
 
In the absence of new renal obstruction or other renal toxicity greater than or equal 
to CTCAE (per Section 7.10) grade 2 (serum creatinine >1.5 x ULN), the dose of 
carboplatin will not be recalculated for subsequent cycles, but will be subject to dose 
modification as noted. In patients with an abnormally low serum creatinine (≤ 0.6 
mg/dl), due to reduced protein intake and/or low muscle mass, the creatinine 
clearance should be estimated using a minimum value of 0.6 mg/dl. If a more 
appropriate baseline creatinine value is available within 4 weeks of treatment that 
may also be used for the initial estimation of GFR. 
 
Note: The carboplatin dose is calculated in mg, not mg/m2. For the purposes of this 
protocol, the GFR is considered equivalent to the creatinine clearance. Creatinine 
clearance (CrCL) can either be measured or estimated using the formula: 
 
(140-age) wt (kg)    x (0.85 if female) 
72 x creatinine (mg/dl) 
 
7.5.3 
Adverse Events  
• 
Hematologic: 
Myelosuppression 
is 
the 
major 
dose-limiting 
toxicity. 
Thrombocytopenia, neutropenia, leucopenia, and anemia are common but 
typically resolve by day 28 when carboplatin is given as a single agent.  
• 
Allergic reactions: Hypersensitivity to carboplatin has been reported in 2% of 
patients receiving the drug. Symptoms include rash, urticaria, erythema, 
pruritus, and rarely bronchospasm and hypotension. The reactions can be 
successfully 
managed 
with 
standard 
epinephrine, 
corticosteroid, 
and 
antihistamine therapy. Desensitization per the allergy team is allowed. 
• 
Neurologic: Peripheral neuropathies have been observed in 4% of patients 
receiving carboplatin with mild paresthesia being the most common. 
• 
Gastrointestinal: Nausea and vomiting are the most common gastrointestinal 
events; both usually resolve within 24 hours and respond to antiemetics. Other 
gastrointestinal events include diarrhea, weight loss, constipation, and 
gastrointestinal pain.  
• 
Hepatic toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT have 
been reported. 
• 
Other: Pain and asthenia are the most common miscellaneous adverse events. 
Alopecia has been reported in 3% of the patients taking carboplatin. 
7.5.4 
Preparation  
When available, prediluted vials of carboplatin should be utilized. Otherwise, the 
preparation of carboplatin should proceed as described below: 
 


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2018 
Immediately before use, the contents of a carboplatin vial must be reconstituted with 
either sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP. The following shows the proper diluent volumes to be used to obtain 
a carboplatin concentration of 10 mg/mL: 
 
Vial size 
Diluent volume 
50 mg 
5mL 
150 mg 
15 mL 
450 mg 
45 mL 
 
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. 
Therefore, needles or intravenous sets containing aluminum parts that may come in 
contact with the drug must not be used for the preparation or administration of 
carboplatin. 
 
7.5.5 
Storage and Stability  
Intact vials of carboplatin are stable for the period indicated on the package when 
stored at room temperature (15-30˚C or 59-86˚F) and protected from light. When 
prepared as described above, carboplatin solutions are stable for 8 hours at room 
temperature if protected from light. The solution should be discarded after 8 hours 
since no antibacterial preservative is contained in the formulation. 
7.5.6 
Supply  
 
Commercially available.  
 
7.6 
Clinical Trials Agreement 
The agent supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company 
(hereinafter referred to as a Collaborator 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/industry/ipo.html) contained 
within the terms of award, apply to the use of the Agent in this study: 
 
1. 
The Agent may not be used for any purpose outside the scope of this protocol, 
nor can the Agents be transferred or licensed to any party not participating in the 
clinical study.  The Collaborator’s data for the Agent are confidential and 
proprietary to the Collaborator 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 another investigational Agents, 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. 


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RTOG 1010; version date November 15, 
2018 
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, 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 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 the Collaborator 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 the Collaborator for 
advisory review and comment prior to submission for publication.  The Collaborator 
will have 30 days from the date of receipt for review.  The 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 the 
Collaborator’s intellectual property rights, are protected.  Copies of abstracts must be 
provided to CTEP for forwarding to the Collaborator 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. 
 
7.7 
Dose Modifications: Trastuzumab 
NOTE: The trastuzumab dose will not be modified. 
7.7.1   
Infusion-Associated Symptoms  
Treatment with trastuzumab will be permanently discontinued in any patient who 
experiences either an anaphylactic reaction (a Grade 4 [CTCAE version 4.0] 
allergic/hypersensitivity reaction) or a grade 3 reaction that is consistent with an allergic 
reaction characterized by severe bronchospasm.  
7.7.2   
Cardiac Toxicity: Asymptomatic Decrease in LVEF 
The decision to continue or stop trastuzumab is based on the measured LVEF as it 
relates to the facility's lower limit of normal (LLN) and change in the LVEF from 
baseline.  
 


44                
RTOG 1010; version date November 15, 
2018 
Relationship of 
LVEF to facility's 
LLN 
Decrease of <10% from 
baseline 
Decrease of 10-15% from 
baseline 
Decrease of >16% 
from baseline 
Within normal 
limits 
Continue 
Continue 
Hold trastuzumab 
and repeat 
MUGA/Echo in  4 
weeks 
1-5% below LLN 
Continue trastuzumab 
and repeat MUGA/Echo 
in 4 weeks 
Hold trastuzumab and 
repeat MUGA/Echo in 4 
weeks 
Hold trastuzumab 
and repeat 
MUGA/Echo in  4 
weeks 
≥ 6% below LLN 
Continue trastuzumab 
and repeat MUGA/Echo 
in 4 weeks 
Hold trastuzumab and 
repeat MUGA/Echo in 4 
weeks 
Hold trastuzumab 
and repeat 
MUGA/Echo in  4 
weeks 
• In light of the variability inherent in the assessment of ejection fraction, consideration 
should be given to repeating the study to confirm an observed decline. 
• Trastuzumab must be permanently discontinued if 2 consecutive "hold" categories 
occur. 
• If the LVEF is maintained at a "Continue trastuzumab and repeat MUGA/Echo in 4 
weeks" or improves from a "Hold" to a "Continue", additional MUGA scans or 
echocardiograms prior to the next required MUGA scan/echocardiogram may be 
obtained at the discretion of the investigator.   
 
Patients with an asymptomatic > 20% decrease in LVEF or a decrease of LVEF > 10% 
below the institutional lower limit of normal should be considered for treatment of 
incipient congestive heart failure (CHF). Trastuzumab will be discontinued permanently 
in patients deemed to require treatment for cardiac dysfunction.  
 
Symptomatic decrease in LVEF: Patients who develop signs or symptoms of CHF 
should receive treatment for CHF according to institutional guidelines (e.g., ACE 
inhibitors, angiotensin-II receptor blockers, -blockers, diuretics and cardiac 
glycosides). Trastuzumab will be discontinued permanently in patients deemed to 
require treatment for cardiac dysfunction. If cardiac toxicity occurs during 
chemoradiation then continuation of paclitaxel/carboplatin/radiation treatment is at the 
discretion of the investigator. 
 
7.8 
Dose Modifications: Paclitaxel and Carboplatin (7/26/11) 
All dose modifications will reflect the most severe toxicity that is observed, including 
hematologic and nonhematologic toxicity, skin toxicity, and creatinine toxicity. 
 
Chemotherapy doses that are missed due to treatment related toxicity are not made up. 
 
7.8.1 
Hematologic Adverse Events (2/22/12) 
The dose of paclitaxel, carboplatin, trastuzumab, and radiation will be modified 
according to blood counts within 72 hours of the day of treatment as shown in the table 
below. Dose reductions of paclitaxel and carboplatin are permanent. 
 
Treatment Day Blood Counts 
Dosage 
ANC 
 
Platelet Count 
≥ 1,000 mcL 
AND 
> 75,000 mcL 
Full 
dosage 
paclitaxel, 
carboplatin, and trastuzumab. 
500-999 mcL 
OR 
50,000-75,000 mcL 
Full dose trastuzumab. Hold 
carboplatin 
and 
paclitaxel. 


