A Phase II Trial of Modified FOLFOX-6 Induction Chemotherapy Followed by Esophagectomy and Post-operative Response Based Concurrent Chemoradiotherapy in Patients With Locoregionally Advanced Adenocarcinoma of the Esophagus, Gastro-esophageal Junction, and Gastric Cardia
Phase: PHASE2
Conditions: Adenocarcinoma of the Esophagus, Adenocarcinoma of the Gastroesophageal Junction, Adenocarcinoma of the Gastric Cardia, Stage IIIA Esophageal Cancer, Stage IIIB Esophageal Cancer, Stage IIIC Esophageal Cancer
Sponsor: Case Comprehensive Cancer Center

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Study Number: 
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ClinicalTrials.gov#   NCT 02037048 
Protocol date: 
 07/24/2019 
STUDY TITLE:  A Phase II Trial of modified FOLFOX-6 Induction Chemotherapy 
Followed by Esophagectomy and Post-operative Response Based Concurrent 
Chemoradiotherapy in Patients with Locoregionally Advanced Adenocarcinoma of the 
Esophagus, Gastro-esophageal Junction, and Gastric Cardia. 
SITES: 
Cleveland Clinic, Main 
Wooster Milltown Specialty and Surgery Center 
Cleveland Clinic Cancer Centers, Sandusky 
Cleveland Clinic Cancer Center, Strongsville 
Hillcrest Hospital 
Fairview Hospital 
Cleveland Clinic Cancer Center, Mansfield 
PRINCIPAL INVESTIGATOR: 
Michael J. McNamara, M.D. 
Cleveland Clinic  
Taussig Cancer Institute 
Solid Tumor Oncology 
9500 Euclid Avenue, 
 
Cleveland Ohio, 44195 
 
 
  
CO-INVESTIGATORS: 
Neil Woody, MD 
Cleveland Clinic 

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Taussig Cancer Institute 
Radiation Oncology 
9500 Euclid, Avenue, 
 
Cleveland, OH, 44195 
 
  
 
David J Adelstein, MD  
Cleveland Clinic  
Taussig Cancer Institute 
Solid Tumor Oncology 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
 
 
Daniela Allende, MD  
Cleveland Clinic  
Pathology and Laboratory Medicine Institute 
Anatomic Pathology 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
   
 
Alok Khorana, MD 
Cleveland Clinic  
Taussig Cancer Institute 
Solid Tumor Oncology 
9500 Euclid Avenue, 
 
 
 
 
 Matthew Walsh, MD  
Cleveland Clinic  
Digestive Disorder Institute-General Surgery 
500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
   
 
Sudish C. Murthy, MD  
Cleveland Clinic  
Heart and Vascular Institute 
Thoracic and Cardiovascular Surgery 
9500 Euclid Avenue,
  

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Cleveland Ohio, 44195 
 
 
 
Daniel Raymond, MD 
Cleveland Clinic  
Heart and Vascular Institute 
Thoracic and Cardiovascular Surgery 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
 
 
Siva Raja, MD  
Cleveland Clinic  
Heart and Vascular Institute 
Thoracic and Cardiovascular Surgery 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
 
 
Davendra Sohal, MD, MPH 
Cleveland Clinic  
Taussig Cancer Institute 
Solid Tumor Oncology 
9500 Euclid Avenue, 
 
Cleveland Ohio, 44195 
 
 
 
Kevin Stephans, MD 
Cleveland Clinic  
Taussig Cancer Institute 
Radiation Oncology 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 
 
 
 
Gregory Videtic, MD, CM, FRCPC 
Cleveland Clinic  
Taussig Cancer Institute 
Radiation Oncology 
9500 Euclid Avenue, 
  
Cleveland Ohio, 44195 

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Usman Ahmad, MD 
Cleveland Clinic 
Heart and Vascular Institute 
Thoracic and Cardiovascular Surgery 
9500 Euclid Avenue, 
 
Cleveland Ohio 44195 
 
  
 
Joanna Bodmann, CNP 
Cleveland Clinic 
Medical Oncology 
Taussig Cancer Institute 
Solid Tumor Oncology 
9500 Euclid Avenue, 
 
Cleveland, Ohio 44195 
 
  
 
Cleveland Clinic Cancer Center, Sandusky 
 
George Engeler, MD 
Cleveland Clinic Cancer Center, Sandusky 
Radiation Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
 
 
 
Khalid Siddiqui, MD 
Cleveland Clinic Cancer Center, Sandusky 
Radiation Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
 
 
 
Brian Murphy, MD 
Cleveland Clinic Cancer Center, Sandusky 
Medical Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
 

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 Edward Fanning, MD  
Cleveland Clinic Cancer Center, Sandusky 
Medical Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
Phone: (419) 626-9090 
Email: fanninj@ccf.org 
 
Alfred Vargas, MD 
Cleveland Clinic Cancer Center, Sandusky 
Medical Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
 
 
 
Timothy Adamowicz, DO 
Cleveland Clinic Cancer Center, Sandusky 
Medical Oncology 
417 Quarry Lakes Drive 
Sandusky, OH 44870 
 
   
 
 
Wooster Milltown Specialty and Surgery Center 
 
Lapman Lun, MD 
Wooster Milltown Specialty and Surgery Center 
Medical Oncology 
721 East Milltown Road 
Wooster, OH 44691 
 
 
 
Paul Masci, DO 
Wooster Milltown Specialty and Surgery Center 
Medical Oncology 
721 East Milltown Road 
Wooster, OH 44691 
 
 
 
Deasung Lee, MD Wooster 

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Milltown Specialty and Surgery Center 
Radiation Oncology 
721 East Milltown Road 
Wooster, OH 44691 
 
   
 
Cleveland Clinic Cancer Center-Strongsville 
 
Mir Ali, MD 
Cleveland Clinic Cancer Center-Strongsville 
Medical Oncology 
16761 SouthPark Center 
Strongsville, OH 44136 
 
 
 
Andrew Vassil, MD 
Cleveland Clinic Cancer Center-Strongsville 
Radiation Oncology 
16761 SouthPark Center 
Strongsville, OH 44136 
 
 
 
Erin Naso, CNP 
Medical Oncology 
Cleveland Clinic Cancer Center-Strongsville 
16761 SouthPark Center 
Strongsville, OH 44136 
 
  
 
Fairview Hospital Moll Cancer Center 
 
Seema Misbah, MD 
Fairview Hospital 
Medical Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
 
 
Timothy Spiro, MD 
Fairview Hospital 
Medical Oncology 

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18200 Lorain Avenue 
Cleveland, OH 44111 
 
   
 
Daw Hamed, MD 
Fairview Hospital 
Medical Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
   
 
Donald Eicher, MD 
Fairview Hospital 
Medical Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
    
 
Kevin Kerwin, MD 
Fairview Hospital 
Medical Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
   
 
Ehsan Balagamwala, MD 
Fairview Hospital 
Radiation Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
 
 
Anthony Mastroianni, MD 
Fairview Hospital 
Radiation Oncology 
18200 Lorain Avenue 
Cleveland, OH 44111 
 
   
 
 

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Hillcrest Hospital 
 
Aneel Chowdhary, MD 
Hillcrest Hospital  
Medical Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
Vinit Makkar, MD 
Hillcrest Hospital  
Medical Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
Neha Mitra, MD 
Hillcrest Hospital  
Radiation Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
Michael Nemunaitis, MD 
Hillcrest Hospital  
Medical Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
 
Vitaliy Pishchik, MD 
Hillcrest Hospital  
Medical Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
Henry Blair, MD 
Hillcrest Hospital  
Radiation Oncology 

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6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
Michael Weller, MD 
Hillcrest Hospital  
Radiation Oncology 
6780 Mayfield Rd 
Mayfield Heights, OH 44124 
 
   
 
 
Cleveland Clinic Cancer Center-Mansfield 
 
Saurabh Das, MD 
Cleveland Cancer Center-Mansfield   
 
 
Medical Oncology 
1125 Aspira Court 
Mansfield, OH 44906 
 
   
 
Joycelin Canavan, MD 
Cleveland Cancer Center-Mansfield  
Radiation Oncology 
1125 Aspira Court 
Mansfield, OH 44906 
 
   
 
 
 
STATISTICIAN: 
 
  
 
  
 
 
 
 
SPONSOR: 
Case Comprehensive Cancer Center 
Investigator-Initiated 

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SUPPORT: 
Institutional research funding 
 
CHEMOTHERAPY: 
Oxaliplatin 
5-Flourouracil 
Leucovorin 
Carboplatin 
Paclitaxel 
 
 
 
SCHEMA 
This is a phase II trial in which all patients will receive 4 cycles of induction 
chemotherapy with modified FOLFOX 6 (mFOLFOX6) followed by surgical resection.  
Patients who achieve a positive pathologic response (+PR), defined as less than or equal 
to 50% viable tumor cells remaining in the surgical specimen, will then receive 
postoperative chemo-radiotherapy with the mFOLFOX6 regimen.  Patients who fail to 
achieve an adequate pathologic response, referred to as a negative pathologic response (-
PR) and defined as greater than 50% viable tumor cells remaining in the surgical 
specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and 
paclitaxel.  Patients who develop metastatic disease prior to surgery will be removed 
from the protocol and treated at the discretion of the primary oncologist.  Patients who 
have locoregional disease only after induction therapy but do not undergo surgery should 
receive chemoradiotherapy with carboplatin and paclitaxel if medically appropriate as 
determined by the primary oncologist.   
 
 
 
F = Modified FOLFOX 6, C = Carboplatin, P = Paclitaxel, PR = pathologic response 
 
Pre-treatment evaluation 

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All required pre-treatment investigations will be completed within 6 weeks of the 
initiation of therapy (day 1, cycle 1). 
 
mFOLFOX6 
Oxaliplatin 85 mg/m2 over 2 hours on day 1 
Leucovorin 400 mg/m2 over 2 hours administered simultaneously with oxaliplatin on 
day 1.  If drug availability is limited, may administer leucovorin 100mg total dose or 
substitute levo-leucovorin at 200mg/m2. 
5-fluorouracil 400 mg/m2 IV push over 2-4 minutes on day one immediately after 
completion of leucovorin. 
5-fluorouracil 2400 mg/m2 continuous IV infusion over 44 hours (window 42-48 hours) 
days 1-3. 
Regimen administered every 14 days 
 
Pre-operative evaluation & Surgery 
All patients will be evaluated and restaged approximately 3-4 weeks from the completion 
of induction therapy.  Surgery will be scheduled for 1-2 weeks later (See section 6.0 for 
complete details). 
 
Pathologic response 
A positive pathologic response (+PR) will be defined as  50% residual tumor cells 
remaining relative to residual mucin pools and scarring.  A negative pathologic response 
(-PR) will be defined as >50% residual tumor cells remaining relative to residual mucin 
pools and scarring (see text for full pathologic response assessment). 
 
Adjuvant chemoradiotherapy 
Post-operative chemoradiotherapy will start between 6-12 weeks from the date of 
surgery.  Patients with a pathologic response will receive mFOLFOX6 chemotherapy 
concurrent with radiotherapy.  Patients who do not achieve a pathologic response will 
receive carboplatin and paclitaxel concurrent with radiotherapy.  Patients who have 
locoregional disease only after induction therapy but do not undergo surgery should 
receive chemoradiotherapy with carboplatin and paclitaxel if medically appropriate as 
determined by the primary oncologist.   
 
Adjuvant Carboplatin / Paclitaxel 
Paclitaxel = 50 mg/m2 IV over 1 hour on days 1, 8, 15, 22, 29, and 36. 
Carboplatin = (AUC = 2) IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. 
Chemotherapy will be given only during radiotherapy.   
 
Adjuvant mFOLFOX6 
Refer to above for regimen.  Administered every 2 weeks for 3 cycles concurrent with 
radiotherapy on days 1, 15, and 29. 
 
Adjuvant Radiotherapy 
50.4 Gy/1.8 Gy per fraction/ 28 days 
 

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Note:  The treatment schema above is an outline for therapy.  Please refer to Treatment 
Plan and Dose Delays / Dose Modification, in sections 6 and 7 respectively, for details 
regarding therapy management.   
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
SCHEMA 
 
1.0 
INTRODUCTION 
1.1 
Study Disease 
1.2 
Rationale 
 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
2.2 
Secondary Objectives 
2.3 
Exploratory Objectives 
 
3.0 
STUDY DESIGN 
3.1 
Schema 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Study Participation 
 
4.0 
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION 
 
6.0 
TREATMENT PLAN 
6.1 
Induction Chemotherapy 
6.2 
Restaging and Surgery 
6.3 
Radiotherapy 

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6.4 
Adjuvant Chemotherapy 
6.5 
General Concomitant Medications and Supportive Care Guidelines 
6.6 
Duration of Therapy 
6.7 
Duration of Follow Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
7.1 
Induction Chemotherapy 
7.2 
Adjuvant Chemoradiotherapy 
7.3 
Carboplatin and Paclitaxel Post-operative Chemoradiotherapy 
7.4 
FOLFOX Post-operative Chemoradiotherapy 
7.5 
Radiotherapy 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8.1 
Adverse Events and Potential Risk List 
8.2 
Definitions 
8.3 
Reporting Procedures for All Adverse Events 
8.4 
Serious Adverse Event Reporting Procedures 
8.5 
Data Safety Toxicity Committee 
 
9.0 
PHARMACEUTICAL INFORMATION 
9.1 
Commercial Agents  
 
 
10.0 
EXPLORATORY CORRELATIVE STUDIES 
 
 
 
10.1 
Ki67 Immunohistochemistry 
10.2 
HER2 Expression / Gene Amplification 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT 
12.1 
Definitions of Resection 
12.2 
Response Criteria 
12.3 
Survival 
12.4 
Patterns of Failure 
 
13.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
 
REFERENCES 
 

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1.0 
INTRODUCTION 
 
1.1 
Locoregionally advanced adenocarcinoma of the distal esophagus, 
gastroesophageal junction, and gastric cardia. 
 
The incidence of adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal 
junction (GEJ) has increased dramatically over the last four decades and is now the 
predominant histology of esophageal cancer.   While there are several known risk factors 
for this disease, no effective screening method has been established.  Most patients 
present with solid dysphagia which is associated with locoregionally advanced disease.  
The outcomes for these patients are relatively poor.  Surgery alone cures a minority of 
patients, with 5 year overall survival rates between 10 and 40%.   
 
Various perioperative therapies have been employed in an attempt to improve upon 
surgical outcomes.  A current standard of care for this disease is preoperative 
chemoradiotherapy followed by surgical resection.  Van Hagen et al. reported results 
from a randomized phase III study in 2012 comparing preoperative chemoradiotherapy to 
surgery alone (1).  In this trial, patients randomized to chemoradiotherapy received 41Gy 
with concurrent weekly carboplatin and paclitaxel.  Preoperative therapy was associated 
with improved overall survival (5yr OS 47% v 34%, p=0.003).  Several other studies over 
the past 20 years have demonstrated similar results (2,3).  Despite the demonstrated 
survival advantage with this treatment schedule, most patients with locally advanced 
disease develop distant metastasis and subsequently die.  This pattern of failure suggests 
that further incorporation of an effective systemic therapy could improve outcomes.   
 
Several trials have demonstrated a survival benefit from pre-operative chemotherapy 
alone for patients with ACA of the E/GEJ.  Bancewicz et al. reported results from a 
randomized phase III trial comparing surgery alone to chemotherapy followed by surgery 
in patients with esophageal cancer (4).  A total of 802 patients were included in this 
study.  Patients randomized to chemotherapy received 2 cycles of cisplatin and 5FU. 

