A Phase II Study of Proton Beam Therapy in the Treatment of Esophageal Cancer
Phase: NA
Conditions: Esophagus Cancer, Esophageal Cancer, Cancer of the Esophagus
Sponsor: Washington University School of Medicine

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Rev
 
 
A Phase II Study of Proton Beam Therapy in the Treatment of Esophageal Cancer 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol#: 201803092 
Version Date: 05/16/2023 
 
Principal Investigator: 
Gregory Vlacich, M.D., Ph.D. 
 
 
 
 
Radiation Oncology 
 
 
 
 
(314) 362-8610 
 
 
 
 
gvlacich@wustl.edu 
 
Sub-Investigators 
 
 
 
 
Modality 
Cliff Robinson, M.D.  
 
 
 
Radiation Oncology 
Hyun Kim, M.D. 
 
 
 
 
Radiation Oncology 
Tianyu Zhao, Ph.D. 
 
 
 
 
Radiation Oncology 
Haesong Park, M.D.  
 
 
 
Medical Oncology 
Bryan Meyers, M.D.  
 
 
 
Cardiothoracic Surgery 
Beth Bottani, CMD 
 
 
 
 
Radiation Oncology 
Jeffrey Bradley, MD  
 
 
 
Radiation Oncology 
Michael Roach, MD  
 
 
 
Radiation Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 

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A Phase II Study of Proton Beam Therapy in the Treatment of Esophageal Cancer 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
03/19/2018 
Amendment #1 Version 
 
 
 
 
 
 
10/19/2018 
Amendment #2 Version 
 
 
 
 
 
 
03/11/2019 
Amendment #3 Version 
 
 
 
 
 
 
04/17/2019 
Amendment #4 Version 
 
 
 
 
 
 
09/17/2019 
Amendment #5 Version 
 
 
 
 
 
 
09/27/2019 
Amendment #6 Version 
 
 
 
 
 
 
12/20/2019 
Amendment #7 Version 
 
 
 
 
 
 
05/16/2023 
 
 
 

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SCHEMA 
 
 
 
Stage II and III esophagus 
cancer
Resectable and 
unresectable
Resectable: 50 Gy(RBE) 
with concurrent 
chemotherapy (per 
medical oncology choice)
Esophagectomy
Unresectable: 60 Gy(RBE) 
with concurrent 
chemotherapy (per 
medical oncology choice)
Follow up

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Table of Contents 
 
SCHEMA ........................................................................................................................................ 4 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 7 
1.1 
Esophageal Cancer ........................................................................................................... 7 
1.2 
Radiation Therapy in the Treatment of Esophageal Cancer ............................................ 7 
1.3 
Proton Beam Therapy in the Treatment of Esophageal Cancer ....................................... 8 
1.4 
Patient-Reported Outcomes (PROs)............................................................................... 10 
1.5 
Study Rationale .............................................................................................................. 11 
2.0 
OBJECTIVES .................................................................................................................... 12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives ..................................................................................................... 12 
3.0 
PATIENT SELECTION .................................................................................................... 12 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 13 
3.3 
Inclusion of Women and Minorities............................................................................... 14 
4.0 
REGISTRATION PROCEDURES ................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ................................................................................. 14 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 14 
4.3 
Assignment of UPN ....................................................................................................... 14 
5.0 
TREATMENT PLAN ........................................................................................................ 14 
5.1 
Chemotherapy ................................................................................................................ 15 
5.2 
Radiation Therapy .......................................................................................................... 15 
5.3 
Surgery ........................................................................................................................... 17 
5.4 
Patient-Reported Outcomes Measures (PROs) .............................................................. 18 
5.5 
Women of Childbearing Potential .................................................................................. 18 
5.6 
Duration of Therapy ....................................................................................................... 19 
5.7 
Duration of Follow-up .................................................................................................... 19 
6.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 19 
6.1 
Definitions ...................................................................................................................... 20 
6.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
21 
6.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 22 
6.4 
Timeframe for Reporting Required Events .................................................................... 22 
7.0 
STUDY CALENDAR ....................................................................................................... 23 
8.0 
DATA SUBMISSION SCHEDULE ................................................................................. 24 
9.0 
MEASUREMENT OF EFFECT........................................................................................ 24 
9.1 
Toxicity .......................................................................................................................... 24 
9.2 
Progression-Free Survival .............................................................................................. 24 
10.0 DATA AND SAFETY MONITORING ............................................................................ 25 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 25 
11.1 Sample Size .................................................................................................................... 26 
11.2 Toxicity Analysis ........................................................................................................... 26 
11.3 Progression-Free Survival and Overall Survival Rates .................................................. 26 