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RTOG 1010; version date November 15, 
2018 
Recheck CBC weekly. When 
ANC > 1,000 and Plt > 75,000, 
resume paclitaxel at 1 dose level 
reduction and carboplatin at 1 
dose level reduction. 
< 500 mcL 
OR 
< 50,000 mcL 
Hold XRT, carboplatin, paclitaxel, 
and trastuzumab; Recheck CBC 
weekly. When ANC > 500 and Plt 
> 50,000 resume XRT, full-dose 
trastuzumab. When ANC >1,000 
and 
Plt 
> 
75,000 
resume 
paclitaxel and carboplatin and 
reduce both  by 1 dose level. 
Patients who experience 4 episodes of ANC < 500 mcl or platelets < 50,000 mcl may complete radiation 
and trastuzumab on study but will not receive additional carboplatin and paclitaxel.  
 
Dose levels for paclitaxel are as follows: 
Weekly Paclitaxel Dose 
50 mg/m2 
Dose Level -1 
40 mg/m2 
Dose Level -2 
30 mg/m2 
Dose Level -3 
20 mg/m2 
There will be no dose level reductions below a weekly dose of 20 mg/m2. 
 
 
Dose levels for carboplatin are as follows: 
Weekly Carboplatin Dose 
AUC = 2 
Dose Level -1 
AUC = 1.5 
Dose Level -2 
AUC = 1.0 
Dose Level -3 
AUC = 0.5 
There will be no dose level reductions below a weekly dose AUC = 0.5. 
 
7.8.2 
Nonhematologic Adverse Events 
Nonhematologic adverse events that will require dose reductions of paclitaxel or 
carboplatin 
include 
treatment 
related 
diarrhea, 
mucositis, 
esophagitis, 
and 
nausea/vomiting/dehydration despite adequate treatment with antiemetic therapy 
(including substance p antagonists and 5-HT3 antagonists) and treatment related 
pulmonary toxicity. Dose reductions of paclitaxel and carboplatin are permanent. 
 


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RTOG 1010; version date November 15, 
2018 
 
 
Toxicity 
Grade 
Agent 
Modification 
1st Episode 
Grade 3 or 4 (for 
the adverse 
events described 
in 7.6.2) 
≥ grade 3 
Carboplatin 
Paclitaxel 
Trastuzumab 
 
Hold until ≤ grade 2; resume, 
dose, reducing carboplatin 
by 1 dose level and 
paclitaxel by 1 dose level; no 
dose reduction for 
trastuzumab 
2nd Episode 
 
≥ grade 3 
Carboplatin 
Paclitaxel 
Trastuzumab 
Hold until ≤ grade 2; resume 
dose, reducing carboplatin 
by 1 dose level and 
paclitaxel by 1 dose level; no 
dose reduction for 
trastuzumab 
3rd Episode 
≥ grade 3 
Carboplatin 
Paclitaxel 
Trastuzumab 
Discontinue all carboplatin, 
paclitaxel. Resume 
trastuzumab when ≤ grade 2 
Paclitaxel 
infusion-related 
reaction  
≥ grade 4 
Paclitaxel 
 
Discontinue paclitaxel. 
Trastuzumab, carboplatin, 
and radiation may be 
continued. 
Carboplatin 
infusion-related 
reaction  
≥ grade 4 
Carboplatin 
 
Discontinue carboplatin. 
Trastuzumab, paclitaxel, and 
radiation may be continued. 
 
7.9 
Modality Review 
The Medical Oncology Co-Chairs, Dr. Howard Safran and Dr. Lawrence Leichman, MD will 
perform a Chemotherapy Assurance Review of all patients who receive or are to receive 
chemotherapy in this trial.  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. 
 
Dr. Safran and Leichman will perform a Quality Assurance Review after complete data for the first 
20 cases enrolled has been received at NRG Oncology. Dr. Safran and Dr. Leichman will perform 
the next review after complete data for the next 20 cases enrolled has been received at NRG 
Oncology. This will continue as complete data is available for subsequent cases. 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. 
 
7.10 
Adverse Events (15-NOV-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) 
 
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. 
7.10.1 Adverse Events (AEs)  


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RTOG 1010; version date November 15, 
2018 
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, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]  
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 event (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: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
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  
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 (4/17/14) 
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,  


48                
RTOG 1010; version date November 15, 
2018 
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. 
 
• 
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 an CTEP-AERS 5 Calendar Day 
Report. Serious adverse events that require 24 hour CTEP-AERS notification are 
defined in the expedited reporting table below. 
• 
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. 
• 
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 3 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).  
 


49                
RTOG 1010; version date November 15, 
2018 
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/Intervention1, 2 
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: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
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. 


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Effective Date: May 5, 2011 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND [or Non-CTEP IND]: None 
 
Not applicable 
 
 
8.0 SURGERY (7/16/13) 
• 
If a stent is placed for nutritional support, it must be placed after EUS. Note: if imaging 
demonstrates adenopathy, then an EUS is not required. 
• 
All patients are highly recommended to undergo endoscopy with biopsy of the tumor site 4 to 6 
weeks after the last radiation treatment.  If there is no evidence of metastatic disease, on CT 
chest/abdomen/pelvis or PET/CT performed on completion of radiotherapy, curative resection will 
be performed 5 to 8 weeks after completion of induction therapy. If studies indicate metastatic 
disease, patients will receive no further protocol treatment. 
• 
Surgical resection may include transthoracic (Ivor Lewis), transhiatal, McKeon, minimally invasive 
or thoracoabdominal esophagectomy.  Overlying mediastinal pleura and adjacent soft tissues 5 
cm proximal and distal to the primary lesion should be included to insure an adequate radial 
margin.  It is recommended that nodal staging include levels 7, 8, 9, 15, 16, 17 and 20. 
• 
The resection will be classified as R0 (all gross tumor removed, microscopically negative 
margins); R1 (all gross tumor removed, microscopically positive margins); or R2 (gross residual 
tumor). 
• 
As surgery is a component of both study arms, a full surgical Quality Assurance Review is 
required for this study; this will be performed by the Surgical Oncology Co-Chair, Dennis Wigle, 
MD, PhD, who will perform the review after complete data for 20 cases have been received at 
NRG Oncology. Dr. Wigle will perform the next review after complete data for the next 20 cases 
enrolled have 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 
have been received at NRG Oncology, whichever occurs first.  Surgical review requires complete 
operative and pathology reports. 
 
 
9.0 OTHER THERAPY 
9.1 
Permitted Therapy 
Patients may receive all concomitant therapy deemed necessary to provide adequate support, 
with the exception of the therapies detailed in Section 9.2. In addition, myeloid growth factors are 
permitted only to treat grade 4 neutropenia. Erythropoietins are allowed to treat anemia according 
to institutional guidelines.  
 
9.2 
Non-Permitted Therapy 
9.2.1 
Other investigational agents; 
9.2.2 
Other cytotoxic agents;  
9.2.3 
Other radiotherapy. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (11/5/14) 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as tissue/specimen submission. If the patient consents to 
participate in the optional tissue/specimen banking in this study, the site is required to submit the 
patient’s specimens as specified in Section 10.0 of the protocol. Note: Sites are not permitted to 
delete the tissue component from the protocol or from the sample consent. 
10.1 
Tissue/Specimen Submission (7/26/11) 
 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.  NRG Oncology  encourages 
participants in protocol studies to consent to the banking of their tissue, blood, and urine. The 


51                
RTOG 1010; version date November 15, 
2018 
NRG Oncology Biospecimen Bank provides specimens to investigators for translational research 
studies. Translational research studies integrate the newest research findings into current 
protocols to investigate important biologic questions.  The NRG Oncology Biospecimen Bank 
also collects tissue for central review of pathology. 
 
 In this study, tissue must be submitted for the purpose of determining if HER2 is overexpressed 
(mandatory for eligibility) and for specimen banking (recommended). 
 