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Most patients had adenocarcinoma histology.  Patients receiving pre-operative 
chemotherapy had superior overall survival (HR 0.79, p=0.004).  Similar results were 
demonstrated by Ychou et al (5).  In this study, patients with ACA of the E and GEJ were 
randomized to receive 6 cycles of perioperative cisplatin and 5FU or surgery alone.  
Survival again favored the chemotherapy arm (5yr OS 43% v 34%, HR 0.79, p=0.02).   
 
However, not all studies investigating perioperative chemotherapy have demonstrated a 
survival benefit in this patient population.  Kelsen et al reported results from a 
randomized phase III trial in which 444 patients with carcinoma of the E/GEJ received 
either surgery alone or 5 cycles of perioperative chemotherapy employing cisplatin and 
5FU (6).  Approximately 50% of patients had adenocarcinoma histology.  In this study, 
there was no significant difference in survival outcomes between the two treatment arms. 
 
Postoperative chemoradiotherapy has also been employed in the management of patients 
with tumors of the GC and GEJ.  MacDonald et al. reported results from a large 
randomized study comparing adjuvant 5FU based chemoradiotherapy to surgery alone in 
556 patients with gastric and GEJ ACA (7).  Adjuvant chemoradiotherapy was associated 
with improved survival (5 yr OS 50% v 41%, p= 0.005).  This study established adjuvant 
chemoradiotherapy as the standard of care for patients with resected gastric cancer. 
 
1.2 
Rationale 
 
We recently completed a single center phase II trial which incorporated two of these 
treatment paradigms: pre-operative chemotherapy and adjuvant chemoradiotherapy.  
Patients with ACA of the E/GEJ received induction chemotherapy followed by surgery 
and post- operative chemoradiotherapy.  Induction chemotherapy consisted of three 
cycles of epirubicin, oxaliplatin, and 5-flourouracil (EOF).  After surgery, patients 
received 50-55Gy in 1.8-2.0 daily fractions with concurrent administration of infusional 
cisplatin and 5-floururacil during weeks one and four. 
 
This therapy schedule was relatively well tolerated.  Sixty patients were enrolled in this 
trial.  Fifty four patients (90%) underwent resection and 48 patients (80%) completed 
adjuvant chemoradiotherapy.  One patient died during induction therapy and 2 patients 
died of postoperative complications.   Unplanned hospitalization occurred in 19% of 
patients during induction therapy and 18% of patients during adjuvant treatment.  The 
Kaplan-Meier 3 year projected locoregional control (LRC) was 84%, distant metastatic 
control (DMC) was 44%, relapse free survival (RFS) was 39%, and overall survival (OS) 
was 42%.  DMC, RFS, and OS were strongly and inversely associated with the amount of 
remaining viable tumor cells at the time of surgical resection.  These outcomes are 
comparable to other tri-modality regimens. 
 
Building on this experience, we now propose to improve upon these outcomes and reduce 
toxicity by replacing EOF with the modified FOLFOX6 regimen and by administering 
adjuvant chemoradiotherapy employing a pathologic response adapted approach.  
 
1.2.1  Induction mFOLFOX6 

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Systemic chemotherapy is often employed for palliation of metastatic gastroesophageal 
cancer.  Several cytotoxic agents are available in this disease, of which platinum 
compounds, the antimetabolite 5-flourouracil, and the taxanes are the most active.   
Combination chemotherapy is frequently administered given greater response rates and 
potentially greater overall survival in the metastatic setting.  Regimens incorporating 3 
drugs are now commonly employed, of which the combination regimen of epirubicin, 
cisplatin, and continuous infusion 5FU (ECF) is an example.  In the perioperative setting, 
both ECF and CF (Cisplatin / 5FU) have improved survival outcomes for patients with 
gastroesophageal cancer compared to surgery alone (5,8). 
 
The FOLFOX chemotherapy regimen was initially designed for use in patients with 
metastatic colorectal cancer.  However, in addition to CRC, this regimen is now broadly 
used to palliate patients with several metastatic gastrointestinal adenocarcinomas, 
including cancers of pancreatic, biliary and gastroesophageal origin.  This regimen 
consists of oxaliplatin in combination with leucovorin modulated bolus and short term 
infusional 5FU.  Several permutations of this regimen exist, for which the modified 
FOLFOX6 regimen is the most commonly utilized.  
 
Oxaliplatin has emerged as the preferred platinum agent for use in combination 
chemotherapy for palliation of metastatic gastroesophageal cancer.  In 2011, Montagnani 
et al. reported the results of a systematic review and meta-analysis comparing cisplatin 
and oxaliplatin in patients with metastatic or unresectable ACA of the stomach or GEJ 
(9).   Oxaliplatin regimens were associated with improved PFS and OS compared to 
cisplatin containing regimens (HR PFS 0.88, p=0.02.  HR OS 0.88, p=0.04).  There did 
not appear to be any difference in response rates.  With the exception of peripheral 
neuropathy, oxaliplatin was generally found to be less toxic.  It was also well tolerated 
among patients over age 65, especially when administered in a biweekly fashion with 
concurrent 5FU.  
 
Furthermore, the FOLFOX regimen appears to be as active as three drug combinations 
like ECF.  In 2010, Enzinger et al. reported in abstract form the results of CALGB 80403 
(10).  This was a randomized phase II trial comparing FOLFOX, irinotecan / cisplatin, 
and ECF.  Each of the various chemotherapy backbones was combined cetuximab.  A 
total of 245 patients enrolled.  Both FOLFOX and ECF appeared comparable, whereas 
the combination of cisplatin and irinotecan was less effective.  FOLFOX and ECF both 
had response rates > 40% (RR ECF 58% v FOLFOX 51%) and similar PFS and median 
OS [PFS (ECF) 5.6 v (FOLFOX) 5.7 months, median OS (ECF) 10 v (FOLFOX) 10 
months).  FOLFOX was better tolerated and required less dose modifications (p=0.0009).  
 
Despite several trials testing agents with activity in the metastatic setting, only the 
combination of oxaliplatin and 5FU (FOLFOX) has demonstrated improved survival 
outcomes compared to 5FU alone in the adjuvant treatment of colon cancer (11).  This is 
especially pertinent given the recently reported outcomes of CALGB 80101 (12).  In this 
study, presented in abstract form, patients with resected gastric and GEJ ACA were 
randomized to adjuvant therapy with either bolus leucovorin modulated 5FU before and 

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after CRT with continuous IV infusion 5FU (arm A) or ECF chemotherapy before and 
after CRT (arm B).  A total of 546 patients were enrolled.  Adjuvant therapy with ECF 
was not associated with improved median OS or DFS [median OS (arm A) 37 v (arm B) 
38 months, p=0.8, median DFS (arm A) 30 v (arm B) 28 months].  The 3 year OS was 
50% in arm A as opposed to 52% in arm B.  Therefore, despite being more active in the 
metastatic setting, ECF chemotherapy does not appear to be more effective than 5FU 
alone in the adjuvant setting for GEJ ACA.   
 
These data provide the rationale to investigate the incorporation of the FOLFOX regimen 
into the perioperative management of gastroesophageal cancer. 
 
1.2.2 Pathologic response adapted chemoradiotherapy 
 
Several trials investigating preoperative concurrent chemoradiotherapy in esophageal 
cancer have demonstrated an association between the pathologic response to therapy and 
overall survival (1,2,3).  We have demonstrated a similar association with the use of 
preoperative chemotherapy.  The percentage of remaining viable cancer cells relative to 
surrounding fibrosis and acellular mucin pools was inversely related to distant metastatic 
control, disease free survival, and overall survival in patients receiving induction therapy 
with EOF followed by surgery and postoperative chemoradiotherapy with cisplatin and 
5FU.  Patients who demonstrated a robust treatment effect achieved an estimated 3 year 
overall survival >60%.  However, the outcomes for patients without evidence for a 
pathologic treatment effect were accordingly quite poor.  It is this later group of patients 
for which introduction of an alternative chemotherapy regimen in the adjuvant setting 
may improve outcomes. 
 
The Taxanes are di-terpene cytotoxic agents produced by plants of the genus Taxus.  
Taxanes stabilize microtubules thereby impairing normal mitotic spindle function 
ultimately resulting in chromosomal breakage and inhibition of cell division (13).  
Commonly employed Taxanes include paclitaxel and docetaxel.  These agents have broad 
therapeutic utility.  Taxanes are active both as single agents and as components of 
combination chemotherapy regimens in gastroesophageal cancer.  Docetaxel is also 
superior to best supportive care in patients with metastatic gastric cancer who have 
progressed on a platinum / 5FU regimen (14). 
 
The combination of carboplatin and paclitaxel has been administered concurrently with 
radiotherapy for various diseases including lung cancer.  The safety of this regimen has 
been well demonstrated.  The previously described CROSS trial, reported in 2012 by Van 
Hagen et al., has established this combination chemotherapy regimen as a standard of 
care in the pre-operative treatment of patients with LRA ACA of the E/GEJ (1).  We plan 
on employing this regimen in the adjuvant setting with concurrent radiotherapy in an 
attempt to salvage patients who have failed to achieve an adequate pathologic response to 
induction therapy with the mFOLFOX6 regimen. 
 
Accordingly, patients who have achieved a pathologic response will continue on 
FOLFOX in the post-operative setting.  Conroy et al. reported results of a randomized 

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phase II study in 2010 comparing CRT with cisplatin and 5FU to the same radiotherapy 
administered with the FOLFOX4 regimen (15).  Patients in this trial were either 
unresectable or medically inoperable.  A total of 97 patients enrolled.  The complete 
endoscopic response rate favored FOLFOX4 (45% v 24%) as did median TTP and OS 
[(TTP) 15 months v 9 months and (OS) 22 months v 15 months respectively], but in this 
relatively small phase II trial, none of these results reached statistical significance.  Dose 
modifications were less common in the FOLFOX arm.  There was one treatment related 
death in the FOLFOX arm compared to 4 in the cisplatin / 5FU arm.  Neurotoxicity was 
more common with FOLFOX (24 v 4%). 
 
Conroy et al. later reported results from a subsequent randomized phase III trial again 
comparing chemoradiotherapy with a FOLFOX regimen to conventional cisplatin and 
5FU (16).  Eligibility required locally advanced esophageal cancer for which patients 
either refused surgery or were unresectable / medically inoperable.  In this study, the rates 
of grade 3 and grade 4 toxicity as well as treatment related death were similar in both 
treatment arms.  Overall survival and progression free survival were also similar [Median 
OS 20.2 months (FOLFOX) v 17.5 months (Cisplatin/5FU), HR=1.06, 95%CI= 0.77-
1.46, 3year PFS 18.2 months (FOLFOX) v 17.4 months (Cisplatin/5FU), HR 1.07: 95% 
CI = 0.80-1.43].  Therefore, chemoradiotherapy employing the FOLFOX regimen 
appears safe with similar efficacy and toxicity to the more commonly investigated 
combination of cisplatin and 5FU. 
 
In summary, we propose to improve outcomes by adapting the postoperative 
chemoradiotherapy to the pathologic response to induction FOLFOX.  Patients whom 
achieve a pathologic response to induction therapy will receive the same chemotherapy 
post-operatively administered concurrent with adjuvant radiotherapy.  Alternatively, 
patients without an adequate pathologic response, who would be expected to have an 
inferior survival, will receive adjuvant radiotherapy with concurrent carboplatin and 
paclitaxel, an alternative regimen with demonstrated activity. 
 
 
2.0 
OBJECTIVES: 
 
2.1 
Primary Objectives:   
2.1.1 To assess the ability of response adapted adjuvant chemoradiotherapy to improve 
the 1 year RFS compared to historical data in patients with >50% remaining 
viable tumor after induction chemotherapy. 
 
 
2.2      Secondary Objectives: 
2.2.1 To determine the rates of symptomatic, endoscopic, and pathologic response to 
induction chemotherapy.  
2.2.2 To determine the rate of R0 resection after induction chemotherapy. 
2.2.3 To establish the toxicity profile of this tri-modality regimen.  
2.2.4 To assess the recurrence free survival (RFS) and overall survival (OS) of this tri-
modality therapy regimen for the entire cohort and in patients who do and do not 
achieve a pathologic response. 

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2.2.5 To assess patterns of failure and assess the rates of distant metastatic control 
(DMC) and locoregional control (LRC) of this tri-modality therapy regimen. 
 
2.3 
Exploratory Objectives:   
2.3.1 Ki-67: 
-To evaluate the pattern of Ki-67 expression in patients with LRA esophageal 
cancer before and after induction chemotherapy. 
-To explore the relationship of Ki-67 expression to clinical and pathologic 
response parameters as well as survival outcomes. 
2.3.2 HER2: 
-To evaluate the relationship between HER2 overexpression (based on 
immunohistochemistry) and gene amplification (based on fluorescence in situ 
hybridization) with clinical and pathologic response parameters and survival 
outcomes. 
 
 
3.0 
STUDY DESIGN 
 
3.1 
Schema  
 
This is a phase II trial in which all patients will receive 4 cycles of induction 
chemotherapy with modified FOLFOX 6 (mFOLFOX6) followed by surgical resection.  
Patients who achieve a positive pathologic response (+PR), defined as less than or equal 
to 50% viable tumor cells remaining in the surgical specimen, will then receive 
postoperative chemo-radiotherapy with the mFOLFOX6 regimen.  Patients who fail to 
achieve an adequate pathologic response, referred to as a negative pathologic response (-
PR) and defined as greater than 50% viable tumor cells remaining in the surgical 
specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and 
paclitaxel.  Patients who develop metastatic disease prior to surgery will be removed 
from the protocol and treated at the discretion of the primary oncologist.  Patients who 
have locoregional disease only after induction therapy but do not undergo surgery should 
receive chemoradiotherapy with carboplatin and paclitaxel if medically appropriate as 
determined by the primary oncologist.   
 
 
 
 
 
SURGERY
Radiation 
Radiation 
F
F
F
F
F
F
F
C
P
C
P
C
P
C
P
C
P
C
P
-PR
+PR

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F = Modified FOLFOX 6, C = Carboplatin, P = Paclitaxel, PR = pathologic response 
 
 
3.2 
Number of Subjects 
 
A total of 33 patients with > 50% viable tumor after induction chemotherapy are required 
to assess the primary endpoint.  We anticipate a total accrual of approximately 66 patients 
(refer to section 14.0 for statistical rationale). 
 
3.3 
Replacement of Subjects 
 
All subjects who have received any protocol therapy will be evaluable for study 
endpoints.  Patients who have signed consent but not received therapy will be replaced. 
 
3.4 
Expected Duration of Study Participation 
 
3.4.1 Duration of therapy 
 
Patients will continue study treatment until completion of all planned therapy, death, 
disease progression, unacceptable toxicity, patient refusal, or the investigator considers it 
to be in the best interest of the patient.   
 
Patients will be taken off study if they have experienced a serious adverse event or 
treatment delays resulting in the following: 
 
-A delay between induction therapy cycles of 4 weeks (6 weeks from initiation 
of the last cycle). 
-A delay between the last dose of induction chemotherapy and surgery >10 
weeks. 
-A delay > 12 weeks between surgical resection and the initiation of adjuvant 
chemoradiotherapy. 
 
The date and reason for discontinuation must be documented.  Every effort should be 
made to complete the appropriate assessments.  These patients will continue to be 
followed. 
 
3.4.2  Duration of follow-up 
 
Patients will be followed for at least 5 years or until death as outlined in section 11.1.2.   
 