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11.4 Patient Reported Outcomes ............................................................................................ 26 
12.0 REFERENCES .................................................................................................................. 27 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 28 
APPENDIX B: MD Anderson Symptom Inventory (MDASI)-Plus ............................................ 30 
APPENDIX C: EuroQol (EQ-5D) ................................................................................................ 32 
APPENDIX D: Reportable Adverse Events from CTCAE version 4.03 ..................................... 35 
APPENDIX E: SF-12 ................................................................................................................... 41 
APPENDIX F: MOS Social Support Survey ................................................................................ 43 
APPENDIX G: 4-Item CES-D...................................................................................................... 45 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Esophageal Cancer 
 
Esophageal cancer is a deadly disease that affects over 16,000 people per year in the United 
States.  The majority of patients present with locally advanced disease (T2-4, or N1-3), and 
standard treatment in the United States for this group is definitive chemoradiotherapy or 
neoadjuvant chemoradiotherapy.  Expected 5-year overall survival (OS) for either of these 
treatments ranges from 20% (definitive) to 35% (neoadjuvant).  However, treatment with 
either bimodality or trimodality therapy is also associated with significant morbidity, both 
during the course of chemoradiation and in the months following completion of treatment, 
with late onset toxicities occurring up to one year after treatment.  These toxicities may 
significantly impact patients’ overall quality of life, and in patients consented for surgery, 
may hinder the ability to receive surgery or exacerbate postoperative complications.  The 
radiotherapy portion of treatment is an important component of both the acute and late side 
effects associated with treatment, which is itself driven by variables such as dose, delivery 
technique (2D, 3D, IMRT), and potentially modality (photons, protons).  Thus, altering 
one or more of these variables has the potential to improve toxicity, operability, and quality 
of life for patients undergoing this aggressive treatment. 
 
1.2 
Radiation Therapy in the Treatment of Esophageal Cancer 
 
Radiation modality has advanced substantially over the past two decades.  Photon therapy 
(such as higher energy X-rays) is the most common radiation modality used for cancer 
treatment.  Since the esophagus is located between critical structures such as the heart 
anteriorly, the spinal cord posteriorly, and the lungs on either side, substantial doses are 
usually delivered to the normal organs in order to treat the tumor adequately.  The current 
use of photon-based technology is called Intensity Modulated Radiation Therapy (IMRT), 
where each beam (typically 5-7) can be further modulated using computer-controlled 
multi-leaf collimators to dynamically block the path of the radiation while the beam is on, 
which effectively allows the dose to be “painted” with various intensities allowing greatest 
dose conformality to the tumor and dose avoidance to the normal structures.  However, 
despite the advantages of IMRT, it is not considered a standard technique in routine clinical 
trials since it takes great expertise in the planning and quality assurance (QA) process. At 
Washington University, we have been using IMRT for treatment of esophageal cancer 
patients since 2006.  Many of our patients receiving definitive chemoradiation therapy have 
been treated on our  prospective clinical trial for locally-advanced esophagus cancer 
(HRPO# 201105449 / 06-1070).  Our accrual to this trial was slow, mainly because most 
of our patients receive trimodality therapy (chemoradiation followed by surgery).  
Nevertheless, this form of photon therapy has been well-tolerated for this inoperable patient 
population. 
 
There have been several trials evaluating the effectiveness and toxicity of photons in the 
management of esophagus cancer. A comprehensive review by Monjazeb and Blackstock 
summarizes toxicity risk for patients receiving chemoradiation alone or chemoradiation 

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followed by esophagectomy. (Monjazeb and Blackstock 2013) For patients receiving 
esophagectomy, the literature suggests a treatment mortality rate between 4%-10%. The 
rate of severe acute hematologic toxicity (≥ grade 3) varies between studies, but ranges 
from 3%-78% and is primarily attributed to chemotherapy.  The common severe acute non-
hematologic toxicities include esophagitis (16%-63%) and pain (3%-24%). As these 
studies used different radiation doses, chemotherapy agents, and toxicity definitions, the 
specifics of expected acute toxicity would be improved by incorporating patient-reported 
outcome instruments.  
 