10.2 
Tissue Collection for Central Review of HER2 for Eligibility – Mandatory (Step 1 
Registration) (7/16/13) 
10.2.1 
It is highly recommended that tissue be sent as early as possible during a patient’s 
clinical evaluation for HER2 determination. Determination of Step 2 patient eligibility 
does not need to be completed prior to sending tumor tissue for HER2 determination. 
The following are recommendations to achieve rapid and efficient HER2 testing: 
• If there is adequate tissue remaining after the initial endoscopic biopsy, this tissue 
should be sent to Dr. Resnick at Rhode Island Hospital, preferably in the form of 
a paraffin block or alternatively 12 unstained slides. 
• A second biopsy to obtain additional pathologic material is highly recommended 
from the endoscopic ultrasound, if performed. (Note: endoscopic ultrasound is not 
required for patients who have adenopathy on CT or whole body PET); If the 
pathologic diagnosis of esophageal cancer has already been made from the initial 
endoscopy, it is highly recommended that tissue (in the form of a paraffin block) 
obtained at the endoscopic ultrasound be directly sent to Dr. Resnick without 
additional pathologic evaluation at the referring institution. 
It is imperative that biopsy material from the initial endoscopy be sent to Dr. Resnick at 
Rhode Island Hospital as soon as it is available.  Material from the EUS, if performed, 
should be sent separately as soon as the EUS has been completed. The biopsy 
material from the EUS will help ensure that there is adequate tissue for HER2 testing 
and can also be used for translational research.  
10.2.2 
Required Pathologic Material for HER2 Testing 
• Representative H & E stained slides (can be a duplicate cut H&E or the 
diagnostic H&E slide) 
• Corresponding paraffin-embedded tissue block of the tumor; if the institution is 
not able to release the blocks, then 12 unstained 5-micron sections on plus slides 
from the primary block are an acceptable alternative to block submission. 
• A Pathology Report documenting that the submitted block contains tumor; 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 surgical pathology numbers and information must 
NOT be removed from the report. Histologic evaluation of submitted tissue by the 
referring institutions pathology department is not required. 
• A Specimen Form (SP) must accompany the tissue that is being submitted for 
HER2 testing.  
• A Specimen Transmittal (ST) form and pathology report must accompany the 
specimens for all patients who consented to the optional tissue/specimen 
collection. 
• Sites 
can 
access 
the 
form 
(no 
password 
required) 
at 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1010&
mode=html&ptid=383 (under “RTOG 1010”). The form must be filled out 
completely and indicate whether the patient has consented to banking of any 
leftover tissue. The ST form is the standard form required for the optional 
tissue/specimen collection and it  will be forwarded to the Biospecimen Resource 
Center after HER2 testing is complete for those patients who consented to tissue 
banking 


52                
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• The physicians will be contacted (generally by e-mail) by Drs. Safran or Resnick 
or an appointed assistant with the results of HER2 testing. 
10.2.3 
Mailing Information 
Pathologic material should be sent by FEDEX to 
 
Murray Resnick, MD, PhD 
Director of Surgical Pathology 
Department of Pathology 
The Rhode Island Hospital 
593 Eddy Street, Providence RI 02930 
401-444-4380 
mresnick@lifespan.org  
 
10.2.4 
Determination of HER2  
To determine HER2 status, dual IHC and FISH testing will be performed and the IHC 
scoring system will per done as per the modified IHC scoring validated in the phase III 
ToGA study and as reviewed by Hofmann et al (2008). This HER2 scoring takes into 
account that the HER2 Testing scoring methodology for gastric cancer differs from that 
used for breast cancer and that the use of the breast testing methodology can 
potentially under-represent the percentage of patients who might test positive and thus 
be eligible for treatment on the study. Gastric tumor cells lining the lumen may not stain 
on the luminal portion of the cell and thus may not have complete membrane staining. 
In the modified gastric system (Hofmann 2008) this pattern will be considered positive 
but would be misinterpreted as negative if the breast cancer scoring system were 
utilized. Therefore, HER2 positivity will be defined using the modified gastric system, 
where IHC 3+ will be defined as moderate to strong complete or basolateral membrane 
staining in > 10% of tumor cells, and IHC2+ if the staining is weak to moderate. As we 
will be dealing with biopsy specimens cohesive clusters or clones will be considered 
positive irrespective of size (<10%). FISH will be defined as positive if the HER2 to 
CEP17 ratio is > 2.0. For tumors with IHC of 0, +1 or +2 by IHC, if they are FISH+ they 
will be considered to be HER2 positive.  
• 
 Immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) 
IHC analysis of samples will be performed using the HercepTest kit (Dako) and 
FISH will be performed with the PathVysion™ detection system (an FDA approved 
in vitro diagnostic test) containing a locus-specific HER-2neu probe (17q11.2-q12-
LSI HER-2/neu Spectrum Orange) and chromosome 17-centromere probe 
(17q11.1-q11.1-CEP17 Spectrum Green). Digestion and pretreatment of the tissue 
are performed according to the vendor protocols, along with appropriate positive and 
negative controls. A total of 120 nuclei are analyzed to determine the amplification 
status of HER-2/neu gene on chromosome 17. Two independent observers score 
the results and the results are verified by a pathologist. A ratio between 
chromosome 17 signals and HER-2/neu gene is calculated to determine the copy 
number of the Her-2/neu gene. 
 
Quality Control: The testing is carried out following ASCO and CAP guidelines. The 
length of time that the tissue is fixed is recorded for each specimen. Each FISH run 
is carried out with both a positive and negative control. Each run is scored by 2 
independent observers and checked by a pathologist before the results are 
released. If there is a discrepancy greater than 0.2 between the 2 scores additional 
cells are scored and a third independent scorer will be used as needed. All results in 
the equivocal range (Her2neu/ CEPH ratio of 1.8-2.1) are repeated and /or sent out 
depending on the case. 
 
Close collaboration with the referring physicians and the molecular biology 
laboratory by e-mail (with Drs. Murray Resnick and Howard Safran) will be ongoing 
throughout the study to ensure that FISH results will be available.  


53                
RTOG 1010; version date November 15, 
2018 
• 
 Process for Evaluating HER2 Status 
Dr. Resnick’s laboratory will report HER2 results by IHC within 3 business days and 
HER2 by FISH within 7 business days from receipt of all required pathology 
materials. HER2 results will be emailed to the two site contacts listed on the 
pathology submission form (i.e. participating site PI and site contact) and NRG 
OncologyRegistration.   
 
The institutional pathologist will be notified in the event that the block may be 
depleted. The paraffin-embedded blocks will be available to the submitting institution 
upon specific request to accommodate individual patient management. Sites 
requesting that tissue blocks be returned for local testing purposes must confirm 
with appropriate personnel (e.g., local pathologist, laboratories) that no tissue blocks 
were retained at the local site. Please use retained materials before requesting the 
NRG Oncology to return submitted tissue blocks to the site.  
 
10.3 
Specimen Collection for Banking  Recommended (11/5/14) 
For patients who have consented to participate in the optional specimen banking 
component of the study  
 
An important objective of this study is to create a tissue bank for patients with esophageal 
adenocarcinoma. Specific translational projects will be determined after accrual is 
completed and closer to the time that the efficacy data will be available, based on the 
state of the science at that time.  Potential projects could include mRNA of ERCC1, TS, 
miRNA analysis or gene expression analysis via laser capture microdissection, SNP 
analysis, topoisomerase II or downstream phosphorylated proteins involved in the HER2 
pathway. Studies from the blood collection could include SNP analysis (DNA repair, 
HER2, VEGF, and EGFR pathways.) Blood markers that could correlate to cardiac 
damage from trastuzumab could be analyzed. 
 
▪ 
All patients, whether there tumor is determined to be HER2 positive or negative , 
will be given the opportunity to participate in tumor tissue banking. If the patient 
consents, then any tumor tissue remaining after HER2 determination will be sent 
from Dr. Resnick’s laboratory to the NRG Oncology Biospecimen Bank.  
▪ 
For HER2 positive patients, a representative H&E stained slide and 
corresponding paraffin-embedded tissue block of the tumor removed at 
esophagectomy surgery should be submitted to the NRG Oncology Biospecimen 
Bank for banking; if the institution is not able to release the blocks, then an H&E 
from the original block and a 2 mm punch of the FFPE block or an H&E with 10 
unstained slides are acceptable. A punch kit and instructions can be requested at 
rtog@ucsf.edu 
▪ 
For HER2 positive patients, plasma and urine will be collected from all 
consenting patients at baseline and prior to surgery and whole blood will be 
collected once at baseline (or at any other time point) and will be shipped directly 
to the NRG Oncology Biospecimen Bank (see Section 10.3.3).  
 
See Appendix V for detailed collection instructions, including information 
pertaining to collection kits. Note: Kits include a shipping label. 
10.3.1  
The following must be provided to the NRG Oncology Biospecimen Bank:  
(1) A Pathology Report documenting that the submitted block contains tumor; 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 surgical pathology numbers and information must NOT be removed from the 
report; (2) a Specimen Transmittal Form documenting the date of collection of the 
tumor, whole blood, plasma, and urine; (3) the NRG Oncology protocol number; (4) the 
patient’s case number; (5) sample collection time point (0 time, # days post-
chemoradiation); and (6) method of storage, for example, stored at -80° C. 