4.0 
PATIENT SELECTION 
 
4.1   
Inclusion Criteria 

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4.1.1 Patients must have a histologic diagnosis of adenocarcinoma of the esophagus, 
GEJ, or GC based on biopsy material or adequate cytologic exam.  Tumors of the 
GC are defined as originating within 5 cm of the GEJ. 
4.1.2 Patients must be clinically staged according to the 7th edition (2010) of the AJCC 
staging system and must have either clinical T3-4a, or N1 disease.  Staging 
should include upper endoscopy with endoscopic ultrasound and a FDG-PET/CT 
scan (with diagnostic CT abdomen/pelvis preferred). 
4.1.3 Patients must have an ECOG performance status of 0-1. 
4.1.4 Patients must have adequate bone marrow function as evidenced by: 
a) Absolute neutrophil count  1,500/µl. 
  
b) Platelet count 100,000/µl. 
4.1.5 Patients must have adequate renal function as evidenced by:  
Serum creatinine (Scr)  1.5mg/dl.  If the Scr > 1.5, patients may still be eligible 
if the calculated GFR (Cockroft-Gault) is  40ml/minute. 
4.1.6 Patients must have adequate hepatic function as evidenced by: 
a) Serum total bilirubin  1.5X the institutional ULN. 
b) Alkaline phosphatase  3X the institutional ULN. 
c) AST/ALT  3X the institutional ULN. 
d) Patients with Gilberts syndrome are eligible provided the total bilirubin is  3 
and the remainder of the liver function tests (ALT, AST, ALK Phos) are 
within the institutional normal range. 
4.1.7 Patients must have a FEV-1 and DLCO > 50% predicted.    
4.1.8 Patients or their legal representatives must be able to read, understand, provide 
and sign informed consent to participate in the trial. 
4.1.9 Patients of childbearing potential must agree to use an effective form of 
contraception during this study and for 90 days following the last dose of 
chemotherapy.  An effective form of contraception is an oral contraceptive or a 
double barrier method. 
4.1.10 Age 18 years 
 
4.2     Exclusion Criteria 
 
4.2.1 Patients with any other diagnosis except for adenocarcinoma (squamous cell 
carcinoma, small cell carcinoma, mixed adenosquamous, lymphoma, sarcoma, 
etc.) will be ineligible.   
4.2.2 Patients with evidence of clinical T4b (unresectable) or M1 (distant metastasis) 
according to the AJCC 2010 staging system will be ineligible. 
4.2.3 No prior chemotherapy, radiation therapy, or surgery for this malignancy will be 
allowed.  Prior endoscopic procedures for superficial disease (endoscopic mucosal 
resection, cryotherapy, photodynamic therapy, etc.) will not exclude a patient.  
Prior dilatation is also allowed. 
4.2.4 Patients with another active malignancy will not be eligible except for:  
a) Resected basal cell carcinoma and squamous cell carcinoma of the skin, 
cervical or prostatic intraepithelial neoplasia, and ductal or lobular 
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b) Patients with localized prostate cancer who have received curative intent 
therapy are also eligible provided: 
1. Surgically treated patients have an undetectable PSA. 
2. Patients treated with brachytherapy have a PSA within the 
institutional normal range. 
3. Patients who have received pelvic external beam radiotherapy are 
not eligible. 
4.2.5 Patients with a clinically apparent active infection will not be eligible (Please 
note, an isolated elevation in the white blood cell count, by itself, does not 
constitute evidence of an infection).    
4.2.6 Patients with known hypersensitivity to any component of the chemotherapy 
regimen will not be eligible. 
4.2.7 Patients with a baseline peripheral neuropathy grade 2 will not be eligible. 
4.2.8 Patients who are receiving any other concurrent investigational therapy, or who 
have received investigational therapy within 30 days of the first scheduled day of 
protocol treatment (investigational therapy as defined as treatment for which there 
is currently no regulatory authority approved indication) will not be eligible. 
4.2.9 Patients who are pregnant or lactating will not be eligible.  Pregnant patients are 
ineligible due to the potential teratogenic effects of cytotoxic chemotherapy and 
radiotherapy. 
4.2.10 Patients with angina, a cardiac ejection fraction <50%, or ischemic heart disease 
are not eligible. 
4.2.11 Patients with any other medical condition, including mental illness or substance 
abuse, deemed by the investigator to be likely to interfere with the patient's ability 
to sign informed consent, cooperate and participate in the study, or interfere with 
the interpretation of the results, will not be eligible. 
4.2.12 Patients with any history of solid organ or bone marrow transplant will not be 
eligible. 
4.2.13 Patients with a known history of infection with hepatitis B or hepatitis C virus 
(active, previously treated, or both) will not be eligible due to the increased risk of 
hepatotoxicity and viral reactivation associated with systemic chemotherapy. 
4.2.14 Patients with known infection with HIV will not be eligible.  HIV infected 
patients are ineligible because of the increased risk for lethal infections when 
treated with marrow suppressive therapy.   
 
4.3  
Inclusion of Women and Minorities 
 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
5.0 
REGISTRATION 
 
All subjects who have been consented are to be registered in the OnCore Database.  For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 

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All subjects will be registered through the Cleveland Clinic Taussig Cancer Institute and 
will be provided a study number by the study coordinator. 
 
Allegheny Health System:  Site study personnel will complete an eligibility checklist, 
eligibility coversheet, and registration form for each subject. The eligibility coversheet 
must be reviewed and signed by 3 different individuals: the primary reviewer (such as a 
research nurse), a secondary reviewer (another nurse or co-investigator) and a co-
investigator or site PI. A registration form must be completed and sent with the eligibility 
checklist / coversheet.   If a subject is ineligible, the checklist will be completed 
(indicating why the subject was ineligible) and the coversheet will be signed by only one 
research team member. Within 1 business day of completion the checklist, coversheet, 
and the registration form must be scanned and sent via secure e-mail to the CCF study 
coordinator / Primary Investigator. Additionally, Allegheny must provide CCF study 
coordinator with the following information:  
 
 
Treating Physician 
 
Enrolling and Treating Nurse 
 
CCF is responsible for registering all subjects – once the eligibility checklist, coversheet, 
and registration form has been received by CCF, the Primary Investigator or designee 
(i.e. CCF Co-I) will review this information and sign the registration form. The 
completed registration form (all signatures obtained) will be sent to Allegheny within 1 
business day from the date in which the Sponsor-Investigator or designee (i.e. CCF Co-I) 
signs the form.  
 
If the patient is registered onto the study (i.e. CCF has approved registration) the CCF 
study coordinator will enter all on study information for the subject within 2 business 
days of receiving the eligibility checklist, coversheet, and registration form.  
 
The on study information that must be entered into OnCore is detailed in the data 
management plan. The study coordinator will document the date in which the eligibility 
information was received and confirm its completion.  Once this has been done, the 
patient will be put ‘on study’ in OnCore.  
 
This registration process is also described in the Manual of Operating Procedures 
(MoOP). 
 
6.0  TREATMENT PLAN 
 
All patients will undergo initial screening investigations as outlined in section 11.0 which 
include a history and physical examination, performance status assessment (ECoG), EGD 
with EUS, PET/CT (with a diagnostic CT abd/pelvis preferred), PFT (spirometry with 
DLCO), cardiac stress testing (dobutamine stress echocardiogram preferred), laboratory 
investigations (CBC and CMP or BMP, HFP), and serum -HCG (for women of 
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6.1 
Induction Chemotherapy 
 
Modified FOLFOX-6: 
 
 
 
After completion of staging, informed consent and registration, all patients will receive 
induction chemotherapy with 4 cycles of the mFOLFOX 6 regimen.  Cycles will be 
administered every 2 weeks (14 days).  A window of +/- 2 days is acceptable  for 
administration of chemotherapy.  Chemotherapy dose calculation will use actual body 
weight.  The BSA will not be capped..   
 
Oxaliplatin 85 mg/m2 over 2 hours on day 1 
Leucovorin 400 mg/m2 over 2 hours administered simultaneously with oxaliplatin on 
day 1.  If drug availability is limited, may administer leucovorin 100mg total dose or 
substitute levo-leucovorin at 200mg/m2. 
5-fluorouracil 400 mg/m2 IV push over 2-4 minutes on day one immediately after 
completion of leucovorin. 
5-fluorouracil 2400 mg/m2 continuous IV infusion over 44 hours (window 42-48 hours) 
days 1-3. Residual chemotherapy will be discarded.   
 
Standard anti-emetics may be employed.  Patients will receive 5-FU via a portable 
infusion pump through an indwelling venous access device. 
 
6.2 
Restaging and Surgery 
 
6.2.1 Restaging 
 
At 3-4 weeks (A window of 2-5 weeks is acceptable and will not be considered a 
deviation) after discontinuation of 5-fluorouracil, patients will be fully restaged to assure 
there is no contraindication to surgical resection.  Repeat staging will consist of the 
following studies as outlined in section 11:  Dysphagia assessment based on history 
(defined in section 11.0), PET/CT (with diagnostic CT abdomen/pelvis preferred), EGD 
with EUS and biopsy, CMP or BMP & HFP, CBC, and CTCs. 
  
6.2.2 Surgery 
 
Surgery will be scheduled for approximately one week later (4-5 weeks after completion 
of induction chemotherapy.  A window of 3-7 weeks is acceptable and will not be 
considered a deviation).  Patients will proceed to surgery irrespective of whether there is 
apparent loco-regional progression after pre-operative chemotherapy unless the disease is 
felt to be unresectable (cT4b) or there has been interval development of distant metastasis 
(cM1 disease).  It is recommended that potential metastatic disease be biopsied if possible 
for pathologic confirmation.  Patients with biopsy confirmed metastatic disease will be 
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abnormalities which are not amenable to biopsy but are felt to represent metastatic 
disease by the treating physicians will likewise be taken off study.  Every attempt to 
obtain histologic confirmation of metastatic disease should be made. Patients who have 
locoregional disease only after induction therapy but do not undergo surgery should 
receive chemoradiotherapy with carboplatin and paclitaxel if medically appropriate as 
determined by the primary oncologist.  Reasons to not receive surgery for locoregional 
disease include an unresectable primary tumor (T4b), the patient declines surgery, or the 
patient is felt to be medically inoperable. 
 
 
The choice of surgical procedure will be at the discretion of the operating physician and 
will consist of either a trans-thoracic esophagectomy, trans-hiatal esophagectomy, or total 
gastrectomy with Roux-en-Y esophagojejunostomy depending on the location and extent 
of the tumor at surgery.  An appropriate lymphadenectomy (2-field lymphadenectomy is 
recommended) will also be performed and immediate reconstruction is anticipated if 
possible.  The goal of surgery is an R0 resection. 
 
6.3 
 Radiotherapy 
 
Radiotherapy will start between 6 and 12 weeks after surgery.  If > 12 weeks have 
elapsed before adjuvant chemoradiotherapy can be administered, patients will be taken 
off of this study.   
 
Equipment:  
Modality- Xrays with nominal energy of 4 MV or greater.  
 
Tumor dose: 50.4 Gy/1.8 Gy per fraction over 28 days; at the discretion of the treating 
physician, patients with pathologic positive margins may have their total dose increased 
from 54 Gy to 60 Gy.  
 
Target volume definitions:  
Gross target volume (GTV): As patients are being treated in the adjuvant setting there is 
no GTV.  
Clinical Taregt volume (CTV): Treatment will be given to the postoperative esophago-
gastric bed and draining regional lymphatic nodal beds. Any known residual disease will 
be included within the post-operative fields.  Unless there is a positive surgical margin, 
the esophageal anastomosis will not be treated.   
 
Dosimetry: Use of IMRT is not recommended for use in this study. IMRT can be 
considered on a case by case basis and must be approved by the PI (Dr. Michael 
McNamara) prior to treatment.   
 
Heterogeneity corrections will be used. A 3-dimensional conformal radiotherapy plan 
will be generated for each case.  A clinical target volume (CTV) and a planning target 
volume (PTV) will be identified for each case.  At the discretion of the treating physician 
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a margin of at least 1cm to create the PTV and the prescription isodose line will cover  
95 % of the PTV. Dose variation within the PTV may be +/- 7%. Dose volume histogram 
(DVH) data will be calculated for the treatment plan.  For organs at risk (OARs), the 
mean lung dose (MLD), the volume of lung receiving 20 Gy (V20), doses to heart, 
kidneys, liver, spinal cord will be documented for each course.  
 
Normal Tissue Constraints: (per RTOG 1010). At the discretion of the treating physician, 
up to 10% variation in dose-volume constraint objectives is acceptable.  
Liver: V30 should be <30% 
Kidney: V20 should be <30% 
Heart:Considering whole heart, maximum dose to 0.03cc should be <,52 Gy mean dose 
should be < 32 Gy, and V40 should be < 50%. 
Lung: MLD<20 Gy, V20<30% 
Spinal cord: Maximum dose to 0.03cc of cord is <50 Gy (per RTOG 1010).  
 
Major interruptions in radiation therapy are not acceptable. Every attempt should be 
made to complete the prescribed course of radiation therapy on schedule. 
 
Mucositis and dysphagia may be significant as a result of this treatment.  These toxicities 
are reversible, and will not serve as an indication for treatment interruption.  Appropriate 
supportive measures will be utilized.  All patients are anticipated to have a jejunostomy 
feeding tube inserted at the time of surgery, which will be kept in place until adjuvant 
therapy is complete and the patients have recovered sufficiently. 
 
 
6.4 
Adjuvant Chemotherapy 
 
 
6.4.1 Carboplatin and Paclitaxel: 
 
Patients with >50% remaining viable tumor (-PR) will receive adjuvant 
chemoradiotherapy with carboplatin and paclitaxel.  Carboplatin and paclitaxel will be 
given weekly for a maximum of 6 doses concurrent with radiotherapy.  Chemotherapy 
will only be given concurrent with radiotherapy.  Chemotherapy will use actual body 
weight.  The BSA will not be capped and there will be no dose adjustments for obese 
patients.  
 
Please note, a window of +/-2 days of the anticipated cycle interval is acceptable for the 
administration of chemotherapy 
 
Paclitaxel = 50 mg/m2 IV over 1 hour on days 1, 8, 15, 22, 29, and 36. 
Carboplatin = (AUC = 2) IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. 
 
Patients may receive standard premedication for paclitaxel including: 
Dexamethasone 20mg IV, Benadryl 25-50mg IV, and famotidine 20mg IV or ranitidine 
50mg IV 30-60 minutes immediately prior to chemotherapy. 
 

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Carboplatin will be given AFTER the paclitaxel.   
 
Carboplatin dose will be calculated using the Calvert formula: 
 
Carboplatin dose = AUC x (CrCl + 25) 
 
The maximum CrCl used should be 125ml/min.  A 24 hour urine collection may be used 
to better estimate the actual GFR but is not required nor recommended. 
 
The CrCl should be calculated using the Cockroft-Gault equation: 
 
CrCl (ml/min) = (140-age) (actual weight in kg) (0.85 in females only) 
72 x serum creatinine (mg/dl) 
 
Note: For subsequent doses, a >10% change in the calculated creatinine clearance, based 
on the serum creatinine, will warrant a recalculation of the carboplatin dose. 
 
6.4.2 Modified FOLFOX6 
 
Patients with  50% remaining viable tumor (+ PR) will receive adjuvant 
chemoradiotherapy with mFOLFOX6.  Chemotherapy will only be given concurrent with 
radiotherapy.  FOLFOX will be administered beginning on days 1, 15, and 29.  A 
window of +/- 2 days of the anticipated cycle interval is acceptable for the administration 
of chemotherapy.  The last cycle of FOLFOX chemotherapy can be initiated no later than 
3 days prior to the expected radiotherapy completion date (i.e. all chemotherapy must be 
delivered concurrent with radiotherapy).Chemotherapy dose calculation will use actual 
body weight.  The BSA will not be capped and there will be no dose adjustments for 
obese patients.   
 