With respect to patient outcome measures from our experience at the Siteman Cancer 
Center, we completed an internal trial that used IMRT to a dose of 60 Gy with concurrent 
chemotherapy (HRPO# 201105449 / 06-1070).  The 2-year progression-free survival (PFS) 
and overall survival (OS) rates from that experience are 25% (95% CI of 11-62%) and 36% 
(95% CI of 7-49%), respectively. These results are consistent with the literature. Overall, 
60 Gy with concurrent chemotherapy has been well-tolerated. Many patients died of 
intercurrent illness due to associated comorbidities and/or advanced age.  
 
We previously published a retrospective analysis of 45 patients treated with 
chemoradiation followed by esophagectomy. (Trovo, Bradley et al. 2008)  We do not 
expect proton therapy at preoperative doses (i.e., 50 Gy) to improve PFS (37%) or OS 
(63%), although there are limited published data for proton therapy in this setting.  
 
1.3 
Proton Beam Therapy in the Treatment of Esophageal Cancer 
 
Radiation therapy for esophagus cancer has primarily employed photons.  Literature review 
reveals only one recently published prospective experience with proton beam therapy 
(PBT).  M.D. Anderson Cancer Center (MDACC) in Houston, TX tested proton beam 
radiation therapy in 62 patients receiving chemoradiotherapy. (Lin, Komaki et al. 2012) 
Patients received 50.4 Gy (RBE) in 1.8 Gy daily fractions using passively scattered protons 
and were followed for toxicity.  All patients received concurrent chemotherapy, with drug 
choice left to the treating physician.  Some patients received induction chemotherapy 
(42%). The median follow-up period for survivors was 20.1 months. The most common 
grade 2 to 3 adverse events were dysphagia (43.6%), esophagitis (46.8%), fatigue (43.6%), 
nausea (33.9%), anorexia (30.1%), and radiation dermatitis (16.1%). There was one case 
each of grade 2, 3, and 5 radiation pneumonitis.  There were two total grade 5 events, one 
from radiation pneumonitis and one from ventricular tachycardia that occurred at a dose of 
45 Gy during treatment. The investigators also reported survival outcome measures. The 
estimated 3-year overall survival was 51.7%. The 3-year relapse-free, distant metastasis-
free, and local-regional control rates were 40.5%, 66.7%, and 56.5%, respectively. 
MDACC has an ongoing phase II randomized trial testing passively scattered proton beam 
radiation therapy versus IMRT, but there are no results reported yet (Lin et al. Personal 
communication). Other ongoing phase I trials at Loma Linda University and the University 
of Pennsylvania are also unreported to date. 
 
Proton dosimetric studies appear favorable compared to x-rays, specifically with regard to 
adjacent normal tissue doses (Figure 1, Table 1).  For example, Zhang et al. demonstrated 

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that in comparison to IMRT, PBT planning results in better sparing of the lung (improved 
mean lung dose of 2.9 Gy). (Zhang, Zhao et al. 2008) MDACC has also recently examined 
their experience in the first 50 PBT patients treated with surgery after chemoradiation 
compared to 165 patients treated with IMRT or 208 with 3D.  They found that PBT 
significantly improved postoperative pulmonary complication rates compared to 3D (OR 
0.26, 95%CI 0.09, 0.70).  IMRT trended to worse postoperative complication rates 
compared to PBT (OR 1.74, 95%CI 0.66, 4.61). (Lin, Wang et al. 2012) 
 
 
Figure 1. Comparison plan of proton beam therapy (PBT)(left side) versus intensity modulated 
radiation therapy (IMRT)(right side) in three image planes.  The target doses to the esophagus are 
not different.  However, the normal tissue doses to the adjacent normal tissues (lung, heart, spinal 
cord, and liver) are better with PBT. 
  
TL Mean 
Cord Max 
Liver Mean 
Heart Mean 
Eso. Mean 
PTV Mean 
PTV % 
PTV Max 
CTV Mean 
GTV Mean 
IMRT (avg) 
990 
4012 
1135 
2104 
2194 
5285 
95.9 
5702 
5323 
5320 
PBT (avg) 
694 
3217 
296 
1159 
2251 
5309 
96 
5744 
5352 
5360 
difference 
-296 
-795 
-839 
-945 
57 
24 
0 
42 
29 
39 
p-value 
0.0001 
0.0001 
0.0001 
0.0001 
0.13 
0.17 
0.96 
0.12 
0.75 
0.81 
Table 1.  Average dose of PBT compared to IMRT to normal structures are significantly reduced without 
compromising tumor (Gross Tumor Volume (GTV), Clinical Target Volume (CTV), Planning Target Volume (PTV)) 
coverage.  Units are in centigray.  TL=Total Lung; Eso=Esophagus  