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RTOG 1010; version date November 15, 
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10.3.2 
Frozen Biospecimen Storage Conditions 
 
Store frozen biospecimens at –80 C (-70C to -90C) until ready to ship. If a -80C 
Freezer is not available:  
• Samples can be stored short term in a -20 C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal Form (ST) the storage conditions used and 
time stored. 
 
10.3.3 
Specimen Collection Summary 
 
Mandatory Specimens (All Patients) 
Specimens: 
Collected When: 
Submitted As: 
Shipped: 
Corresponding H&E stained 
slides of the primary tumor 
Removed at 
diagnostic 
endoscopy 
H&E stained slide( can 
be a duplicate H&E 
slide or the diagnostic 
slide) 
 
 
Dr. Resnick 
Rhode Island 
Hospital, 
Providence 
1 block primary tumor OR 
12 unstained slides from the 
primary block 
Removed at 
diagnostic 
endoscopy 
Formalin fixed paraffin-
embedded block 
Dr. Resnick 
Rhode Island 
Hospital, 
Providence 
 
Mandatory Specimens (All Patients)  
1 block primary tumor OR  
12 unstained slides from the 
primary block  
 
Removed at 
endoscopic 
ultrasound (if 
performed) Biopsy 
recommended but 
not required for 
HER2 + patients  
Formalin fixed paraffin-
embedded block 
Dr. Resnick 
Rhode Island 
Hospital, 
Providence 
Corresponding H&E stained 
slides of the primary tumor  
Removed at 
endoscopic 
ultrasound (if 
performed) Biopsy 
recommended but 
not required for 
HER2 + patients 
H&E stained slide (can be 
a duplicate H&E slide or 
the diagnostic slide) 
 
Dr. Resnick 
Rhode Island 
Hospital, 
Providence 


55                
RTOG 1010; version date November 15, 
2018 
 
Recommended Specimens (HER2 Positive Patients Only) 
Specimens: 
Collected When: 
Submitted As: 
Shipped: 
1 block residual primary tumor or 
2-mm punch of block or ten 5 
micron unstained slides 
Removed at 
esophagectomy 
surgery 
Formalin fixed paraffin 
embedded 
NRG Oncology 
Biospecimen 
Bank, San 
Francisco  
Shipped ambient 
Corresponding  H&E stained 
slide of the residual primary 
tumor(matching the block 
material) 
Removed at 
esophagectomy 
surgery 
H&E stained slide (can 
be a duplicate H&E 
slide or the diagnostic 
slide) 
 
NRG Oncology 
Biospecimen 
Bank, San 
Francisco  
Shipped ambient 
PLASMA: 5-10 mL of 
anticoagulated whole blood in 
EDTA tube #1 (purple/lavender 
top) and centrifuge  
Before treatment 
start and after 
chemoradiation prior 
to surgery  
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL cryovials 
(5 to 8) 
NRG Oncology 
Biospecimen 
Bank, San 
Francisco  
Plasma sent 
frozen on dry ice 
via overnight 
carrier (Monday-
Wednesday; 
Canada: 
Monday-
Tuesday) 
See Appendix V 
Whole blood for DNA : 5-10 mL 
of anticoagulated whole blood in 
EDTA tube #2(purple/lavender 
top) and mix 
Before treatment 
start  
Note: If site missed 
this collection time 
point they may collect 
whole blood for DNA 
at a later time point 
instead but must note 
this on the ST Form. 
Frozen whole blood 
samples containing 1 
mL per aliquot in 1 mL 
cryovials. (3 to 5) 
NRG Oncology 
Biospecimen 
Bank, San 
Francisco  
Whole blood sent 
frozen on dry ice 
via overnight 
carrier (Monday-
Wednesday; 
Canada: 
Monday-
Tuesday) 
See Appendix V 
10-20 mL clean-catch urine  
 
Before treatment 
start and after 
chemoradiation prior 
to surgery 
Two 5-10 mL urine 
aliquots in 2 sterile 15 
ml polypropylene 
centrifuge tubes. Store 
frozen at  
-20°C or 80°C 
NRG Oncology 
Biospecimen 
Bank, San 
Francisco  
Urine sent frozen 
on dry ice via 
overnight courier 
(Monday-
Wednesday; 
Canada: 
Monday-
Tuesday) 
See Appendix V 
 


56                
RTOG 1010; version date November 15, 
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10.3.4 
Submit materials for Tissue Banking as follows: (7/16/13) 
Courier Address (Fed Ex, UPS, etc.): For FFPE and Frozen Specimens 
NRG Oncology Biospecimen Resource 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
Questions: 415-476-RTOG (7864)/FAX 415-476-5271; RTOG@ucsf.edu 
 
10.4 
Reimbursement (11/5/14) 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new National Clinical Trials Network (NCTN) Program. 
This information will be made available with the other registration materials in the Oncology 
Patient Enrollment Network (OPEN) portal system.  
 
10.5 
Confidentiality/Storage  
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.5.1 
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. 
10.5.2 
Specimens for central review will be retained until the study is terminated. Specimens 
for tissue banking will be stored for an indefinite period of time. 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 
11.1 
Study Parameters: See Appendix I. 
 
11.2 
Measurement of Response 
• 
Pathologic response will be evaluated after the patient has had surgery and will be 
based on the pathology review of the submitted surgical specimen according to the 
following: 
• 
Pathologic Complete Response (pCR): On review of the resected esophageal 
specimen and accompanying lymph nodes no cancer is recognized by the 
pathologist and margins are free of tumor. 
• 
Microscopic Cancer: Gross tumor is not seen by the pathologist but tumor remains in 
the microscopic analysis or any part of the entire specimen submitted for pathology 
review. 
• 
No Response: Gross cancer is found on pathologic examination of the resected 
esophageal cancer and draining lymph nodes. 
 
11.3 
Criteria for Discontinuation of Protocol Treatment 
• 
Progression of disease 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), as defined in Section 6.0 and/or 7.0 
• 
Patient decides to withdraw from the study 
 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified in the protocol. 


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RTOG 1010; version date November 15, 
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11.4 
Quality of Life and Health Utility Assessments 
11.4.1 
The Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E) is a 
multidimensional, QOL instrument specifically designed and validated for use with 
patients with esophageal cancer patients that the patient can complete in 10 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 FACT-E has been translated into 16 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.   
11.4.2 The EuroQol (EQ-5D) is a two-part questionnaire that the patient can complete in 
approximately 5 minutes. Note: The EQ-5D has been translated into multiple languages; 
these translations are available from the EuroQol web site at http://www.euroqol.org/. The 
site research nurse or CRA should encourage the patient not to skip questions on the 
EQ-5D or take breaks during the completion of this questionnaire, as this will invalidate 
the assessment. If this occurs, sites will document it on the Health Utility Measurement 
(HP) form. 
 
 
12.0 
DATA COLLECTION (15-NOV-2018) 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1720  
 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 (7/16/13) 
 
 
 
Item 
Due 
 
Specimen Form (SP) 
 
 
 
 
To be submitted with tumor sample for 
HER2 testing to Dr. Resnick (see Section 
10.2.2) after Step 1 registration 
 
Demographic Form (A5) 
Within 2 wks of Step 2 registration 
Initial Evaluation Form (I1) 
 
Pathology Report (P1)  
 
Quality of Life/Health Utility Forms  
▪ FACT-E (FA) 
▪ EQ-5D (HP) 
 
 
 
Treatment Form (TF) 
Within 1 wk of concurrent systemic treatment 
completion 
Radiotherapy Form (T1)  
Daily Treatment Record (T5) [copy to HQ  
 
Within 1 wk of RT end 
Post Treatment Response Form (F2) 
4-6 weeks after the last radiation treatment 


58                
RTOG 1010; version date November 15, 
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post biopsy 
 
Initial Follow-Up Form (FS) 
Just prior to resection (must include all 
toxicities up to the surgical resection) 
 
 
Surgical Form (S1) 
Within 4 wks post surgical resection 
Operative Report (S2) 
 
Surgical Pathology Report (S5) 
 
 
 
 
 
Maintenance Treatment Form (SF) 
 
Within 1 wk of completion of cycles 1-5, 6-10 
and 11-13 
 
Quality of Life/Health Utility Forms  
▪ FACT-E (FA) 
 
 
 
6 wks post chemo/RT but prior to 
esophagectomy, 1 yr from start of treatment, 
and 2 yrs from start of treatment 
 
 
▪ EQ-5D (HP) 
 
1 yr from start of treatment and 2 yrs from 
start of treatment 
 
 
Follow-Up Form (F1) 
PET/CT or CT Scan Report (C3) 
Every 4 mos from the end of surgery x 2 yrs, 
then annually 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.2) 
(11/5/14) 
 
NOTE: ALL DIGITAL RT DATA REQUIRED IN DICOM FORMAT VIA TRIAD ALL REQUIRED 
STRUCTURES MUST BE LABELED PER DICOM STANDARD NAME AS LISTED IN SECTION 
6.5. 
 