Oxaliplatin 85 mg/m2 over 2 hours on day 1. 
Leucovorin 400 mg/m2 over 2 hours administered simultaneously with oxaliplatin on 
day 1.  If drug availability is limited, may administer leucovorin 100mg total dose or 
substitute levo-leucovorin at 200mg/m2. 
5-fluorouracil 400 mg/m2 IV push over 2-4 minutes on day one immediately after 
completion of leucovorin. 
5-fluorouracil 2400 mg/m2 continuous IV infusion over 44 hours (window 44-48 hours) 
days 1-3. Residual chemotherapy will be discarded. 
 
Standard anti-emetics may be employed.  Patients will receive 5-FU via a portable 
infusion pump through an indwelling venous access device 
 
6.5 
General Concomitant Medications and Supportive Care Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood 
products, cytokines, antibiotics, anti-emetics, etc when appropriate. 
 

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6.5.1 Gastrointestinal toxicity 
 
Nausea / vomiting- standard anti-emetics will be employed at the initiation of treatment.  
Chemotherapy related nausea and emesis will be aggressively managed at the discretion 
of the investigator.   
   
Diarrhea- any grade gastrointestinal toxicity is common with 5-fluorouracil.  Aggressive 
pro-active management will be employed to minimize this toxicity.  Dose modifications 
will be incorporated as outlined in section 7.  For uncomplicated grade 1 and-2 diarrhea, 
patients will be instructed to maintain adequate oral hydration and eat frequent small 
meals if possible.  Standard doses of loperamide will be used if necessary.  Patients will 
be instructed to take 4 mg as an initial dose followed by 2 mg every 4 hours or after every 
unformed stool.  The maximum dose of 16 mg per day will be used in this protocol. It is 
suggested that loperamide be continued until the subject is free from diarrhea for 12 
hours. Other agents such as diphenoxylate / atropine (trade name Lomotil) can be used 
for mild to moderate diarrhea which is not fully controlled with the use of Imodium at the 
discretion of the investigator.   
 
For more severe diarrhea (grade 3-4) or moderate grade 2 diarrhea with complicating 
features (severe nausea / vomiting, decreased performance status, fever, neutropenia), IV 
hydration and hospitalization will be considered.  Dose modifications will be employed 
as previously outlined.  Consideration for testing for a coincident Clostridium difficile 
infection is also recommended in the appropriate clinical context.   
 
Note that diarrhea after an esophagectomy or total gastrectomy is not uncommon, and 
may be due to multiple factors unrelated to the chemotherapy.  Appropriate adjustments 
in diet or tube feeding should be made in addition to the interventions described above. 
 
Mucositis-  No specific prophylactic measures will be employed.  Oral cryotherapy is 
specifically contraindicated given the potential for LPD (described in section 7.1.6) in 
patients receiving oxaliplatin.  Recommendations for patients with established mucositis 
include atraumatic cleansing and oral rinses with salt & baking soda solution every 4-6 
hours.  Topical therapy with BMX (equal parts lidocaine / diphenhydramine / aluminum 
hydroxide) may be employed for patients with > grade 1 symptoms.  If necessary, 
appropriate systemic analgesics will also be prescribed. 
 
6.5.2 Neurotoxicity 
 
Peripheral neuropathy- peripheral neuropathies (both motor and sensory) are commonly 
associated with the use of oxaliplatin as well as paclitaxel.  No specific prophylactic 
measures are recommended as part of this protocol.  Patients with established neuropathy 
will require dose adjustment / modification as outlined in section 7.1.5 (FOLFOX) and 
7.3.3 (carboplatin / paclitaxel).    
 
6.6 
Duration of Therapy  
 

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Patients will continue study treatment until completion of all planned therapy, death, 
disease progression, unacceptable toxicity, patient refusal, or the investigator considers it 
to be in the best interest of the patient.   
 
The study protocol will also be discontinued for patients who have experienced a serious 
adverse event or treatment delays resulting in the following: 
 
A delay between induction therapy cycles of 4 weeks (6 weeks from initiation 
of the last cycle). 
 
A delay between the last dose of induction chemotherapy and surgery >10 weeks. 
 
 
A delay between surgical resection and the initiation of adjuvant 
chemoradiotherapy > 12 weeks. 
 
The date and reason for discontinuation must be documented.  Every effort should be 
made to complete the appropriate assessments.  These patients will continue to be 
followed. 
 
6.7 
Duration of Follow Up 
 
Patients will be followed for at least 5 years or until death as outlined in section 11.1.2.   
 
7.0  
DOSE DELAYS / DOSE MODIFICATIONS 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 4.0 for all treatment related acute toxicity and adverse event reporting 
unless otherwise specified.  CTCAE version 4.0 can be downloaded from 
http://ctep.info.nih.gov.  
 
Dose reductions beyond those specified in this protocol are not allowed and will be 
considered protocol violations. 
 
7.1 
Induction Chemotherapy   
 
Any dose reductions during induction chemotherapy will be permanent and continued 
throughout subsequent courses of pre-operative treatment.  A delay between induction 
therapy cycles of 4 weeks (6 weeks from initiation of the last cycle) will require that 
the induction therapy be discontinued and the patient proceed to surgery.  These patients 
will be removed from the study protocol.  These patients will continue to be followed. 
 
For patients who receive post-operative FOLFOX chemoradiotherapy, all dose reductions 
/ modifications established during pre-operative therapy will apply for adjuvant therapy 
as well.  Please refer to post-operative chemoradiotherapy dose modifications for specific 
details. 
 

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Dose Level Definitions: Pre-operative chemotherapy 
Agents  
Level 0 
Level -1 
Level -2 
Oxaliplatin 
85mg/m2 
68mg/m2 
51mg/m2 
Bolus 5-FU 
400mg/m2 
320mg/m2 
240mg/m2 
Infusional 5-FU 
2400mg/m2 
1920mg/m2 
1440mg/m2 
Leucovorin dose will not be modified for toxicity.  Leucovorin will not be given without 
concurrent administration of 5-FU. 
 
 
7.1.1 Hematologic toxicity:  Pre-operative chemotherapy 
 
Hematologic toxicity parameters are based on the CBC on the day of treatment, or within 
48 hours of the day of therapy.   
 
Erythropoietic stimulating agents will not be allowed.   
 
White blood cell growth factor (Filgrastim / Pegfilgrastim) support may be used at the 
discretion of the treating physician during induction therapy but will not be allowed 
during the post-operative concurrent chemoradiotherapy.  
 
If a treatment delay is required due to hematologic toxicity, a CBC will be repeated 
weekly. 
 
For cycle 1 of induction chemotherapy, the CBC must meet eligibility criteria for the 
protocol.  For cycles 2-4 of induction chemotherapy, the ANC must be  1,200 and the 
platelet count must be  75,000 for treatment to proceed.  Unless otherwise specified, a 
dose level reduction applies for all agents (Oxaliplatin, bolus 5-FU, and infusional 5-FU) 
in the regimen except for leucovorin.   
 
ANC <1200:  Delay FOLFOX and check CBC weekly and resume therapy when the 
ANC is  1200.  If therapy is delayed for 1 week, resume at the same dose level and add 
Filgrastim / pegfilgrastim.  If therapy is delayed > 1 week, reduce one dose level and add 
Filgrastim / pegfilgrastim.  For subsequent cycles of therapy, if the ANC is <1200, delay 
FOLFOX and check the CBC weekly.  Resume therapy when the ANC is  1200 with 
another dose level reduction.  If therapy is held  4 weeks, the patient will proceed to 
surgery and will be taken off the study. 
 
Febrile Neutropenia: Check the CBC weekly and Resume therapy once the ANC is  
1200.  FN will require one dose level reduction and the addition of filgrastim / 
pegfilgrastim.  If therapy is held  4 weeks, the patient will proceed to surgery and will 
be taken off the study. 
 
A second occurrence of Febrile neutropenia despite appropriate dose modification and 
growth factor support will require cessation of induction therapy.  Once the patient has 
recovered, he / she will go to surgery.  In that event, in the adjuvant setting, carboplatin 
and paclitaxel will be administered regardless of pathologic response. 

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Plt < 75,000:  Delay FOLFOX and check a CBC weekly and resume therapy when the 
platelet count is   75,000.  If therapy is held for 1 week, resume at the same dose level.  
If two consecutive cycles of therapy are held for 1 week or if therapy is held for > 1 
week, resume with one dose level reduction.  For subsequent cycles of therapy, if the 
platelets are < 75,000, delay FOLFOX and check a CBC weekly.  Resume therapy when 
the platelet count is  75,000 with one dose level reduction.  If therapy is held  4 weeks, 
the patient will proceed to surgery and will be taken off the study. 
 
Dose reductions below level -2 are not allowed and will require discontinuation of 
induction therapy.  In that event, patients will proceed directly to surgery and receive 
carboplatin and paclitaxel in the adjuvant setting regardless of pathologic response. 
 
 
7.1.2 Gastrointestinal toxicity 
 
Diarrhea  grade 2 requires that FOLFOX be held until diarrhea < grade 2 and institution 
of supportive measures with subsequent cycles.  If diarrhea occurs despite maximum 
supportive care (as outlined in this protocol), the following dose reductions / 
modifications are required. 
 
Grade 1 diarrhea: Continue FOLFOX without modification.   
Grade 2 diarrhea: Delay FOLFOX and reevaluate weekly.  Resume therapy when  grade 
1 and reduce 5-FU one dose level. 
Grade 3 diarrhea: Delay FOLFOX and reevaluate weekly.  Resume therapy when  grade 
1 and reduce oxaliplatin and 5-FU one dose level. 
Grade 4 diarrhea: If patients experience grade 4 diarrhea despite appropriate supportive 
care, induction therapy will be stopped and the patient will proceed to surgery once they 
have recovered sufficiently.  In that event, in the adjuvant setting, carboplatin and 
paclitaxel will be administered regardless of pathologic response. 
 
7.1.3 Mucositis 
 
Treatment will be delayed if  grade 2 mucositis is present on the day of therapy.  
Patients will be reevaluated weekly and therapy will resume when grade  1.  
 
Grade 1-2 mucositis at any point during therapy will not affect subsequent FOLFOX 
dosing.   
Grade 3 mucositis at any point during therapy will require one dose level reduction in 5-
FU only. 
Grade 4 mucositis during therapy will require that induction therapy be stopped and the 
patient proceed to surgery once they have recovered sufficiently.  In that event, in the 
adjuvant setting, carboplatin and paclitaxel will be administered regardless of pathologic 
response. 
 
7.1.4 Nausea / Vomiting 

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Treatment will NOT be held for chemotherapy related nausea and / or emesis. 
 
Grade 1-3 nausea / emesis at any point during therapy will not require dose modification 
but may lead to hospitalization for antiemetic control 
 
Grade 4 nausea / emesis at any point during therapy despite appropriate prophylactic and 
supportive management will require that induction therapy will be stopped and the patient 
will proceed to surgery once they have recovered sufficiently.  In that event, in the 
adjuvant setting, carboplatin and paclitaxel will be administered regardless of pathologic 
response 
 
7.1.5 Neurotoxicity 
 
Oxaliplatin neurotoxicity will be graded according to the Oxaliplatin-Specific 
Neurotoxicity Scale  
 
 
 
Grade 1 neurotoxicity will not require dose modification 
Grade 2 neurotoxicity that is not persistent (< grade 2 at the time of treatment) will not 
require dose modification  
Grade 2 neurotoxicity which persists to the time of treatment will require one dose level 
reduction of oxaliplatin 
Grade 3 neurotoxicity which is  grade 2 at the time of treatment will require one dose 
level reduction of oxaliplatin 
Grade 3 neurotoxicity which is persistent or any grade 4 neurotoxicity will require 
discontinuation of oxaliplatin.  Induction chemotherapy will proceed with 5-FU and 
leucovorin alone.  In that event, in the adjuvant setting, patients will receive 
chemoradiotherapy with 5-FU and leucovorin alone regardless of the pathologic response 
to therapy 
 
7.1.6 Laryngopharyngeal dysesthesia 
 
Laryngopharyngeal dysesthesia (LPD) is an acute neurotoxicity associated with 
oxaliplatin and often precipitated by exposure to cold.  LPD is characterized by the 
sensation of dyspnea and difficulty swallowing without objective evidence of either.  It 
must be distinguished from platinum hypersensitivity (PH) reactions.  PH is suggested by 
the presence of true bronchospasm and laryngospasm often associated with hypoxemia.  
Patients with LPD are typically hemodynamically stable with the exception of mild 
Grade 1 
Parasthesias/dysesthesias of short duration that resolve prior to subsequent 
cycles 
Grade 2 
Parasthesias/dysesthesias interfering with function, but not with ADLs 
Grade 3 
Parasthesias/dysesthesias with pain or functional impairment interfering with 
ADLs 
Grade 4 
Parasthesias/dysesthesias that are disabling 

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tachycardia.  Hypotension suggests PH.  PH can further be distinguished from LPD by 
the presence of hives/rash sometimes with pruritis. 
 
If a patient develops symptoms consistent with LPD, the oxaliplatin infusion should be 
held until the diagnosis is confirmed.  Consideration should then be given to the 
administration of anxiolytics.  The patient should be observed in the clinic until 
symptoms resolve.  If the diagnosis is confirmed and the symptoms resolve, the 
oxaliplatin infusion can be completed at 1/3 the initial rate of infusion.  Since LPD is 
often associated with the rate of oxaliplatin infusion, subsequent doses of oxaliplatin 
should therefore be given over 6 hours.  Dose reduction is not required.  Premedication 
with steroids or anti-histamines are not helpful in the prevention of LPD.   
 
While LPD is typically seen during or shortly after the administration of oxaliplatin, 
patients will be instructed to avoid cold beverages within the first 48 hours of 
administration and to exercise caution throughout treatment. 
 
7.1.7 Allergic reactions 
 
Oxaliplatin, like other platinum drugs, is associated with a significant risk of 
hypersensitivity reactions, typically after multiple doses of therapy.  Symptoms include, 
but are not limited to, dyspnea with laryngospasm and / or bronchospasm, hypotension, 
hypoxia, hives, and pruritis.  Pretreatment with steroids and anti-histamines may be 
helpful in some patients but are not sufficiently adequate to allow retreatment of patients 
who have developed grade 3-4 hypersensitivity reactions. 
 
For patients who have experienced a grade 1-2 platinum hypersensitivity reaction, 
subsequent cycles of FOLFOX (including adjuvant chemo-radiotherapy if applicable) 
will require premedication with the following regimen: 
Dexamethasone 20mg PO 12 and 6 hours prior to oxaliplatin infusion. 
Dexamethasone 20mg IV, diphenhydramine 50mg IV, and either ranitidine 50mg IV or 
famotidine 20mg IV 30-60 minutes immediately prior to oxaliplatin infusion. 
 
If patients develop a recurrent hypersentivity reaction (any grade) despite these measures, 
or any Grade 3-4 hypersensitivity reaction, oxaliplatin will be discontinued and 
chemotherapy will continue with 5-FU alone.  Patients who require discontinuation of 
oxaliplatin due to hypersensitivity in the preoperative setting will receive adjvant CRT 
with 5-FU and leucovorin alone regardless of the pathologic response.   
 
Patients experiencing a hypersentivity reaction will be managed in the usual fashion per 
institutional protocol. 
 
7.1.8 Pulmonary fibrosis 
 
In the case of unexplained respiratory symptoms such as nonproductive cough, dyspnea, 
or new radiographic pulmonary infiltrates, all treatment should be held until further 

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investigation suggests an alternative etiology or oxaliplatin interstitial fibrosis has been 
excluded.  Patients who develop oxaliplatin related lung injury will be taken off study. 
 