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At the Kling Proton Therapy Center at the Siteman Cancer Center, we have an opportunity 
to study PBT for esophagus cancer patients.  Protons differ substantially from photons in 
that protons are charged particles accelerated through a cyclotron to high energies (250 
MeV) and released into the patient.  By its interaction with various materials in its path and 
through the patient’s tissue, the beam can be modulated to deliver a dose that covers the 
tumor volume.  However, unlike photons, protons have a finite range and can be modulated 
to stop immediately past the tumor’s edge.  With very simple 2 to 3 beam arrangements, 
the entire tumor volume can be fully encompassed while maximally sparing the 
surrounding normal organs.   
 
1.4 
Patient-Reported Outcomes (PROs) 
 
The Patient Reported Outcomes are symptom measures assessed using the MD Anderson 
Symptom Inventory (MDASI)-Plus module [4] (Appendix B) and the QOL questionnaire 
called the EuroQol (EQ-5D) (Appendix C), as well as the SF-12 (Appendix E), MOS Social 
Support Measure (Appendix F), and 4-item CES-D (Appendix G).  We have chosen these 
instruments since all are validated tools that have been widely used to measure symptoms 
scoring and QOL measures.  All of these surveys are administered to the patient by the 
clinical or research staff prior to starting therapy. PROs have not been reported for 
esophagus cancer. Thus, this trial would be one of the first to incorporate PRO measures 
using protons for the treatment of esophagus cancer.    
 
1.4.1 MDASI-Plus 
 
The MDASI-plus is a reliable, validated tool for assessing cancer-related symptoms 
regardless of therapy or specific cancer diagnosis. (Cleeland, Mendoza et al. 2000; 
Wang, Williams et al. 2010) Patients are asked to fill out a twenty-seven question 
inventory, ranking their symptoms on a 0 (no problems) to 10 (worst imaginable) 
scale before treatment, weekly during treatment, and in treatment follow-up. 
 
1.4.2 EQ-5D 
 
The EQ-5D is a standardized 2-part, patient-administered instrument used for direct 
and indirect assessment of health state utilities; it is cognitively simple, takes only 
a few minutes to complete, and yields a utilities index value for health status 
(Pickard 2007). The first part asks respondents to “check the ONE box [next to the 
appropriate statement] that best describes your health TODAY” for each of 5 health 
dimensions, including mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (Johnson & Coons, 1998). The second part of the EQ-5D is a 
visual analogue scale (VAS) valuing current health state.  Both the 5-item index 
score and the VAS score are transformed into a utility score between 0 “Worst 
health state” and 1 “Best health state.” For this study, we will report both the health 
state classification instrument and the visual analog scale (VAS) utilities. The 
former is considered to satisfy the “community preferences” recommendation of 
the Panel on Cost Effectiveness, whereas the VAS is considered to satisfy the 

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Panel’s “patient preferences” recommendation.(Gold 1996) Over 30 published 
studies provide evidence to support its validity and reliability in cancer.  
 
1.4.3 SF-12 
 
The 12-item SF-12 is a shorter, yet valid alternative to the SF-36 for measuring 
physical and mental functional status in the general population (Ware, Kosinski, 
Keller 1995) (Ware, Kosinski, Keller 1996).  The SF-12 has well-established 
norms, has been extensively validated, is sensitive to changes over time, has 
established minimally clinically important changes, and has been used in cancer 
studies (Ramsey et al 2002) (Scarpa et al 2009) (Siassi et al 2009).  We have 
experience using the SF-12 in our research (Lian, Jeffe, Schootman 2008).  The SF-
12 will be measured at each of 7 interviews, and mental and physical component 
scores will be calculated in addition to calculating the measure’s eight individual 
subscales (physical functioning, social functioning, role limitations due to physical 
problems, body pain, general health, role limitations due to emotional problems 
general health, vitality, and mental health).  Higher scores indicate better quality of 
life.  
 