Item 
Due 
Preliminary Dosimetry Information  
 
†Digital Data Transmission Form (DT) 
Within 1 
week of 
RT start  
CT data, critical normal structures, all GTV, CTV, and PTV contours  
 
Digital beam geometry for initial and boost beam sets 
 
Doses for initial boost and composite sets of concurrent treated beams 
 
Digital DVH data for all required critical normal structures, GTV, CTV, and 
PTVs for total dose plan  
RTOG 1010 Datasheet located on the NRG Oncology/RTOG website at 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study+1010 
 
 
 
Submit via TRIAD with Digital RT Data listed above 
 
 
Final Dosimetry Information 
Within 1 
week of 
RT end 
Radiotherapy Form (T1)  
 
Daily Treatment Record (T5) [copy to HQ]  
 
 
 
 


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13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Endpoints 
13.1.1 
Primary Endpoint 
Disease-free survival (failure: disease persistence or recurrence, or distant metastases, 
or second primary, or death due to any cause) 
 
13.1.2 
Secondary Endpoints 
▪ 
 Pathologic complete response at surgery 
▪ 
 Overall survival (OS) (failure: death due to any cause) 
▪ 
 Adverse events 
▪ 
 Health-related quality of life (HRQoL) as measured by FACT-E 
▪ 
 Quality adjusted survival 
▪ 
 Molecular correlates of efficacy 
▪ 
 Predictors of cardiotoxicity 
 
13.2 
Stratification 
Patients will be stratified before randomization with respect to the presence of 
adenopathy (No vs. Yes—celiac absent vs. Yes—celiac present ≤ 2 cm). The permuted 
block randomization method described by Zelen (1974) will be used because it balances 
patient factors other than institution. 
 
13.3 
Sample Size and Power Justification 
13.3.1 
The sample size calculations are based on the primary hypothesis that the addition of 
trastuzumab during preoperative chemoradiation and for 12 months of maintenance 
following surgery will increase the median disease-free survival (DFS) from 15 months 
to 25 months, for HER2-overexpressing patients (HER2 positive) with esophageal 
adenocarcinoma.  
 
The required sample size for the primary endpoint of DFS is based on the following 
conditions: 
 
▪ 
DFS times are exponentially distributed with (at least approximately) constant 
hazards in both treatment arms 
▪ 
The control arm will have a median DFS of 15 months (monthly hazard of 
0.04621) 
▪ 
The experimental arm will have a median DFS of 25 months (monthly hazard of 
0.02773) 
▪ 
Hazard ratio (experimental/control) = 0.60 
▪ 
Two-sided test at  = 0.05 
▪ 
Statistical power of 90% 
▪ 
5 years of accrual with 3 years of follow-up 
▪ 
Two interim significance tests and a final test are planned using the Haybittle-
Peto (Lan 1983; O’Brien 1979) rule for efficacy and the lan-DeMets (Lan 1983) 
beta spending function for futility 
 
Patients will be registered to the trial and then their HER2 status will be centrally 
evaluated.  It is projected that 1 out of 3 patients evaluated will be HER2 positive.  All 
patients who are HER2 positive will be randomized to the study treatment arms. Using 
the group sequential design method (Pocock 1977) with 2 interim analyses, 162  DFS 
events are required to detect an increase in median DFS from 15 months to 25 months, 
translating into a hazard ratio (experimental/control) of 0.60. Given the conditions 
above, a total sample size of 183 HER2 positive patients will be required to be accrued 
uniformly over 5 years with an additional 3 years of follow-up. Guarding against an 
ineligibility or lack-of-data rate of up to 7%, the targeted accrual of HER2 positive 
patients for this study will be 197 patients.  It is projected that a total of 591 patients 
will need to be registered and evaluated for HER2 status. 


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13.3.2 
Considerations for Increasing Sample Size 
Two years after the study has been activated, if the following criteria are met: 
▪ 
accrual is as projected 
▪ 
toxicity is acceptable  
▪ 
rate of patients screened positive for HER2 is as projected then consideration will 
be given to increasing the sample size to detect a smaller increase in DFS, per the 
table below:  
 
Sample Sizes With 2-Sided Alpha = 0.05 
Increase in 
Median DFS to 
(months) 
Hazard Ratio 
90% Power 
 
 
Evaluable  
Sample Size 
Total  
Sample Size 
Total To Be 
Screened 
27 – original 
0.56 
148 
160 
480 
26.5 
0.57 
156 
168 
504 
26 
0.58 
164 
177 
531 
25.5 
0.59 
173 
187 
561 
25 – revised 
0.60 
183 
197 
591 
If there is a decision to increase the sample size, the extent of the increase will depend 
on the actual rates of accrual and HER2 positivity. 
13.3.3 
Patient Accrual 
Patient accrual is projected to be 3 HER2 positive cases per month, with a ramp-up 
period in the first 6 months. The expected monthly accrual in months 1 through 3 and 
months 4 through 6 following activation are 0 and 1, respectively.  If the total accrual 
during months 13 through 18 of the study is ≤ 20% of the targeted accrual (< 4 cases in 
total), then the protocol will be discontinued per NCI-CTEP accrual guidelines for phase 
III studies. If the total accrual during months 13 through 18 is between 21% and 49% (4 
to 8 cases), then the protocol will continue to accrue subjects and will be evaluated 
again at the end of month 24.  If the accrual during months 22 through 24 is at least 
50% of the targeted accrual (≥ 5 cases in total), the NCI-CTEP accrual guidelines for 
phase III studies will have been met and the study will continue accrual; otherwise, the 
study will be discontinued. 
 
13.4 
Power Information for Health Reported Quality of Life – FACT-E 
The Functional Assessment of Cancer Therapy – Esophagus (FACT-E) will be used to 
measure HRQOL, with the focus on the Esophageal Cancer Subscale (ECS). Protocol-
eligible patients will be included in the QOL analysis only if they have provided baseline 
and at least one subsequent measurement. The FACT-E will be collected on all cases 
participating in this portion of the trial and will be collected at 4 time points: pretreatment 
(baseline); 6 to 8 weeks following chemoradiation with or without trastuzumab at the time 
of restaging prior to surgical resection; 1 year from start of treatment; and 2 years from 
start of treatment. 
 
The primary HRQOL endpoint will be to determine whether the addition of trastuzumab to 
chemoradiation improves the FACT-E Esophageal Cancer Subscale (ECS) score, as 
measured by the proportion of patients on each treatment arm with improvement, defined 
as an increase in the ECS score of at least 5 points. Given the recent development and 
validation of this tool, the power calculations shown below cover a number of possible 
proportions for improvement over the control arm.  The power calculations are all based 
on a 1-sided, α=0.05, chi-squared test and the assumption of an 80% participation rate. 


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Power Calculations for ECS Score 
p0 
pa 
n/arm* 
Power 
0.30 
0.55 
73 
90 
0.30 
0.60 
73 
97 
0.40 
0.65 
73 
89 
0.40 
0.70 
73 
97 
0.50 
0.75 
73 
91 
0.50 
0.80 
73 
98 
*If the participation rate is higher, there will be more power to detect the hypothesized 
differences; if the participation rate is lower, there will be less power. 
 