7.1.9 Palmer-Plantar erythema (Hand-Foot syndrome) 
 
The development of  grade 2 palmer-plantar erythema will require that any remaining 5-
FU be discontinued and all therapy held until  grade 1.  5-FU will then be reintroduced 
at one dose level reduction. 
 
7.1.10 Cardiovascular toxicity 
 
The development of any grade 5-FU related cardiac toxicity will require urgent 
discontinuation of any remaining 5-FU.  Manifestations of 5-FU cardiotoxicity include 
chest pain / angina, myocardial infarction, and arrhythmia.  Rechallenge with 5-FU is not 
permitted.  If patients develop 5-FU related cardiotoxicity during preoperative therapy, 
they will proceed to surgery if medically appropriate and they will receive carboplatin 
and paclitaxel in the adjuvant setting regardless of pathologic response. 
 
7.1.11 Other non-hematologic toxicity 
 
All other non-hematologic grade 3 toxicity related to FOLFOX will require induction 
therapy to be held until  grade 1.  FOLFOX may then resume with one dose level 
reduction.    
 
All other Grade 4 non-hematologic toxicity will mandate discontinuation of induction 
chemotherapy.  The patient may proceed to surgery if medically appropriate and will 
receive carboplatin and paclitaxel in the adjuvant setting regardless of pathologic 
response. 
 
7.2 
Adjuvant Chemoradiotherapy 
 
Dose Level Definitions: carboplatin and paclitaxel post-operative chemoradiotherapy. 
 
Agents 
Level 0 
Level -1 
Level -2 
Carboplatin 
AUC 2.0 
AUC 1.6 
AUC 1.2 
Paclitaxel 
50mg/m2 
40mg/m2 
30mg/m2 
 
Dose Level Definitions: Post-operative FOLFOX chemoradiotherapy. 
Agents  
Level 0 
Level -1 
Level -2 
Oxaliplatin 
85mg/m2 
68mg/m2 
51mg/m2 
Bolus 5-FU 
400mg/m2 
320mg/m2 
240mg/m2 
Infusional 5-FU 
2400mg/m2 
1920mg/m2 
1440mg/m2 
Leucovorin dose will not be modified for toxicity.  Leucovorin will not be given without 
concurrent administration of 5-FU. 
 

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All dose modifications during adjuvant chemoradiotherapy will be permanent.  No dose 
escalation is permitted.   
 
For patients who receive post-operative (adjuvant) FOLFOX based chemoradiotherapy, 
all dose modifications / reductions established during pre-operative therapy will be 
continued in the post-operative setting. 
 
No growth factor therapy will be allowed during adjuvant chemoradiotherapy.  Patients 
receiving post-operative FOLFOX who required filgrastim / Pegfilgrastim for 
neutropenic fever will start adjuvant therapy without growth factor support and one dose 
level reduction.  If patients have already had two dose level reductions during induction 
chemotherapy and required growth factor support for febrile neutropenia, FOLFOX cycle 
length will extended to 21 days.  Patients would therefore receive only two cycles of 
chemotherapy with radiation.   Otherwise, dose level reductions below Level -2 are not 
allowed.  Chemotherapy will be stopped and patients will continue radiotherapy 
 
For patients who received filgrastim / pegfilgrastim for indications other than neutropenic 
fever, all dose modifications / reductions during pre-operative chemotherapy will be 
continued during post-operative chemoradiotherapy.  No further dose reductions / 
modifications will be required for initiation of post-operative therapy. 
 
Chemotherapy will only be administered during Radiotherapy.  Missed doses will not be 
made up after the completion of radiotherapy.  For patients on FOLFOX, the last cycle of 
chemotherapy can be initiated no later than 3 days prior to the expected radiotherapy 
completion date (i.e. all chemotherapy must be delivered concurrent with radiotherapy). 
 
Chemotherapy will start within 24 hours of initiating radiotherapy during week 1.   
 
Post-operative radiotherapy should begin on a Monday if possible, but should not start 
after Wednesday. 
 
 
7.3 
Carboplatin and Paclitaxel Post-operative Chemoradiotherapy 
 
7.3.1 Hematologic toxicity (carboplatin / paclitaxel) 
 
Dose modifications are based on the CBC from the day of expected treatment or within 
48 hours prior.  If therapy is held for hematologic toxicity, a CBC will be rechecked 
weekly. 
 
If the patient experiences multiple toxicities, dose level reductions / modifications will be 
based on the worst toxicity. 
 
Dose level reductions below Level -2 are not allowed.  Chemotherapy will be stopped 
and patients will continue radiotherapy. 
 
ANC  1200:  No dose adjustment. 

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ANC <1200:  Hold chemotherapy and check the CBC weekly.  Resume when the ANC is 
 1200.  If therapy was delayed for 1 week, resume at the same dose level.  If therapy is 
held > 1 week or two consecutive cycles are delayed, reduce one dose level carboplatin / 
paclitaxel. 
 
Febrile neutropenia = Hold therapy and check the CBC weekly.  Resume when the ANC 
is  1200 with one dose level reduction of carboplatin and paclitaxel.  A second 
occurrence of Febrile neutropenia despite appropriate dose modification will result in the 
discontinuation of chemotherapy.  Radiotherapy will be completed. 
 
Plt <100,000:  Delay therapy until the platelet count  100,000 and resume at the same 
dose level.  If two consecutive cycles of therapy are delayed for a platelet count of < 
100,000 or a single cycle is delayed > 1 week, one dose level reduction is required. 
  
7.3.2 Gastrointestinal toxicity (carboplatin / paclitaxel) 
 
Diarrhea  grade 2 requires that chemotherapy be held until diarrhea < grade 2 and 
institution of supportive measures with subsequent cycles.  If diarrhea occurs despite 
maximum supportive care (as outlined in this protocol), the following dose reductions / 
modifications are required. 
 
Grade 1 diarrhea: Continue chemotherapy without modification.   
Grade 2-3 diarrhea: Delay chemotherapy and reevaluate weekly.  Resume therapy when 
 grade 1 and reduce one dose level. 
Grade 4 diarrhea: If patients experience grade 4 diarrhea despite appropriate supportive 
care, chemotherapy will be discontinued.  Radiotherapy will be completed. 
 
7.3.3 Neurotoxicity- peripheral neuropathy (carboplatin / paclitaxel) 
 
Grade 1 neurotoxicity will not require dose modification 
Grade 2 neurotoxicity that is not persistent (< grade 2 at the time of treatment) will not 
require dose modification  
Grade 2 neurotoxicity which persists to the time of treatment will require one dose level 
reduction of carboplatin and paclitaxel 
Grade 3 neurotoxicity which is  grade 2 at the time of treatment will require one dose 
level reduction of carboplatin and paclitaxel 
Grade 3 neurotoxicity which is persistent or any grade 4 neurotoxicity will require 
discontinuation of chemotherapy.  Radiotherapy will be completed 
 
7.3.4 Allergic reactions (carboplatin / paclitaxel) 
 
Both carboplatin and paclitaxel are known to be associated with systemic infusion 
reactions and anaphylaxis.  Standard premedication will be given as prophylaxis 
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dexamethasone  20mg IV, Benadryl 25-50mg IV, and famotidine 20mg IV or ranitidine 
50mg IV 30-60 minutes immediately prior to chemotherapy. 
 
Grade 1-2 infusion reactions / hypersensitivity:  The infusion will be temporarily held 
and the patient will be examined.  Chemotherapy can be resumed at the discretion of the 
treating physician provided the patient has returned to baseline and is asymptomatic. 
Mild infusion reactions will require that patients receive dexamethasone 20mg PO 12 and 
6 hours prior to chemotherapy with subsequent cycles of therapy in addition to the 
standard premedications. 
 
Chemotherapy will be discontinued in patients who develop a recurrent infusion reaction 
of any grade despite these premedications.  Radiotherapy will be completed. 
 
Grade 3-4 infusion reaction / hypersensitivity:   Requires appropriate immediate therapy 
and will result in discontinuation of chemotherapy.  Radiotherapy will be completed.  
 
7.3.5 Other non-hematologic toxicity 
 
All other non-hematologic grade 3 toxicity related to carboplatin and paclitaxel will 
require induction therapy to be held until  grade 1.  Chemotherapy may then resume 
with one dose level reduction.    
 
All other Grade 4 non-hematologic toxicity will require the discontinuation of 
chemotherapy.  Radiotherapy will be completed. 
 
7.4 
FOLFOX Post-operative Chemoradiotherapy 
 
FOLFOX dose reductions / modifications during post-operative chemoradiotherapy are 
the exact same as those listed above for induction chemotherapy with the exception of 
hematologic toxicity, which is outlined below.  Dose reductions / modifications that were 
required during pre-operative induction will be maintained during the post-operative 
adjuvant therapy. 
 
Dose level reductions below Level -2 are not allowed.  Chemotherapy will be stopped 
and patients will continue radiotherapy. 
 
Management of diarrhea, mucositis, chemotherapy related nausea and vomiting, LPD, 
neurotoxicity, allergic reactions, palmer-plantar erythema, pulmonary fibrosis, and 
cardiovascular toxicity is the exact same as listed for induction chemotherapy, with the 
following exceptions: 
 
Grade 4 diarrhea, mucositis, or chemotherapy related nausea and vomiting will require 
chemotherapy be discontinued.  Radiotherapy should be completed. 
 
Persistent Grade 3 or any Grade 4 neurotoxicity will require discontinuation of 
Oxaliplatin.  Radiotherapy with concurrent 5FU will be completed. 

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Grade 3/4 or recurrent platinum hypersensitivity reactions will require discontinuation of 
Oxaliplatin.  Radiotherapy with concurrent 5FU will be completed. 
 
Pulmonary fibrosis (as defined in section 7.1.8): Both radiotherapy and chemotherapy 
will be discontinued.  The patient will remain on study. 
 
 
7.4.1 Hematologic toxicity 
 
Hematologic toxicity parameters are based on the CBC from the day of treatment, or 
within 48 hours of the day of therapy.  Erythropoietic stimulating agents will not be 
allowed.  White blood cell growth factor (Filgrastim / Pegfilgrastim) support may not be 
used during chemoradiotherapy. 
 
ANC  1200:  No dose adjustment 
 
ANC <1200:  Hold chemotherapy and check the CBC weekly.  Resume when the ANC is 
 1200.  If therapy is delayed one week, resume without dose modification.  If therapy is 
held > 1 week or two consecutive cycles are delayed,reduce one dose level FOLFOX. 
 
Febrile Neutropenia: Hold therapy and recheck the CBC weekly.  Resume when the ANC 
is  1200 with one dose level reduction of FOLFOX.  A second occurrence of Febrile 
neutropenia despite appropriate dose modification will require discontinuation of further 
chemotherapy.  Radiotherapy will be completed. 
 
Plt < 100,000:  Delay FOLFOX and recheck the CBC weekly.  Resume when the platelet 
count is  100,000.  If therapy is delayed one week, resume without dose modification.  If 
two consecutive cycles of therapy are delayed for a platelet count < 100,000 or a single 
cycle is delayed > 1 week, one dose level reduction is required. 
 
7.5 
Radiotherapy 
 
Radiation treatment will be interrupted for grade 4 in-field toxicity and will not be 
resumed until resolution to  grade 2.  Examples of potential in-field toxicity include: 
• radiation pneumonitis 
•  pleuritis 
•  pericarditis 
•  inflammation  ulceration of esophagus (esophagitis)   
• neoesophagus (gastritis, etc). 
 
Aggressive supportive care is encouraged throughout the course of radiotherapy.  Every 
attempt should be made to complete treatment despite acute toxicity.   
 
Radiotherapy will be permanently discontinued in patients who experience a treatment 
interruption lasting  4 weeks.  Patients will remain on study.  Chemotherapy will only 

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be given concurrent with radiotherapy in the adjuvant setting and therefore, will also be 
discontinued. 
 
8.0 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated 
with the observed AEs (Sections 8.3 and 8.4).  The treatment period is considered to 
begin with signing of the informed consent document and lasts up to 30 days from the 
end of therapy. 
 
The clinical course of each event during the treatment period will be followed until 
resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  If an event is related to treatment or participation, follow-
up is not required once it is determined to be a chronic, stable, and an ongoing condition. 
 
Serious adverse events that are still ongoing at the end of the treatment period will 
necessitate follow-up to determine the final outcome.  Any serious adverse event that 
occurs after the treatment period and is considered to be possibly related to the study 
treatment or study participation will be recorded and reported immediately. 
 
8.1 
Adverse Events and Potential Risks 
 
8.1.1  Carboplatin 
The most common side effects are myelosuppression (dose related) nausea and vomiting, 
hepatic toxicity, electrolyte imbalance (hypomagnesemia, hypocalcemia, hyponatremia), 
peripheral neuropathy, fatigue, allergic reactions, and renal insufficiency.   
 
Please refer to the manufacturers package insert for further information. 
 
8.1.2 5-Flourouracil 
 
Gastrointestinal and hematopoietic toxicity are common with 5-FU.  Mucositis, diarrhea, 
anorexia, and nausea are the most frequent gastrointestinal side effects.  
Granulocytopenia, anemia, and thrombocytopenia may occur.  Other toxicities include 
Hand-Foot syndrome, alopecia, and photosensitivity dermatitis.  Ocular toxicity including 
tear duct stenosis, photophobia, and conjunctivitis is uncommon.  Neurologic toxicity is 
also uncommon, but may manifest as confusion, headache, or an acute cerebellar 
syndrome.   
 
Chest pain as a result of myocardial ischemia secondary to coronary vasospasm is a rare 
but notable toxicity which requires urgent medical attention and discontinuation of 
further 5-FU administration.  Patients with dihydropyrimidine dehydrogenase (DPD) 
deficiency may experience significant, life threatening gastrointestinal and hematologic 
toxicity. 
 
Please refer to the manufacturers package insert for further information. 

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8.1.3 Leucovorin 
 
Allergic / anaphylactic reactions have been described with this agent but are uncommon.  
Leucovorin may enhance the toxicity of 5-Flourouracil when given concomitantly.   
 
Please refer to the manufacturers package insert for further information. 
 
8.1.4 Oxaliplatin 
 
The most common side effects include fatigue, nausea, diarrhea, vomiting, anorexia, 
anemia, thrombocytopenia, leukopenia, and peripheral neuropathy.  Less common 
toxicities include laryngopharyngeal dysesthesia (LPD) and hypersensitivity reactions.   
 
Please refer to the manufacturers package insert for further information. 
 
8.1.5  Paclitaxel 
 
Myelosuppression, peripheral neuropathy, alopecia, myalgias and arthralgiasis, and 
nausea and vomiting are the most common toxicities associated with paclitaxel.   Fatigue 
and anorexia are also frequently noted.  Acute allergic / anaphylactoid reactions can be 
serious and necessitate premedication.  Other toxicities include stomatitis, mucositis, 
pharyngitis, increased liver function tests with possible hepatic failure, arrhythmias, heart 
block, ventricular tachycardia, myocardial infarction (MI), bradycardia, alterations of 
taste, seizures, mood swings, sensation of flashing lights; blurred vision, scintillating 
scotoma, Stevens-Johnson Syndrome, rash, pruritus, infiltration (erythema, induration, 
tenderness, rarely ulceration) and radiation recall reactions.   
 
Please refer to the manufacturers package insert for further information. 
 
8.2 
Definitions 
 
8.2.1 Adverse events 
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to research participant as a 
result of the participant’s involvement in a research study.  The event can include 
abnormal laboratory findings, symptoms, or disease associated with the research study.  
The event does not necessarily have to have a causal relationship with the research, any 
risk associated with the research, the research intervention, or the research assessments. 
 