1.4.4 MOS Social Support 
 
The 19-item Medical Outcomes Study (MOS) Social Support Survey was designed 
for use with patients with chronic diseases and measures how often different kinds 
of support are available, if needed (Sherbourne, Stewart 1991).  Response choices 
range from “none of the time” (1) to “all of the time” (5).  A mean social support 
score for all 19 items is computed with higher scores indicating a greater 
availability of social support. Social isolation and lack of social support are related 
to increased mortality from a number of causes (Berkman et al 1993; Berkman, 
Syme 1979; Orth-Gomer, Johnson 1987; Kaplan et al 1998) and social support has 
been associated with cancer patients’ QOL in previous studies (Jeffe et al 2012; 
Waters et al 2013).  We hypothesize that lower levels of perceived social support 
will be associated with poorer QOL. 
 
1.4.5 4-Item CES-D 
 
The Center for Epidemiological Studies Depression Scale (CES-D) is a 20-item 
measure which evaluates depressive symptoms.  This trial will make use of the 
validated 4-item screening version in order to reduce participant burden (Melchior 
et al 1993).  There will be a referral plan in place for psychosocial counseling 
services for depressed patients. Depression has been shown to be related to QOL in 
other cancer patient populations (Longman et al 1996; Jeffe et al 2012).  We 
hypothesize that depressive symptoms will be associated with poorer QOL. 
 
1.5 
Study Rationale 
 
We plan to include both operable and inoperable patients with esophagus cancer in this 

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prospective trial.  Since both proton and photon treatments are biologically equivalent, we 
do not expect a difference in tumor control compared to IMRT.  We have a prospective 
experience of physician-reported toxicity and patient outcome using IMRT for patients 
with inoperable esophagus cancer that will serve as a comparison group.  For the resectable 
patients receiving trimodality therapy (chemoradiation followed by surgery), we will 
carefully track toxicity and patient outcomes prospectively.  Our central hypothesis is that 
the biologic efficacy for tumor control should be similar between protons and photons, and 
therefore survival measures should be similar between the two groups, but that the main 
difference lies in the total severe toxicities experienced by the patients undergoing therapy. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. To assess patient-reported outcomes of proton beam therapy (PBT) for esophageal 
cancer at 6 months following chemoradiation. 
 
2. To assess physician-reported toxicity of PBT for esophageal cancer. 
 
3. To assess patient-reported outcomes of PBT for esophageal cancer at 12 months 
following chemoradiation. 
 
2.2 
Secondary Objectives 
 
1. To assess progression-free survival (PFS) of PBT for patients with resectable vs. 
unresectable esophageal cancer. 
 
2. To assess overall survival (OS) of PBT for patients with resectable vs. unresectable 
esophageal cancer. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically documented adenocarcinoma or squamous cell 
carcinoma of the cervical or thoracic esophagus or gastroesophageal junction or cardia 
of stomach.   
 
2. Staged by PET/CT and esophagogastroduodenoscopy (EGD) or endoscopic ultrasound 
(EUS) OR CT w/contrast and EGD to have stage II or III disease per AJCC 7th edition 
guidelines.   
 
3. Prior endoscopic mucosal resection (EMR) with a diagnosis of stage II or III 
esophageal cancer (AJCC 7th edition) is eligible, irrespective of margin status. 

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4. Induction chemotherapy prior to concurrent chemoradiation is allowed. 
 
5. Prior thoracic radiation is allowable if degree of overlap with the esophageal 
radiotherapy treatment is deemed to be safe by the treating radiation oncologist. 
 
6. At least 18 years of age. 
 
7. ECOG performance status < 2 (Karnofsky > 60%, see Appendix A) 
 
8. Normal bone marrow and organ function as defined below: 
a. WBC > 2,500/mcL 
b. Platelets > 75,000/mcl 
c. Total bilirubin < 1.5 x IULN 
d. AST(SGOT)/ALT(SGPT) < 3.0 x IULN 
e. Creatinine < 1.5 x IULN         
OR 
Creatinine clearance > 50 mL/min/1.73 m2 for patients with creatinine levels above 
institutional normal 
 
9. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
11. English speaker. 
 