13.5 
Analysis Plan (7/26/11) 
All analyses will be done based on the assigned treatment arm for all eligible patients 
entered. 
13.5.1 
Statistical Methods 
▪  Disease-Free Survival 
Disease-free survival (DFS) will be estimated by the Kaplan-Meier method (Kaplan 
1958). The distribution of DFS estimates between the 2 arms will be compared using 
the log rank test (Mantel 1966).   DFS time will be measured from the date of 
randomization to the date of first failure 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 DFS.  
▪  Overall Survival 
Overall survival (OS) will be estimated by the Kaplan-Meier method (Kaplan 1958). 
The distribution of OS estimates between the 2 arms will be compared using the log 
rank test (Mantel 1966).   OS time will be measured from the date of randomization 
to the date of first failure 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 OS. 
13.5.2 
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 endpoint, DFS, or any secondary endpoints, with the exception of 
reporting of adverse events. 
13.5.3 CDUS Reports 
 
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. 
13.5.4 
Significance Testing for Early Termination and/or Reporting 
 
Unacceptable Toxicity 
The addition of trastuzumab to cisplatin and fluorouracil did not increase toxicity in 
the ToGA trial (Van Cutsem 2009). Furthermore, the addition of trastuzumab to 
cisplatin, paclitaxel, and radiation did not produce cardiac toxicity or increase any 
other toxicity. While it is unlikely that trastuzumab will increase the toxicity of 
chemoradiation, this will be carefully monitored, with a specific focus on the 
following adverse events: 


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▪ 
Grade 3/4 restrictive cardiomyopathy 
▪ 
Patients with incipient CHF defined as an asymptomatic > 20% decrease in 
LVEF or a decrease of LVEF > 10% below the institutional lower limit of normal 
who are judged to require treatment according to institutional guidelines.  
 
To address the safety of adding trastuzumab, the rate of the adverse events 
specified above will be reviewed after 25 and 50 patients have been entered on the 
trastuzumab arm and followed from the start of chemoradiation up to the earlier of 
date of surgery or 6 weeks after completion of chemoradiation. The study chairs 
have determined that a rate of 20% or greater will be considered to be 
unacceptable. According to Fleming’s method with a maximum overall significance 
level of 0.05 if there are:  
 
▪ 
5 or more patients with cardiomyopathy-related events described above out of 
the first 25 evaluable patients, or  
▪ 
6 or more patients with cardiomyopathy-related events described above out of 
the first 50 evaluable patients  
 
then the study will have exceeded the limit for unacceptable cardiomyopathy 
(Fleming 1982).  If the number of unacceptable cardiomyopathy events crosses a 
boundary, as described in the rules above, then the conclusion will be that the 
treatment-related cardiomyopathy rate is greater than 20%.  If this circumstance 
occurs, the study chairs, the NRG Oncology gastrointestinal cancer committee chair, 
and the study statistician will review the adverse event data and make appropriate 
recommendations to the NRG Oncology data monitoring committee (DMC) to 
consider when they review the toxicity results.. These stopping rules provide 95% 
power for concluding that the rate of adverse events specified above exceeds 20%, 
when in fact that is the true rate. 
 
 
Early Evaluation of Adverse Events Between Treatment Arms 
After 50 evaluable patients have been entered and followed from the start of 
chemoradiation up to the earlier date of surgery or 6 weeks after completion of 
chemoradiation, an evaluation of adverse events will be performed, specifically 
including the group of adverse events listed in Section 13.5.4. All grade 3+ 
nonhematologic adverse events, and all grade 3+ adverse events. 
 
 
Primary Endpoint: Disease-Free survival (DFS) 
Three interim significance tests of treatment difference are planned. The timing of 
the interim analyses will be based on DFS failure events, as described in Section 
13.1.1.  The maximum number of events required for the study is 162. Under the 
alternative hypothesis that the addition of trastuzumab will increase median DFS 
from 15 months to 25 months, the projected numbers of events and the nominal 
significance levels for rejecting the H0 or the H1 for each of these two interim 
analyses are shown in the table below:   
 
Nominal Significance Levels for Interim Analyses 
 
Interim Analysis 
Efficacy:  
Reject H0 if p (H0) ≤ 
Futility:  
Reject H1 if p ≥ 
 
# Events (Control Arm) 
#1 
≤ 0.001 
0.83 
81 
#2 
≤ 0.001 
0.25 
122 
 
At each planned interim analysis, the p-value from the log-rank test assessing 
treatment efficacy and futility with respect to DFS will be compared to the nominal 
significance levels in the table above.  If the computed p-value is less than or equal 
to the nominal significance level boundary for rejecting the H0 (efficacy), then 


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accrual to the trial will be stopped (if applicable), it will be concluded that the DFS 
with trastuzumab (Arm 1) is significantly higher than without trastuzumab (Arm 2) 
and the results will be reported.  If the computed p-value is greater67 
 than or 
equal to the nominal significance level boundary for rejecting the H1 (futility), then 
accrual to the trial will be stopped (if applicable) and it will be reported that it cannot 
be concluded that the DFS with trastuzumab (Arm 1) is significantly higher than 
without trastuzumab (Arm 2).  Otherwise, if the p-value falls between the nominal 
significance levels for rejecting the H0 and the H1, accrual to the trial or follow-up (as 
applicable) will continue until the next interim or final analysis.   
 
In addition to accrual, distributions of pretreatment characteristics, frequency and 
severity of adverse events, and compliance with protocol treatment, blinded efficacy 
results will be reported to the NRG Oncology data monitoring committee (DMC), 
following the required number of events for each planned interim analysis.   
13.5.5 
Analysis for Endpoints Related to HRQOL  
Distributions of QOL data collection patterns over all collection points in each 
treatment arm will be described.  To inspect the missing data mechanism for each 
tool, at least a graphical method will be used.  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 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.  
  
 
FACT-E Scoring and Analysis 
▪ 
 The FACT-E will be scored per the FACT-E Scoring Guidelines (Version 4 
www.facit.org), with higher scores indicating better QOL. 
▪ 
 The primary objective in the HRQOL analysis is improvement in the FACT-E 
Esophageal Cancer Subscale (ECS) score, defined as an increase of 5 
points or more from baseline to the assessment at 6 to 8 weeks following 
chemoradiation with or without trastuzumab, at the time of restaging prior to 
surgical resection.  Chi-squared tests will be used to test the null hypothesis 
that the proportion of patients categorized as “improved” will be the same for 
the 2 treatment arms, versus the alternative hypothesis that the proportion of 
patients categorized as “improved” is higher for the trastuzumab arm. 
▪ 
 Improvement in the ECS score, as defined above, will also be compared 
between the treatment arms for changes from baseline to both 1 and 2 years 
with the same methodology as listed above. 
▪ 
 Correlation between pathologic complete response (pCR) and improvement 
in ECS score from baseline to 6 to 8 weeks following chemoradiation will be 
evaluated with chi-squared tests. 


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▪ 
 Chi-squared tests will be used to determine if pCR is prognostic or predictive 
of ECS score at 1 and/or 2 years. 
▪ 
 The definition of improvement for both the Swallowing Index and Eating 
Index Subscale scores are defined as an increase of 2 or more points from 
baseline.  Analyses similar to the ones described above for ECS scores will 
be done for the Swallowing and Eating Index scores. 
 
 
EQ-5D Scoring and Analysis 
▪ 
 The quality-adjusted survival of each treatment will be evaluated and compared 
using EQ-5D if the primary endpoint supports the primary hypothesis. 
▪ 
 The EQ-5D is a 2-part self-assessment questionnaire. The first part consists of 5 
items covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression). Each dimension is measured by a 3-point likert scale 
(1-no problems, 2-moderate problems, and 3-extreme problems). The second 
part is a visual analog scale (VAS) valuing the current health state measured by 
a 100-point scale with a 10-point interval (0-worst imaginable health state, 100-
best imaginable health state). We will transform the 5-item index score and VAS 
score into a utility score between 0 (worst health state) and 1 (best health state) 
for comparative purposes. Patients will complete the EQ-5D at the following time 
points: pretreatment (baseline), at 1 year from the start of treatment, and at 2 
years from the start of treatment. 
▪ 
 To examine trade-offs between the survival time and QOL, they will be 
combined for each patient into a single measurement: quality-adjusted life years 
(QALY). If (and only if) the primary endpoint hypothesis is substantiated, a 
quality-adjusted survival analysis will be conducted. The quality-adjusted survival 
analysis will not be done until after the primary endpoint results are published. 
QALY is defined by the weighted sum of different time episodes added up to a 
total quality-adjusted survival time. QALY will be analyzed at 2 time points: at 1 
year and 2 years from start of treatment, using the EQ-5D. 
13.5.6 
Analysis for Reporting the Initial Treatment Results 
The primary hypothesis of this study is that the addition of trastuzumab during 
preoperative chemoradiation and for 12 months of maintenance following surgery will 
increase the median DFS from 15 months to 25 months, for HER2 positive patients 
with esophageal adenocarcinoma.  This major analysis will occur after at least 162 DFS 
failure events have been observed, unless an early stopping rule is satisfied. 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 
 
All eligible patients randomized will be included in the comparison and will be grouped by 
assigned treatment in the analysis.  The primary hypothesis of treatment benefit will be 
tested using the log-rank statistic with a significance level of 0.05, given that the 2 interim 
analyses were carried out per Section 13.5.4. Additional analyses of treatment effect will 
be performed using the Cox proportional hazard model with the stratification factor 
included as a fixed covariate, as well as any factors that show an imbalance between the 
arms (eg, age, gender, race, Karnofsky performance status, etc.). 
 