Adverse events may be the result of the interventions and interactions used in the 
research (a); the collection of identifiable private information in the research (b); an 
underlying disease, disorder, or condition of the subject (c); and/or other circumstances 
unrelated to the research or any underlying disease, disorder, or condition of the subject 
(d).  In general, adverse events that are at least partially the result of (a) or (b) would be 

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considered related to the research, whereas adverse events solely related to (c) or (d) 
would be considered unrelated to the research. 
 
External adverse events are adverse events experienced by subjects enrolled in multi-
center clinical trials at sites other than the sites over which the Institutional Review Board 
(IRB) has jurisdiction. 
 
Internal adverse events are adverse events experienced by subjects enrolled at the sites 
under the IRBs jurisdiction for either multicenter or single-center research projects 
 
8.2.2 The significance of an adverse event is used to describe the patient/event outcome 
or action criteria associated with event as opposed to threat to a patient's life or 
functioning (i.e., moderate to severe or life-threatening).  Based on the National Cancer 
Institute guidelines for the Cancer Therapy Evaluation Program, severity can be defined 
by the following grades of events 
 
Grades 1 are mild adverse events (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance). 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; 
noninvasive intervention; transfusion; elective interventional radiological procedure; 
therapeutic endoscopy or operation). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life-threatening physiologic consequences; need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death 
 
8.2.3 Serious adverse events 
 
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes: 
 
-Results in death 
-Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk of 
death at the time of the event.  It does not refer to an adverse event which 
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-Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization 
will be considered as serious, unless at least one of the following expectations is 
met: 
-The admission results in a hospital stay of less than 12 hours or 
-The admission is preplanned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) or 
-The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care).   
However it should be noted that invasive treatment during a hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a 
serious adverse event dependent on clinical judgment.  In addition where local 
regulatory authority is specifically require a more stringent definition, the local 
regulation takes precedent. 
-Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person's ability to conduct normal lifes 
functions 
-Is a congenital anomaly/birth affect. 
-Is an important medical event.  Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate 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.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood disease or disorders, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
 
8.2.4 Expectedness 
 
Adverse events can be Expected or Unexpected 
 
An expected adverse event is and events the previously known or anticipated to result 
from participation in the research study or any underlying disease, disorder, or condition 
of the subject.  The event is usually listed in the investigator brochure, consent form or 
research protocol. 
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject. 
 
8.2.5 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event in the 
study drug.  Attribution will be assigned as follows: 

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Definite - The AE is clearly related to the study drug 
 
Probable - The AE is likely related to the study drug. 
Possible - The AE may be related to the study drug. 
Unlikely - The AE is a doubtfully related to the study drug. 
Unrelated - The AE is clearly not related to the study drug. 
 
8.3  
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subjects 
participation in the study.  The clinical course of each event will be followed up until 
resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  If the event is related to the study treatment or 
participation, follow-up is not required once it has been determined to be a chronic, 
stable, and an ongoing condition. 
 
The investigator is responsible for assuring that all adverse events observed or reported 
by the subject which occur after the subject has signed the informed consent are fully 
recorded in the subjects case report form, subjects medical records, and/or any other 
institutional requirement.  Source documentation must be available to support all adverse 
events. 
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an adverse event. 
 
The investigator will provide the following for all adverse events: 
-Description of the event 
-Date of onset and resolution 
-Grade of toxicity 
-Attribution of relatedness to the investigational agent 
-Action taken as a result of the event 
-Outcome of the event 
 
In this study, descriptions and grading scale is found in the NCI common terminology 
criteria for adverse events (CTCAE) version of 4.0 available at http://ctep.cancer.gov will 
be utilized for AE reporting. 
 
8.4 
Serious Adverse Event Reporting Procedures 
 
Serious adverse events that occur beginning with the signing of the informed consent 
form, during treatment, or within 30 days of the last dose of treatment must be reported to 
the Cleveland Clinic IRB and local IRB (Allegheny) per IRB policy. 
 
8.5 
Data Safety Toxicity Committee 
 

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It is the Case Comprehensive Cancer Center’s Principal Investigator's responsibility to 
ensure that all serious adverse events are reported to the Case Comprehensive Cancer 
Centers data safety toxicity committee.   
 
9.0 
PHARMCEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the agents administered in 
this study can be found in section 8.0. 
 
9.1.1 Carboplatin 
 
Chemical Name 
 
Platinum, diammine[1,1-cyclobutanedicarboxylato(2-)-O,O]-, (SP-4-2). 
 
Other Names 
 
Paraplatin® 
 
Classification 
 
Antineoplastic.  Alkylating agent. 
 
Molecular Formula 
 
C(6)H(12)N(2)O(4)Pt 
 
Mode of Action 
 
Carboplatin is a cisplatin analog with similar antineoplastic activity, but with a different 
adverse effect profile than cisplatin.  Carboplatin has a carboxycyclobutane moiety 
replacing the chloride atoms on cisplatin.  The major antineoplastic mechanism of action 
for carboplatin is the production of crosslinks within and between strands of 
deoxyribonucleic acid (DNA).  Normal DNA synthesis is inhibited by this disruption of 
cellular DNA conformation.   
 
Metabolism 
 
Carboplatin is predominately excreted in the urine.  Minimal hepatic metabolism occurs.  
 
Product description 
 
Carboplatin is available as 50mg, 150mg, and 450mg individual vials. 
 
Solution preparation 
 

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Immediately before use, the content of each vial must be reconstituted with either sterile 
water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP, 
according to the following schedule: 
Vial Strength Diluent Volume 
50 mg 5 ml 
150 mg 15 ml 
450 mg 45 ml 
These dilutions all produce a carboplatin concentration of 10 mg/ml. 
 
Storage requirements 
 
Carboplatin for injection should be protected from light and stored at controlled room 
temperature, 15 to 30 degrees centigrade (59 to 86 degrees Fahrenheit).   
 
Stability 
 
Unopened vials of PARAPLATIN are stable for the life indicated on the package when 
stored at 25°C (77°F); excursions permitted from 15°-30°C (59°-86°F) [see USP 
Controlled Room Temperature]. Protect from light. When prepared as directed, 
PARAPLATIN solutions are stable for 8 hours at room temperature (25°C). Since no 
antibacterial preservative is contained in the formulation, it is recommended that 
PARAPLATIN solutions be discarded 8 hours after dilution. 
 
Route of administration 
 
Carboplatin is administered intravenously over 30 mintues after paclitaxel.  Aluminum 
reacts with carboplatin to form an inactive precipitate; therefore, intravenous sets and 
needles containing aluminum which may come in contact with carboplatin should not be 
used. 
 
Prior aminoglycoside therapy may potentiate carboplatin-induced renal toxicity 
 
Drug Procurement 
 
Carboplatin is commercially available in the United States.  The cost of this agent will be 
the subjects responsibility. 
 
9.1.2 5-Flourouracil  
 
Chemical Name 
 
5-fluoro-2,4 (1H,3H)-pyrimidinedione. 
 
Other Names 
 
Adrucil® 

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Classification 
 
Antineoplastic. Antimetabolite.   
 
Molecular Formula 
 
C(4)H(3)FN(2)O(2) 
 
Mode of Action 
 
5-Flourouracil belongs to the class of agents referred to as antimetabolites.  Its principle 
mechanism of action is thought to be inhibition of the enzyme Thymidylate Synthase 
(TS).  Decreased activity of TS results in thymidine depletion and a subsequent reduction 
in the synthesis of DNA.   TS inhibition accounts for the S-phase specificity of 
cytotoxicity.  Other metabolites of 5-FU may incorporate into DNA and RNA, 
destabilizing these molecules and interfering with DNA repair.   
 
Metabolism 
 
5-Flourouracil is predominately metabolized by the liver. 
 
Product description 
 
5-Flourouracil is available as follows: 500mg/10ml vial, 1000 mg/20 ml, 2500mg/50ml 
vial, and 5000mg/100ml vial. 
 
Solution preparation 
 
Reconstitution is not required.  The product should be visually inspected for particulate 
material.  If precipitation has occurred as a result of exposure to cold temperature, 5-FU 
should be heated to 140 degrees farenheit and shaken vigorously to allow dissolution. 5-
Flourouracil may be dispensed in a syringe or dilute in 50-1000 mL 0.9% normal saline 
or dextrose 5% water for infusion. 
 
Storage requirements 
 
5-Flourouracil should be stored at room temperature and protected from light. 
 
Stability 
 
Solutions of 5-FU are stable for 7 days when stored at 37°C and several weeks when 
stored at 25°C. 
 
Route of administration 
 

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5-Flourouracil will be administered as an intravenous push over 2-4 minutes followed by 
a continuous IV infusion over 44 hours delivered via a portable infusion pump.  All 
patients will require an implantable venous access catheter. 
 
Drug Procurement  
 
5-Flourouracil is commercially available.  The cost of this agent will be the subjects 
responsibility. 
 
 
9.1.3 Leucovorin  
 
Chemical Name 
 
Calcium N -[p -[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-
pteridinyl]methyl]amino]benzoyl]-L-glutamate(1:1).  
 
Other Names 
 
Folinic acid 
 
Classification  
 
Chemotherapy modulating agent.  Antidote. 
 
Molecular Formula  
 
C(20)H(21)CaN(7)O(7) 
 
Mode of Action   
 
Leucovorin enhances the therapeutic and toxic effects of flouropyrimidines.  Leucovorin 
is converted to 5, 10-methylenetetrahydrofolate, which acts to stabilize the binding of the 
5-Flourouracil metabolite, 5-Fluorodeoxyuridine monophosphate, to thymidylate 
synthase, thereby augmenting inhibition of this enzyme. 
 
Metabolism  
 
Leucovorin is predominately metabolized by the liver. 
 
Product description 
 
Leucovorin calcium is supplied as a single use 50mg, 100mg, 200mg, 350mg, and 500mg 
sterile lyophilized powder. 
 
Solution preparation 
   

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Powder for injection can be reconstituted using bacteriostatc water for injection U.S.P or 
sterile water for injection. Dilute in 100-1000 mL NS, D5W for infusion. When doses 
>10 mg/m2 are required, reconstitute using sterile water for injection, not a solution 
containing benzyl alcohol.  
 
Leucovorin should not be mixed in the same infusion as 5-FU, as these agents may 
precipitate. 
 
Storage requirements 
 
Lyophilized powder should be stored at room temperature and protected from light.    
 
Stability 
 
When reconstituted with Sterile Water for Injection, USP, use immediately and discard 
any unused portion.  When reconstituted with Bacteriostatic Water for Injection, USP, the 
solution can be refrigerated and stored for up to 7 days. The final parenteral admixture is 
stable for 24 hours at room temperature (25°C) and for 4 days when stored under 
refrigeration (4°C).  
 
 
Route of administration 
 
Leucovorin is administered intravenously over 2 hours concurrent with oxaliplatin.  
Longer infusion schedules over 6 hours are permissible in the setting of oxaliplatin dose 
modification. Due to the calcium content, Leucovorin solutions should never be 
administered at a rate greater than 160mg/minute. 
 
Drug Procurement   
 
Leucovorin is commercially available.  The cost of this agent will be the subjects 
responsibility. 
 
 
9.1.4 Oxaliplatin  
 
Chemical Name    
 
cis-[(1R,2R)-1,2-cyclohexanediamine-N,N’][oxalate(2-)-O,O’] platinum 
 
Other Names 
 
Eloxatin® 
 
Classification  
 
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Molecular Formula 
 
C(8)H(14)N(2)O(4)Pt 
 
Mode of Action 
 
The principle mechanism of anti-neoplastic activity is attributed to the formation of inter- 
and intra-strand DNA / platinum cross-links.  This results in inhibition of DNA 
replication, transcription, and induction of apoptosis.  Cytotoxicity is cell cycle 
nonspecific. 
 
Metabolism 
 
Oxaliplatin undergoes non-enzymatic conversion forming several active and inactive 
derivatives.  There is no evidence for cytochrome P450 mediated oxaliplatin metabolism.  
The predominant mechanism of elimination is renal excretion. 
 
Product description 
 
Sterile, preservative-free Lyophilized powder for reconstitution is supplied as 50mg and 
100mg vials.  
 
Solution preparation 
   
Oxaliplatin is reconstituted by adding 10ml (for the 50mg vial) or 20ml (for the 100mg 
vial) of Water for Injection, USP or 5% Dextrose Injection, USP.  The reconstituted 
solution must be further diluted in an infusion solution of 250-500 ml of 5% dextrose 
injection, USP.  Reconstitution or final dilution must never be performed with a sodium 
chloride solution or other chloride-containing solutions. Do not use needles or 
administration sets containing aluminum during preparation. 
 
Storage requirements 
   
Powder may be stored at room temperature under normal lighting conditions. 
 
Stability 
  
Reconstituted solution in original vial may be stored for up to 24 hours under 
refrigeration [2-8 degrees C (36-46 degrees F)].  Final solution for infusion should be 
immediately administered but can be kept for up to 6 hours at room temperature. 
 
Route of administration 
   

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Oxaliplatin will be given IV over 2 hours in this study.  Infusion time may be increased to 
6 hours as outlined above. Flush infusion line with D5W prior to administration of any 
concomitant medication. 
 
Drug Procurement 
 
Oxaliplatin is commercially available.  The cost of this agent will be the subjects 
responsibility. 
 
 
9.1.5 Paclitaxel  
 
Chemical Name 
 
5,20-Epoxy-1,2,4,7,10,13-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 
13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine 
 
Other Names 
 
Taxol® 
 
Classification 
 
Antineoplastic.  Antimicrotubule agent. 
 
Molecular Formula 
 
 C(47)H(51)NO(14) 
 
Mode of Action:   
Paclitaxel stabilizes microtubules by preventing depolymerization.  This stability results 
in the inhibition of the normal dynamic reorganization of the microtubule network that is 
essential for mitotic cellular functions. 
 
Metabolism 
 
Paclitaxel is predominately metabolized by the cytochrome P450 enzymes CYP2C8 and 
CYP3A4. 
 
Product description 
 
Paclitaxel is supplied as a clear to slightly yellow viscous solution intended for 
reconstitution.  Paclitaxel is available in 30mg/5ml, 100mg/16.7ml, 150 mg/25ml, and 
300mg/50ml multidose vials.  Each mL of solution contains 6 mg paclitaxel, 527 mg of 
purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) dehydrated 
alcohol, USP. 

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Solution preparation 
  
Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose 
Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose 
in Ringer’sInjection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are 
physically and chemically stable for up to 27 hours at ambient temperature 
(approximately 25° C) and room lighting conditions. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration 
whenever solution and container permit. Upon preparation, solutions may show haziness, 
which is attributed to the formulation vehicle. No significant losses in potency have been 
noted following simulated delivery of the solution through IV tubing containing an in-
line (0.22 micron) filter.  Data collected for the presence of the extractable plasticizer 
DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration 
when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC 
containers and administration sets is not recommended. Paclitaxel solutions should be 
prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC 
containing administration sets, such as those which are polyethylene-lined, should be 
used. 
 
Paclitaxel should be administered through an in-line filter with a microporous membrane 
not greater than 0.22 microns.  Although particulate formation does not indicate loss of 
drug potency, solutions exhibiting excessive particulate matter should not be used. 
 
Storage requirements 
   
Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F). Protect from light.  
 
Stability 
 
Unopened vials of paclitaxel are stable until the date indicated on the package when 
stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor 
refrigeration adversely affects the stability of the product. Upon refrigeration, 
components in the TAXOL vial may precipitate, but will redissolve upon reaching room 
temperature with little or no agitation. There is no impact on product quality under these 
circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the 
vial should be discarded. Solutions diluted for infusion in D5W and NS are stable for up 
to 3 days at room temperature (25°C).  
 
Route of administration 
 
Paclitaxel is administered intravenously over 1 hour before carboplatin. 
 
Drug Procurement 
 

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Paclitaxel is commercially available.  The cost of this agent will be the subjects 
responsibility. 
 
10.0  EXPLORATORY CORRELATIVE STUDIES 
 
 
10.1 
Ki67 Expression in Locally Advanced Esophageal Adenocarcinoma 
 
10.1.1 Background 
 
 
The Ki67 antibody was first discovered in the early 1980s by researchers in Kiel, 
Germany.  While the exact function of Ki67 remains undefined, it appears to be 
necessary for cellular replication.  Ki67 is a nuclear protein which is expressed during all 
phases of the cell cycle (G1, S, G2, M) but is absent during quiescence (Go).  Ki67 
therefore serves as a marker of proliferation (17).     
 
Over the past two decades, Ki67 expression has been investigated in various 
malignancies, including cancers of the breast, prostate, colon, and rectum.  While the data 
are inconsistent and sometimes conflicting, increased Ki67 expression appears to have 
prognostic utility.  For example, Stuart-Harris et al. reported results from a systematic 
review and meta-analysis evaluating various proliferation markers with respect to 
survival outcomes in patients with early breast cancer (18).   In this study, Ki67 
overexpression was associated with diminished OS and DFS by univariate and 
multivariate analysis (HR OS 1.73, HR DFS 1.84).   
 
Ki67 expression has also been explored as a predictive marker for response to treatment 
in studies investigating neoadjuvant therapy.   Von Minckwitz et al. evaluated the ability 
of Ki67 and other biomarkers to predict for a pathologic complete response to pre-
operative therapy (19).  Patients were randomized to receive chemotherapy with 4 cycles 
of dose dense doxorubicin and docetaxel with or without concurrent tamoxifen.  While 
Ki67 expression did not correlate with pathologic complete response rates, patients with 
low Ki67 expression appeared to respond preferentially to tamoxifen. 
 
In contrast to these results, Carlomagno et al. reported results from a phase II study 
investigating the ability of various biomarkers to predict for pathologic response after 
preoperative chemoradiotherapy in patients with rectal cancer (20).  In this study, 46 
patients received pre-operative chemoradiotherapy with 5FU and oxaliplatin.  Ki67 
expression in >30% of cells on the initial biopsy specimen was associated with a 
favorable pathologic response.  Furthermore, pathologic response correlated with disease 
free survival.   
 
Similar results were seen in a retrospective study reported by Fasching et al (21).  Ki67 
expression in core biopsy specimens was investigated prior to the administration of pre-
operative chemotherapy in patients with early breast cancer.  In this study, high Ki67 
expression prior to initiation of pre-operative therapy was an independent predictor of 
pCR (OR 3.5, p=0.01) and OS (HR 8.1, p=0.0001).  

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Andrade et al. reported results from a retrospective analysis investigating several 
biomarkers in patients with rectal cancer who again received pre-operative therapy (22).  
In contrast to the previously mentioned studies, Ki67 expression was evaluated in the 
surgical specimen after pre-operative chemoradiotherapy.  Patients with <50% of cells 
expressing Ki67 were felt to have a low proliferative index (LPI).  Patients with a LPI 
after pre-operative chemoradiotherapy had superior overall survival compared to patients 
with an elevated Ki67 expression (p=0.041).   
 
10.1.2 Rationale for Analysis 
 
It appears that elevated Ki67 expression at the time of diagnosis may predict for 
pathologic response to neoadjuvant chemotherapy.  Furthermore, increased expression of 
Ki67 after pre-operative chemotherapy may be indicative of aggressive tumor biology 
and may be associated with inferior survival outcomes.  We plan to prospectively analyze 
Ki67 expression on tumor specimens before and after pre-operative chemotherapy and 
correlate these findings with clinical and pathologic response parameters as well as 
survival outcomes 
 
10.1.3 Collection of specimens 
 
Biopsy / surgical material for Ki67 evaluation will be obtained from the following 
procedures: 
 
1) Pre-treatment staging upper endoscopy. 
2) Surgical resection specimen. 
 
10.1.4 Handling of specimens 
 
Biopsy material / surgical pathology will be handled per institutional protocol. 
 
10.1.5 Laboratory 
 
Biopsy specimens / surgical pathology will be processed in the Cleveland Clinic 
laboratory per institutional protocol. 
 
10.2 
HER2 Gene Amplification and Protein Overexpression in Locally Advanced 
Esophageal Adenocarcinoma 
 
10.2.1 Background 
 
The human epidermal growth factor receptor 2 (HER2) is a trans-membrane glycoprotein 
receptor with cytoplasmic tyrosine kinase activity.  It belongs to the ErbB family, which 
is comprised of ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).  
Ligand binding to inactive ErbB monomers stimulates the formation of homo / hetero-
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transduction through various signaling cascades including the mitogen-activated protein 
kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways.  While HER2 lacks 
binding affinity for the EGFR family of ligands, it is the preferred hetero-dimeric binding 
partner for other members of the ErbB family.  Ligand binding and subsequent signal 
transduction through the ErbB family of receptor tyrosine kinases results in augmented 
cellular proliferation and survival and influences differentiation and apoptosis (23). 
HER2 gene amplification by fluorescence in situ hybridization (FISH) and / or protein 
overexpression by immunohistochemistry (IHC) has been demonstrated in various 
malignancies, including breast, gastric, and ovarian cancer (23).  In breast cancer, HER2 
gene amplification  or protein overexpression offers both prognostic and predictive 
information, identifying a small group of tumors with aggressive biology that are often 
more responsive to monoclonal antibodies and small molecule tyrosine kinase inhibitors 
which target the HER2 oncoprotein.    
Approximately 20% of patients with gastric cancer demonstrate either HER2 
overexpression or gene amplification (referred to as HER2 positive) (23).  Many of these 
patients appear to obtain benefit from the addition of trastuzumab to standard 
chemotherapy in the metastatic setting.  The trastuzumab for gastric cancer (ToGA) trial 
was a multinational, randomized, phase III, open label study comparing the combination 
of cisplatin and capecitabine (or 5-fluorouracil) with or without the addition of 
trastuzumab in HER2 positive patients with gastric and GEJ adenocarcinoma (24).  
Patients received 6 cycles of chemotherapy administered every 3 weeks.  Patients in the 
investigational arm received trastuzumab concurrently with chemotherapy and then as 
maintenance every 3 weeks until they developed progressive disease.  The primary 
endpoint of the study, overall survival, favored treatment with trastuzumab.   Patients 
randomized to the trastuzumab arm had a median overall survival of 13.8 months 
compared to 11.1 months in patients who received chemotherapy alone (HR 0.74, 95% 
CI 0.60-0.91, p=0.0046).  In a post hoc analysis, patients with higher levels of HER2 
protein expression appeared to obtain greater benefit with the addition of trastuzumab 
compared to HER2 positive patients with lower levels of expression.  Patients who were 
HER2 IHC 3+ or HER2 IHC 2+ / FISH amplified (high HER2 expression) were 
compared to patients who were FISH amplified but only IHC 0-1+ (low HER2 
expression).  Patients with high HER2 expression obtained a median overall survival of 
16.0 months compared to 11.8 months in patients with low levels of expression (HR 0.65, 
95% CI 0.51-0.83).  This study, reported by Bang et al in 2010, established a new 
standard of care for patients with HER2 positive gastric cancer.  While a treatment effect 
could not be excluded in patients with gastroesophageal junction adenocarcinomas, they 
represented only 20% of subjects in the investigational arm.  Therefore, it remains 
unclear if we can extrapolate these results to patients with adenocarcinoma of the GEJ 
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It also remains unclear whether HER2 overexpression or gene amplification is a 
prognostic factor in patients with gastroesophageal adenocarcinoma.   Phillips et al. 
recently reported the results of a retrospective analysis exploring the relationship between 
clinicopathologic features, survival outcomes and HER2 status (25).  Pathologic 
specimens from 156 patients enrolled in 2 prospective phase II studies of perioperative 
chemoradiotherapy for locoregionally advanced adenocarcinoma of the esophagus and 
GEJ were examined.  Twenty three percent of the specimens analyzed were found to be 
HER2 positive.  With the exception that HER2 positive tumors were more likely to be 
poorly differentiated when compared to HER2 negative disease (p<0.001), there was no 
association between clinicopathologic features and HER2 status.  Furthermore, there was 
no difference in survival outcomes or local control between HER2 positive and HER2 
negative subjects. 
Similar results were reported by Janjigian et al. in 2012 (26).  This study was a 
retrospective review of 381 patients enrolled in 6 prospective studies of first line 
chemotherapy (without trastuzumab) for metastatic gastroesophageal adenocarcinoma.  
In this study, 20% of patients were found to be HER2 positive.  HER2 positive patients 
were more likely to have intestinal histology and liver metastasis when compared to 
HER2 negative patients.  However, on multivariate analysis, HER2 did not emerge as an 
independent predictor of overall or disease free survival. 
In contrast to these findings, Chan et al. reported results of a systematic review and meta-
analysis in 2012 which suggested that HER2 overexpression or gene amplification is 
associated with an inferior survival in patients with operable esophageal cancer (27).  
This study evaluated 14 trials and included 1464 patients with locoregional esophageal 
SCC and ACA.  Various perioperative management strategies were employed, but 
notably only one trial utilized preoperative chemoradiotherapy.  The overall 5 year 
mortality was higher in HER2 positive patients [OR 1.43 (95% CI 1.04-1.95) p=0.03].   
HER2 was found to be a poor prognostic factor in both esophageal SCC and ACA. 
10.2.2 Rationale for Analysis 
 
HER2 gene amplification or protein overexpression serves as a predictive marker in 
patients with gastric cancer for response to trastuzumab.  Unlike in breast cancer, it 
remains unclear if HER2 also provides prognostic information for patients with 
locoregionally advanced gastroesophageal adenocarcinoma.  We plan to investigate the 
association between HER2 status and clinical and pathologic response parameters and 
survival outcomes in patients with LRA ACA of the DE and GEJ.  We will evaluate 
HER2 protein expression by IHC and gene amplification by FISH. 
 
10.2.3 Collection of specimens 
 

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Biopsy material for HER2 evaluation will occur as part of the initial upper endoscopy 
with endoscopic ultrasound.  Specimens from the surgical resection specimen will also be 
evaluated for HER2 expression by IHC and gene amplification by FISH. 
 
10.2.4 Handling of specimens 
 
Biopsy material / surgical specimens will be handled per institutional protocol. 
 
10.2.5 Laboratory 
 
HER2 evaluation by immunohistochemistry (IHC) and fluorescence in situ hybridization 
(FISH) will be performed in the Cleveland Clinic laboratory per institutional protocol. 
11.0 
STUDY PARAMETERS AND CALENDAR: 
 
11.1 
Study Parameters 
 
The following studies and evaluations will be obtained and recorded as part of this 
investigational protocol: 
 
Informed consent 
History and physical examinations 
Performance status assessment (ECOG) 
EGD with EUS and biopsy 
PET/CT (with diagnostic CT abdomen/pelvis preferred) 
CT Chest /abdomen / pelvis with contrast 
PFT (spirometry with DLCO) 
Cardiac stress testing (dobutamine stress echocardiogram preferred) 
BMP (basic metabolic panel)  
HFP (hepatic function panel) 
CMP (complete metabolic panel) 
CBC 
Ki67 (exploratory study) 
HER2 by IHC and FISH (exploratory study) 
Dysphagia assessment (see section 12.2) 
-HCG (in women of child bearing potential) 
 
 
11.1.1  Screening evaluation 
 
Screening studies and evaluations will be used to determine the eligibility of each subject 
for study inclusion.  All evaluations must be completed  42 days (6 weeks) prior to 
administration of protocol therapy. 
 
Informed consent 
History and physical exam  
Performance status (ECOG) 
EGD / EUS 

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PET / CT (with diagnostic CT abdomen / pelvis preferred) 
PFT (Spirometry with DLCO) 
Cardiac stress test (dobutamine stress echocardiogram preferred) 
CBC 
BMP and HFP (a CMP may substitute for BMP and HFP) 
Serum -HCG in women of childbearing potential 
Correlative study- Ki67 IHC and HER2 FISH / IHC will be performed on initial biopsy 
specimens after enrollment. 
 
 
11.1.2 Treatment period 
 
 
Pre-operative chemotherapy 
All subjects will receive 4 cycles of mFOLFOX6, administered every 14 days.  
Chemotherapy can be administered within +/- 2 days of the 14 day cycle.  
 
Cycle 1 / Day 1 
H & P, Performance status (ECOG)  
Dysphagia evaluation  
BMP, CBC  
Please note all studies / evaluations may be performed within 1 week prior to starting 
protocol therapy.   
 
Cycle 2 / Day 1 
H & P, Performance status (ECOG) 
BMP, CBC 
Please note all studies / evaluations may be performed within 48 hours prior to C2/D1 
 
Cycle 3 / Day 1  
H & P, Performance status (ECOG) 
BMP, CBC 
Dysphagia evaluation  
Please note all studies / evaluations may be performed within 48 hours prior to C3/D1 
  
Cycle 4 / Day 1 
H & P, Performance status (ECOG) 
BMP, CBC 
Please note all studies / evaluations may be performed within 48 hours prior to C4/D1 
 
Pre-operative assessment 
Approximately 3-4 weeks (a window of 2-5 weeks is acceptable and will not be 
considered a deviation) after the completion of chemotherapy, all subjects will undergo a 
pre-operative evaluation including the following: 
 
H & P, Performance status (ECOG) 
Dysphagia evaluation 

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CBC 
BMP, HFP (a CMP may be substituted for a BMP and HFP) 
EGD/EUS 
PET/CT (PET/CT with diagnostic CT abdomen/pelvis is preferred) OR CT chest / 
abdomen / pelvis with IV/oral contrast 
 
Surgical Pathology 
In addition to standard pathologic evaluation, including assessment of residual tumor 
viability, the following exploratory studies will be obtained:  Ki67 IHC and HER2 FISH / 
IHC. 
 
Post-operative assessment   
Approximately 4-6 weeks (a window of 3-8 weeks is acceptable and will not be 
considered a deviation) after surgery, all subjects will be evaluated prior to initiating 
post-operative chemoradiotherapy.  Review of the pathologic data will be performed and 
the post-operative chemoradiotherapy regimen will be identified.  In addition, all subjects 
will undergo the following: 
 
H & P, Performance status (ECOG) 
CBC  
HFP, BMP (a CMP may be substituted for a BMP and HFP) 
 
Post-operative chemoradiotherapy 
All subjects will initiate adjuvant chemoradiotherapy between 6 – 12 weeks post-
operatively.  All patients receiving adjuvant therapy will be seen and evaluated weekly 
during chemoradiotherapy.  FOLFOX cycle length is 14 days.  Carboplatin and paclitaxel 
is administered in one 36 day cycle on chemotherapy days 1, 8, 15, 22, 29, and 36.  
Chemotherapy will only be administered if radiotherapy is ongoing.  Please note all 
chemotherapy can be given within a window of +/- 2 days of the anticipated cycle 
interval.  All subjects will undergo at least the following weekly assessments:  
 
Weekly post-operative adjuvant therapy assessments 
H & P, Performance status (ECOG) 
CBC, BMP 
Please note all assessments / evaluations may be performed within 48 hours prior to 
scheduled chemotherapy 
 
Post-therapy follow up 
Follow-up visits after completion of therapy are recommended approximately every 3 
months for the first 2 years.  After 2 years from the completion of therapy, follow-up 
visits are recommended every 4-6 months for a total of 5 years.  After 5 years, annual 
follow-up visits are recommended but not required.   
 