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13.6 
Gender and Minorities 
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, possible interaction 
between race/ethnicity and treatment have been considered. Based on studies RTOG 
9405 and RTOG 0113, it is projected that 72% of the patients will be men and 28% 
women; 3% will be of Hispanic or Latino ethnicity and 97% will not; racial distribution will 
be 73% white, 26% black or African American, and 1% Asian. Assuming no differences 
between the ethnicities, or among the races, the statistical power for detecting the 
hypothesized treatment difference is 78% for males and 40% for females. Assuming no 
differences between genders or the ethnicities, the statistical power is 79% for whites and 
37% for Blacks/African-Americans. The projected non-White/Black accrual rate is too low 
for any meaningful treatment comparisons. Assuming no differences between the 
genders, or among the races, the statistical power for detecting the hypothesized 
treatment difference in non-Hispanic/Latino ethnicity will be 88%.  The projected 
Hispanic/Latino accrual rate is too low for any meaningful treatment comparisons. 
 
The following table lists the projected accrual by gender, ethnic, and racial categories.   
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
5 
7 
Not Hispanic or Latino 
53 
137 
190 
Ethnic Category: Total of all subjects 
55 
142 
197 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
1 
2 
Black or African American 
14 
37 
51 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
40 
104 
144 
Racial Category: Total of all subjects 
55 
142 
197 
 


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alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19:305-313. 
 
Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: a phase III study of 
trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 
(HER2)-positive advanced gastric cancer (GC). Proc Am Soc Clin Oncol. 2009;LBA 4509.  
 
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line 
treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719-726. 
 
Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for 
esophageal adenocarcinoma. N Engl J Med. 1996;335:462-467.  
 
Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in 
adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol. 2001;19:3058-
3065. 
 
Williams J, Russell I, Durai D, et al. What are the clinical outcome and cost-effectiveness of endoscopy 
undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET) 
Health Technol Assess 2006;10(40):iii-iv,ix-x,1-195. 
 
Wu AW, Jacobson KD, Frick DL, et al. Validity and responsiveness of the EQ-5D as a measure of health-
related quality of life in people enrolled in an AIDS clinical trial. Qual Life Res. 2002;11:273-282. 
 
Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-137.  
 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 1974;27:365-375. 
 


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APPENDIX I 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-continued on next page- 
 
 
 
Assessments 
Prior to 
Step 1 
registration 
Prior to Step 1 
registration but 
must be within 56 
days prior to Step 
2 registration 
Within 56 days 
prior to Step 2 
registration 
 
Within 14 days prior to Step 
2 registration 
 
Pathologically 
confirmed diagnosis 
X 
 
 
 
Endoscopy w/ biopsy 
X 
 
 
 
Endoscopic ultrasound 
 
 
Pts not 
exhibiting 
adenopathy on 
CT or whole-
body PET/CT 
 
Determination of HER2 
status by central 
laboratory 
 
 
X 
 
History/physical w/ 
weight 
 
 
 
X 
Chest/abdominal/pelvic 
CT or whole-body 
PET/CT 
 
X 
X* 
 
Bronchoscopy 
 
 
Pts w/ tumors 
at the level of 
the carina or 
above* 
 
EKG 
 
 
X 
 
Med/Rad Onc Surg. 
Eval 
 
 
X 
 
Echocardiogram or 
MUGA for LVEF 
 
 
X 
 
Performance status 
 
X 
 
X 
CBC w/ diff, ANC, 
platelets, Hgb 
 
X 
 
X 
Na, K, BUN,  Glucose 
Within 14 
days prior to 
Step 1 
registration 
 
 
 
Creatinine 
 
 
 
X 
Bilirubin, AST 
 
X 
 
 
Pregnancy test  
(if applicable) 
 
Urine or serum 
 
Serum 
Arterial blood gas 
 
 
Recommended 
 
PFTs 
 
 
X 
 
Plasma/urine for 
banking, if patient 
consents (HER2+ 
patients only) 
 
 
Before 
treatment start 
 


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APPENDIX I 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (continued) 
 
Assessments 
Prior to 
Step 1 
registration 
Prior to Step 1 
registration but 
must be within 56 
days prior to Step 
2 registration 
Within 56 days 
prior to Step 2 
registration 
 
Within 14 days prior to Step 
2 registration 
 
Whole blood for 
banking, if patient 
consents (HER2+ 
patients only) 
 
 
Before 
treatment start 
(or at any other 
visit during or 
after treatment) 
 
Tissue for banking, if 
patient consents  (For 
all patients) 
 
Collected from 
diagnostic biopsy 
and from 
endoscopic 
ultrasound, if 
performed , and if 
biopsy performed 
 
 
FACT-E, if patient 
consents 
 
 
 
X 
EQ-5D, if patient 
consents 
 
 
 
X 
* See Section 3.0 for details and exceptions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I 
STUDY PARAMETER TABLE: DURING TREATMENT ASSESSMENTS (7/16/13) 
 
Assessments 
Every wk 
during 
chemo/RT 
After chemo/RT 
completion and prior to 
surgery 
At 6-8 wks post-treatment but 
prior to surgery 
Endoscopy w/ biopsy 
 
Highly Recommended 
 
History/physical w/ weight 
X 
X 
 
Chest/abdominal/pelvic CT or 
whole-body PET/CT 
 
X 
 
Echocardiogram or MUGA for 
LVEF 
 
X 
 
Performance status 
X 
X 
 
CBC w/ diff, ANC, platelets, 
Hgb 
X 
X 
 
Na, K, BUN,  Glucose 
X 
X 
 
Creatinine 
X 
 
 
Bilirubin, AST 
Every 2 wks 
X 
 
Adverse event evaluation 
X 
X 
 
Plasma/urine for banking, if 
patient consents (HER2+ 
patients only) 
 
X 
 
Tissue for banking, if patient 
consents  (For all patients 
only) 
 
At time of esophagectomy (if performed) 
FACT-E, if patient consents 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I 
STUDY PARAMETER TABLE: FOLLOW-UP ASSESSMENTS (7/16/13) 
 
 
Assessments 
Every 4 months after 
surgery for 2 years, then 
annually 
At 1 and 2 years from 
treatment start 
History/physical w/ weight 
Arm 1: Every 6 wks during 
maintenance trastuzumab 
Arm 2: Every 4 months for 2 
years then annually 
 
Chest/abdominal/pelvic CT or whole-body 
PET/CT 
X 
 
Echocardiogram or MUGA for LVEF 
Arm 1: At 3, 6, 9 and 12 
months  from the start of 
maintenance trastuzumab 
Arm 2:  6 and 12 months post-
surgery 
 
Performance status 
X 
 
Adverse Event Evaluation 
X 
 
FACT-E, if patient consents 
 
X 
EQ-5D, if patient consents 
 
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  
 
5 
Death  
 
 


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APPENDIX III 
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
ESOPHAGUS and ESOPHAGEAL JUNCTION 
 
 
 
DEFINITION OF TNM 
 
Primary Tumor (T)* 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
High-grade dysplasia** 
T1 
Tumor invades lamina propria, muscularis mucosae, or submucosa 
T1a 
Tumor invades lamina propria or muscularis mucosae 
T1b 
Tumor invades submucosa 
T2 
Tumor invades muscularis propria 
T3 
Tumor invades adventitia 
T4 
Tumor invades adjacent structures 
T4a 
Resectable tumor invading pleura, pericardium, or diaphragm 
T4b 
Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, 
etc. 
 
* 1) At least maximal dimension of the tumor must be recorded and 2) multiple tumors require the T(m) 
suffix. 
**High-grade dysplasia includes all noninvasive neoplastic epithelia that was formerly called carcinoma in 
situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract. 
 
Regional Lymph Nodes (N)* 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in 1-2 regional lymph nodes 
N2 
Metastasis in 3-6 regional lymph nodes 
N3 
Metastasis in ≥ 7 regional lymph nodes 
*Number must be recorded for total number of regional nodes sampled and total number of reported 
nodes with metastasis. 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
 
 


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APPENDIX III (Continued) 
 
AJCC STAGING SYSTEM 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
ESOPHAGUS and ESOPHAGEAL JUNCTION 
 
ANATOMIC STAGE/PROGNOSTIC GROUPS 
 
 
 
Squamous Cell Carcinoma 
Stage 
T 
N 
M 
Grade 
Tumor Location** 
0 
Tis 
N0 
M0 
1, X 
Any 
IA 
T1 
N0 
M0 
1, X 
Any 
IB 
T1 
N0 
M0 
2-3 
Any 
 
T2-3 
N0 
M0 
1, X 
Lower, X 
IIA 
T2-3 
N0 
M0 
1,X 
Upper, middle 
 
T2-3 
N0 
M0 
2-3 
Lower, X 
IIB 
T2-3 
N0 
M0 
2-3 
Upper, middle 
 
T1-2 
N1 
M0 
Any 
Any 
IIIA 
T1-2 
N2 
M0 
Any 
Any 
 
T3 
N1 
M0 
Any 
Any 
 
T4a 
N0 
M0 
Any 
Any 
IIIB 
T3 
N2 
M0 
Any 
Any 
IIIC 
T4a 
N1-2 
M0 
Any 
Any 
 
T4b 
Any 
M0 
Any 
Any 
 
Any 
N3 
M0 
Any 
Any 
IV 
Any 
Any 
M1 
Any 
Any 
**Location of the primary cancer site is defined by the position of the upper (proximal) edge of the tumor 
in the esophagus 
 
 
Adenocarcinoma 
Stage 
T 
N 
M 
Grade 
0 
Tis 
N0 
M0 
1, X 
IA 
T1 
N0 
M0 
1-2, X 
IB 
T1 
N0 
M0 
3 
 
T2 
N0 
M0 
1-2, X 
IIA 
T2 
N0 
M0 
3 
IIB 
T3 
N0 
M0 
Any 
 
T1-2 
N1 
M0 
Any 
IIIA 
T1-2 
N2 
M0 
Any 
 
T3 
N1 
M0 
Any 
 
T4a 
N0 
M0 
Any 
IIIB 
T3 
N2 
M0 
Any 
IIIC 
T4a 
N1-2 
M0 
Any 
 
T4b 
Any 
M0 
Any 
 
Any 
N3 
M0 
Any 
IV 
Any 
Any 
M1 
Any 
 
 


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APPENDIX IV 
 
Pathology Assessment of the Surgical Specimen  
 
The entire esophageal specimen and lymph nodes will be submitted for local pathological review. 
 
The gross appearance of treated tumor varies from mucosal ulceration to a fibrous scar or a prominent 
mass lesion in the case of a less than profound tumor regression.  The ulcerated or scarred gross lesions 
should be blocked and sequentially and entirely submitted for histopathologic evaluation (approximately 3 
mm in thickness).  One section from each block should be evaluated by hematoxylin and eosin (H&E) 
staining.  If gross tumor is present and large (> 5cm), representative sections of the tumor may be 
evaluated. 
 
Pathologic complete response is defined as no viable residual tumor cells.  Acellular residual mucin pools 
should be noted but also considered  pathologic complete response. 
 
Down-staging will be determined by comparing pre-radiation clinical staging (CT scan, PET scan and 
EUS) to the pathologic size and stage (both tumor and nodal staging). Residual tumor grading will be per 
Wu (2007).  See diagram below: 
 
From Wu T, Chirieac LR, Abraham SC, et al. Am J Surg Pathol. 2007;31:58-64.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX V (11/5/14) 
 
 BIOSPECIMEN COLLECTION INSTRUCTIONS 
 FFPE PLUG KIT INSTRUCTIONS 
 BLOOD COLLECTION KIT INSTRUCTIONS 
 URINE COLLECTION KIT INSTRUCTIONS 
 
Shipping Instructions: 
 
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 94143-1800 
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 ST has the consent boxes checked off.  
❑ 
Check that all samples are labeled with NRG Oncology study and case number, and include date 
of collection as well as collection time point. 
 
❑ 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/ slide box. Place a small wad of padding in 
top of container If you can hear the slides shaking they are likely to 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. Place padding in top of container so that if you shake the 
container the blocks are not shaking. If you can hear them shaking they are likely to break 
during shipping.  
o Slides, Blocks or Plugs can be shipped ambient or with a cold pack either by 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 -80C until ready to ship. 
 
❑ 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by email at: RTOG@ucsf.edu or (415)-476-7864 or fax (415)-476-5271 


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 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.  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: 
 
For Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the 
NRG Oncology Biospecimen Bank by email at: RTOG@ucsf.edu or call 415-476-RTOG(7864) /FAX 476-
5271. 
US Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank at UCSF 
Campus Box 1800 
2340 Sutter Street, Room S341  
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE shipments 
NRG Oncology Biospecimen Bank at UCSF  
2340 Sutter Street, Room S341  
San Francisco, CA 94115 


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 BLOOD COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of plasma as specified in protocol 
Kit contents: 
• One Purple Top EDTA tube #1 for plasma  (A) 
• One Purple Top EDTA tube #2 for Whole Blood (B) 
• Eighteen (18) 1 ml cryovials 
• Specimen Transmittal Form 
• Styrofoam container (inner)  
• Cardboard shipping (outer) box 
• Kit Instructions 
• Absorbent shipping material (3) 
• Biohazard bags (3) 
• UN1845 DRY Ice Sticker 
• UN3373 Biological Substance Category B Stickers 
 
Preparation and Processing of Plasma 
A) Plasma: Purple Top EDTA tube #1 
 
❑ 
Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with 
the NRG Oncology study and case number, collection date and time, 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 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on 
the ST. 
3. If the interval between specimen collection and processing is anticipated  
 
to be more than one hour, keep specimen on ice until centrifuging   
 
is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are  
necessary for the plasma collected (5 to 8) 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. If  
any aliquots have  less than 0.5 ml, the volume must be marked on the aliquot  
tube. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C 
6. Store frozen plasma -70 to -90 Cuntil ready to ship on dry ice.   
7. See below for storage conditions. 
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED, and include collection time point 
on ST. 
 
B) Whole Blood For DNA: Purple Top EDTA tube #2  
❑ 
Label as many 1ml 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 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 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”. If any aliquots have  
less than 1 ml, the volume must be marked on the aliquot tube. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen -70 to -90 C until ready to ship on dry ice.  
5. See below for storage conditions. 
 


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BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED, and include 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 –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
❑ 
Samples can be stored short term in a -20 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 liquid 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.  
 
 BLOOD COLLECTION KIT INSTRUCTIONS   
❑ 
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 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.  
❑ 
For questions regarding collection, shipping or to order a Blood Collection Kit, please Email 
RTOG@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  94115Contact Phone 415.476.7864 


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URINE COLLECTION KIT INSTRUCTIONS  
 
This Kit is for collection, processing, storage, and shipping of Urine Specimens 
 
Kit Contents: 
• 
One (1) Sterile Urine collection cup 
• Two 15 ml polypropylene centrifuge 
tubes 
• 
Two 7 ml disposable pipets 
• Biohazard bags 
• 
Absorbent Paper Towel 
• Parafilm for sealing outside of tubes 
 
Preparation and Processing of Urine Specimens: 
❑ 
A clean catch urine specimen will be collected.  To collect the specimen, use the following 
instructions: 
• 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.  
• After urinating a small amount into the toilet bowl to clear the urethra of contaminants, collect a 
sample of urine in the collection cup. 
• After 10-25 mL urine has been collected, remove container from the urine stream without 
stopping the flow of urine. 
• Finish voiding the bladder into the toilet bowl. 
❑ 
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.  
❑ 
Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
❑ 
Discard remaining Urine and collection cup. 
❑ 
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”. 
❑ 
Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and seal 
the bag. Freeze and store Urine samples in a-20C or -80C Freezer until ready to ship 
 
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 –20C or 80C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available,  
▪ 
Samples can be stored short term in a -20 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). 
❑ 
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.  
❑ 
Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
❑ 
Include all NRG Oncology paperwork in a sealed plastic 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 breaking the tubes.  
❑ 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 


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URINE COLLECTION KIT INSTRUCTIONS (continued) 
 
 
❑ 
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 ordering, collection, or shipping a Urine Collection Kit, please Email 
RTOG@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