H & P, Performance status (ECOG) 
CBC, BMP, HFP, and CT scans are not mandatory but should be performed based on 
symptoms at the discretion of the investigator 

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11.2  Calendar 
 
Pretreatment testing will be performed within the 6 weeks (42 days) of initiation of cycle 
1 / day 1. 
 
 
 
 
(•) = A PET/CT (with diagnostic CT of the abdomen/pelvis) is preferred.  
However, in the event a PET/CT cannot be obtained, a CT chest / abdomen / 
pelvis may suffice. 
(••) = For women of child bearing potential. 
NOTE: A CMP may substitute for the combination of a BMP and HFP. 

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NOTE: Chemotherapy can be administered within a window of +/- 2 days of the 
anticipated cycle interval. 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Definitions of Resection 
 
R0 resection is defined as the resection of all gross and microscopic tumor, i.e. absence of 
tumor at the inked margins of resection.   
   
R1 resection is defined as microscopic involvement at the inked margins of resection.   
 
R2 resections is defined as gross residual disease 
 
 
12.2 
Response Criteria 
 
12.2.1 Symptomatic response 
 
Dysphagia:  Dysphagia will be assessed throughout treatment.  Dysphagia response is 
defined as improvement in dysphagia by  1 grade from pretreatment baseline.  Severity / 
grade of dysphagia will be recorded during pre-operative chemotherapy on day 1 / cycle 
1, day 1 / cycle 3, and at the pre-operative medical oncology physician visit, scheduled at 
the time of pre-operative re-staging.   
 
Dysphagia will be assessed as follows: 
 
Level 1: No dysphagia.  Dose not require dietary modification 
Level 2: Minimal dysphagia - able to swallow liquids and most solid foods, experiencing 
occasional difficulty.  Diet is modified   
Level 3: Moderate dysphagia  - able to swallow liquids and very soft foods.   
Level 4: Severe dysphagia - unable to swallow liquids or solids.  Requires an enteral 
feeding tube or parenteral nutritional support 
 
 
 
12.2.2 Dysphagia response will be recorded as follows: 
 
Complete response = complete resolution of dysphagia to level 1 which remains stable 
until surgery 
Partial response = improvement in dysphagia by  1 level without complete resolution of 
symptoms during pre-operative chemotherapy which remains stable until surgery 
Stable disease = no change in dysphagia 
Progressive disease = worsening dysphagia  one level during pre-operative 
chemotherapy without transient benefit 
Transient response = improvement in dysphagia by  1 level by day 1 / cycle 3 with 
return to baseline grade or worse at pre-operative evaluation 

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12.2.3 Endoscopic response   
 
EGD with endoscopic ultrasound is required for initial staging and will be repeated prior 
to surgery.  The primary role of repeat endoscopy is to ensure resectability.  However, 
endoscopic response rate will be recorded as follows:   
 
Complete response = no residual abnormality (cyT0N0-Stage 0) 
Partial response = any improvement in the clinically determined T or N stage (without 
reciprocal deterioration in T or N) when compared to the pretreatment clinical stage as 
assessed by EGD/EUS. 
Stable disease = no change in the clinical T or N stage when compared to the 
pretreatment assessment. 
Progressive disease = any increase in the T or N stage (irrespective of any reciprocal 
improvement in the T or N stage) when compared to the pretreatment clinical stage as 
assessed by EGD/EUS.   
 
Note:  Locoregional progressive disease will not preclude surgical intervention provided 
the disease remains potentially resectable at re-evaluation (i.e. no cT4b or cM1 disease).   
Patients with evidence for distant metastases will be considered inoperable. 
 
Note:  Clinical response (symptomatic / endoscopic) will not be used to determine post-
operative adjuvant therapy. 
 
12.2.4  Pathologic response  
 
Pathologic response of the primary tumor will be reported as the treatment effect. The 
treatment effect estimates the amount of residual viable tumor relative to residual mucin 
pools or scarring.  The relative extent of invasion of both viable tumor cells and acellular 
mucin pools / scarring will also be reported along with final pathologic stage. 
 
Treatment effect will be quantified and described as follows: 
Complete pathologic response (pCR)  = No residual cancer cells 
Major pathologic response (pMjR) = 1-25% residual cancer cells 
Intermediate pathologic response (pIR) = 26-50% residual cancer cells 
Minor pathologic response (pMnR)= 51-75% residual cancer cells 
No pathologic response (pSD) = >75% residual cancer cells 
 
Positive pathologic response (+PR) = complete, major, and intermediate pathologic 
response.   
 
Negative pathologic response (-PR) = minor or no pathologic response. 
 
Patients who have achieved a complete, major, or intermediate pathologic response 
(50% viable tumor), referred to as a positive pathologic response (+PR), will continue to 
be treated with FOLFOX during the adjuvant period concurrent with radiotherapy.  

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Patients with a minor (pMnR) or no (pSD) pathologic response (>50% viable tumor), 
referred to a negative pathologic response (-PR), will receive adjuvant 
chemoradiotherapy with carboplatin and paclitaxel. 
 
12.3 
Survival   
 
Overall survival is defined as the length of time from starting treatment until death due to 
any cause.  Recurrence free survival will be defined as the time from starting treatment 
until first recurrence or death from any cause. 
 
 
12.4 
Patterns of Failure 
 
Sites of first recurrence will be defined as loco-regional, distant, or combined (loco-
regional and distant).  Locoregional failure is recurrent disease in the radiotherapy field.  
Distant failure is recurrent disease outside of the radiotherapy field.   
 
 
13.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
 
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management.  
OnCore is a Clinical Trials Management System housed on secure servers maintained at 
Case Western Reserve University.  OnCore properly used is compliant with Title 21 CFR 
Part 11.  Access to data through OnCore is restricted by user accounts and assigned roles.  
Once logged into the OnCore system with a user ID and password, OnCore defines roles 
for each user which limits access to appropriate data. User information and password can 
be obtained by contacting the OnCore Administrator at oncore-registration@case.edu. 
 
OnCore is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. This study will utilize electronic 
Case Report Form completion in the OnCore database.  A calendar of events and required 
forms are available in OnCore. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws.  
13.2.1 Written informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures.  The Principal Investigator will ensure that the subject is given full and 

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adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. 
13.2.2 Subject data protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history. 
 
13.2.3  Retention of records 
 
The Principal Investigator of The Case Comprehensive Cancer Center / Cleveland Clinic 
Cancer Institute supervises the retention of all documentation of adverse events, records 
of study drug receipt and dispensation, and all IRB correspondence for as long as needed 
to comply with national and international regulations. No records will be destroyed until 
the Principal Investigator confirms destruction is permitted.  
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform 
audits or inspections, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.   
13.2.6 Data safety and monitoring plan 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI regulations 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
In our prior phase II protocol, investigating induction chemotherapy followed by surgery 
and adjuvant chemoradiotherapy, exploratory analysis demonstrated an association 
between the percentage of viable tumor at the time of esophagectomy and survival 
outcomes.  More specifically, both overall survival (OS) and recurrence free survival 

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(RFS) were superior in patients with  50% viable tumor compared to patients with 
>50% viable disease [OS (p=0.020; log rank test), RFS (p=0.002; log rank test)].  The 
one year RFS was 93% in patients with  50% viability and 49% in patients with > 50% 
viability.  Our hypothesis is that we will improve RFS in patients with greater than 50% 
tumor viability after induction chemotherapy by employing an alternative adjuvant 
chemotherapy regimen, while maintaining a similar RFS to the prior study in patients 
with  50% tumor viability.  Specifically, if our current pathologic response based 
approach is effective, we would anticipate an improvement in one year RFS from 50% to 
 65% in patients who have > 50% viable tumor after induction chemotherapy.  Thirty-
three patients with > 50% viable tumor will be required to test this hypothesis using a one 
sided test with 5% significance and 80% power assuming this trial will take 3 years to 
accrue and an additional 2 years of follow-up.  Therefore, this study will accrue patients 
until we acquire 33 subjects with greater than 50% viable tumor.  Based on our prior 
phase II protocol, we anticipate that approximately 50% of patients treated according to 
this protocol will have > 50% viable tumor after induction therapy.  Therefore, we 
anticipate a total accrual of approximately 66 patients.  We also expect that patients with 
 50% viable tumor after induction therapy will have a RFS similar to our prior study. 
Therefore, study size calculations are based on expected differences in RFS among those 
with > 50% viable tumor.   
In addition to RFS comparisons between the current and prior studies by tumor viability, 
OS and RFS will be compared between patients with <50% and >50% viable tumor using 
the log-rank test.  Outcomes will be calculated relative to the start of therapy.  Cox 
proportional hazards analysis will be used to estimate the hazard ratio for OS and RFS for 
patients with >50% viable tumor relative to those with <50%.  If there are a sufficient 
number of events, multivariable Cox analysis will be done to adjust for other prognostic 
factors. 
Symptomatic, endoscopic, and pathologic response will be estimated using exact 95% 
confidence intervals, as will R0 resections and toxicities.  Kaplan-Meier analysis will be 
used to estimate local and distant recurrence (patterns of failure). 
The correlative studies are considered only exploratory.  Ki-67 expression will be 
described as mean and standard deviation or median and range, as appropriate. Change in 
Ki-67 expression before and after induction chemotherapy will be assessed using either 
the paired t-test or Wilcoxon signed rank test.  HER2 overexpression will be described as 
frequency counts and percentages.  The prognostic effect of KI-67 and HER2 
overexpression on pathologic response will be assessed with logistic regression analysis, 
and the prognostic effect on OS and RFS with Cox proportional hazards analysis.   

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Data will be analyzed using SAS® software (SAS Institute, Inc., Cary, NC).  Unless 
otherwise noted, all statistical tests will be two-sided, and p<0.05 will be used to indicate 
statistical significance.  
 
  
 
 
 
 
 
 
 
 
 
REFERENCES 
 
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5) Ychou M, Boige V, Pignon J, et al.: Perioperative chemotherapy compared with 
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7) Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery 
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8) Cunningham D, Allum WH, Stenning SP, et al.:  Perioperative chemotherapy 
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9) Montagnani F, Turrisi G, Marinozzi C, et al,:  Effectiveness and safety of 
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leucovorin as adjuvant treatment for colon cancer.  N Eng J Med 2004, 350:2343-
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12) Fuchs CS, Tepper JE, Niedzwiecki D, et al.:  Postoperative adjuvant 
chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma 
using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-
FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT:  
intergroup trial CALGB 80101.  J Clin Oncol (meeting abstracts) May 2011 vol. 
29 no. 15_suppl 4003. 
13) “Taxol [package insert].  Bristol-Myers Squibb Company: 2011.  Princeton, NJ 
08543 USA.  http://packageinserts.bms.com/pi/pi_taxol.pdf 
14) Ford H, Marshall A, Wadsley J, et al. Cougar-02: a randomized phase III study of 
docetaxel versus active symptom control in advanced esophagogastric carcinoma 
(abstract). J Clin Oncol 30: 2012 (suppl 34: abstr LBA4). 
15) Conroy T, Yataghene Y, Etienne PL, et al,:  Phase II randomized trial of 
chemoradiotherpay with Folfox4 or cisplatin plus fluorouracil in esophageal 
cancer. British Journal of Cancer 2010, 103:1349-1355 
16) Conroy T, Galais MP, Raoul JL, et al.:  Phase III randomized trial of definitive 
chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in 
esophageal cancer (EC):  final results of the PRODIGE 5/ACCORD 17 trial. 
17) Yerushalmi R, Woods R, Ravdin PM, et al.: Ki67 in breast cancer: prognostic and 
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18) Stuart-Harris R, Caldas C, Pinder SE, et al.: Proliferation markers and survival in 
early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 
patients.  The Breast 2008, 17:323-34. 
19) Von Minckwitz G, Sinn HP, Raab G, et al.:  Clinical response after two cycles 
compared to HER2, Ki-67,p53, and bcl-2 in independently predicting a 
pathological complete response after preoperative chemotherapy in patients with 
operable carcinoma of the breast.  Breast Cancer Research 2008, 10:R30. 
20) Carlomagno C, Pepe S, D’Armiento FP, et al.:  Predictive factors of complete 
response to neoadjuvant chemoradiotherapy in patients with rectal cancer.  
Oncology 2010, 78:369-75. 
21) Fasching PA, Heusinger K, Haeberle L, et al.:  Ki67, chemotherapy response, and 
prognosis in breast cancer patients receiving neoadjuvant treatment.  BMC Cancer 
2011, 11:486. 
22) Andrade NR, Oshima CTF, Gomes TS, et al.:  Immunoexpression of Ki-67 and 
p53 in rectal cancer tissue after treatment with neoadjuvant chemoradiation.  J 
Gastrointest Canc 2011, 42:34-39. 
23) Almhanna K, Meredith KL, Hoffe S, et al.  Targeting the human epidermal 
growth factor receptor 2 in esophageal cancer.  Cancer Control 2013, 20:11-16. 
24) Bang Y, Van Cutsem E, Feyereislova A, et al,: Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive 
advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-
label, randomized controlled trial.  Lancer 2010, 376:687-697. 
25) Phillips BE, Tubbs RR, Rice TW, et al.:  Clinicopathologic features and treatment 
outcomes of patients with human epidermal growth factor receptor 2- positive 
adenocarcinoma of the esophagus and gastroesophageal junction.  Diseases of the 
Esophagus 2013, 26:299-304. 
26) Janjigian YY, Werner D, Pauligk C, et al.:  Prognosis of metastatic gastric and 
gastroesophageal junction cancer by HER2 status: a European and USA 
international collaborative analysis.  Annals of Onocology 2012, 23:2656-62. 
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J Gastrointest Surg 2012, 16:1821-29. 
 
 

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APPENDIX  
 
PERFORMANCE STATUS CRITERIA* 
 
 
ECOG Performance Status Scale 
 
Grade
Descriptions 
 
 
0 
 
Normal activity. Fully active, able to carry on all pre-
disease performance without restriction. 
 
 
 
1 
 
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, 
office work). 
 
 
 
2 
 
In bed < 50% of the time. Ambulatory and capable of all 
self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
 
 
 
3 
 
In bed > 50% of the time. Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
 
 
 
4 
 
100% bedridden. Completely disabled. Cannot carry on 
any self-care. Totally confined to bed or chair.  
 

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5 
 
 
Dead. 
 
 
 
*Karnofsky performance status can be converted to ECOG using the following 
scale: 
ECOG 0 = Karnofsky = 90-100 
ECOG 1 = Karnofsky = 70-80 
ECOG 2 = Karnofsky = 50-60 
ECOG 3 = Karnofsky = 30-40 
ECOG 4 = Karnofsky = 10-20 
ECOG 5 = Karnofsky = 0 
 
 
SUMMARY OF CHANGES v8 01/16/2018 
 
Protocol 
Date 
Section 
Change 
01/1618 
schema 
Added schema is an outline and to refer to treatment plan for details 
01/16/18 
6.3 
Added IMRT is allowed on a case by case bases 
01/16/18 
6.3 
Removed,   No radiation dose or schedule modification will be 
allowed on this protocol.  Every attempt should be made to complete 
the prescribed course of radiation therapy on schedule. 
01/16/18 
7.3.4 
Changed, Benadryl to 25-50 mg IV 
01/16/18 
 
Protocol version changed to 8.  Protocol  date changed to 01/16/2018 
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