12. Financial coverage for proton therapy. 
 
3.2 
Exclusion Criteria 
 
1. Planned treatment with radiation therapy alone without concurrent chemotherapy or 
chemotherapy alone. 
 
2. Previous or concomitant cancers within the past 3 years other than curatively treated 
carcinoma in situ of the cervix, basal cell carcinoma of the skin, curative treatment for 
transitional cell carcinoma of the bladder, and low risk prostate cancer.  Except for 
prostate cancer (which can be observed if low risk), other cancers listed must have been 
treated in the past 3 years without evidence of recurrence at the time of registration. 
 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 

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arrhythmia not controlled by pacer device, myocardial infarction within 3 months of 
registration, or psychiatric illness/social situations that would limit compliance with 
study requirements 
 
4. Pregnant and/or breastfeeding.  Patient must have a negative pregnancy test within 7 
days of the start of treatment. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
5.0 
TREATMENT PLAN 
 

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5.1 
Chemotherapy 
 
Since this is a radiation modality trial, all patients suitable for concurrent chemotherapy 
with or without experimental therapies on clinical trials or for induction chemotherapy 
prior to neoadjuvant concurrent chemoradiation and patients receiving definitive 
concurrent chemotherapy and radiation are eligible for this study.  This study will not 
mandate use of any one regimen but will defer to the treating oncologist’s 
recommendations.  
 
Dose adjustments for all chemotherapy agents may be made per physician 
discretion/preference.  It is not a protocol violation for changes in a chemotherapy regimen 
during treatment if that is the deemed necessary by the treating medical oncologist.  All 
chemotherapies will be prepared and administered in accordance with the prescribing 
information approved by the Food and Drug Administration (FDA) or other regulatory 
agencies. 
 
Typically, neoadjuvant chemotherapy is completed at the time of the completion of 
concurrent radiation therapy. Patients receiving definitive therapy typically receive an 
additional 4 to 8 weeks of chemotherapy after radiation therapy has been completed. 
 
All chemotherapy labs and procedures will be collected and performed following the 
standard of care process and timeline. 
 
5.2 
Radiation Therapy 
 
3-D CT based planning must be used for all patients.  Passive scattering proton beam will 
be employed. The Mevion S-250 Proton Radiation Beam Therapy System will be used. 
 
5.2.1 Dose Specifications 
 
The daily prescription dose will be 1.8 or 2 Gy RBE (“Relative Biologic 
Equivalence”), at the discretion of the treating radiation oncologist, to be delivered 
to the periphery of the planning target volume (PTV).  The isodose line (generally 
93-98%) chosen will encompass at least 95% of the PTV. 
 
The maximum point dose, minimum point dose, and mean dose to PTV will also 
be reported. 
 
a.) For patients with unresectable esophagus cancer, the total dose will be 60 
Gy (RBE) (at 2 Gy/Fx/day) or 59.4 Gy (RBE) (at 1.8 Gy/Fx/day) to PTV2.  
All doses will be prescribed to the periphery of PTV2. PTV1 will receive 50.4 
Gy (RBE) (at 1.8 Gy/Fx/day) or 50 Gy (RBE) (at 2 Gy/Fx/day). PTV1 will 
encompass volumes that are not apparently involved based on PET/CT and/or 
EUS, but where pathological involvement risk is >20%. 

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b.) For patients with resectable esophagus cancer, the total dose will be 50 Gy 
(RBE) (at 2 Gy/Fx/day) or 50.4 Gy (RBE) at (1.8 Gy/Fx/day) to PTV1. All 
doses will be prescribed to the periphery of the PTV. 
 
5.2.2 Treatment Planning Imaging and Localization Requirements 
 
A volumetric treatment planning CT study will be required to define gross tumor 
volumes (GTV) and planning target volume (PTV).  For this study, the local 
regional nodes (whether clinically positive or negative) will be included in the 
clinical target volume (CTV).  Each patient will be positioned in an individualized 
immobilization device in the treatment position on a flat table.  Contiguous CT 
slices, 3-5 mm thickness of the regions harboring gross tumor and 8-10 mm 
thickness of the remaining regions, are to be obtained starting from the level of the 
cricoid cartilage and extending inferiorly through the liver.  The GTV and PTV and 
normal organs will be outlined on all appropriate CT slices and displayed using 
beam’s eye view.  Normal tissues to be contoured include lungs, skin, heart, spinal 
cord, esophagus, and liver.  A measurement scale for the CT image shall be 
included. 
 
Optimal immobilization is critical for this protocol.  Alpha cradle or approved 
alternative immobilization system is required.  Patients may be placed on the supine 
or prone position.   
 
5.2.3 Volume and ICRU Reference Point Definitions 
 
The definition of volumes will be in accordance with the 1993 ICRU Report #50: 
Prescribing, Recording and Reporting Photon Beam Therapy. 
 
Gross Tumor Volume (GTV) is defined as all known gross disease as defined by the 
planning CT and clinical information.  Gross tumor includes the primary (GTV-P) 
only. 
 
Clinical Target Volume (CTV) is defined as the area of subclinical involvement 
around the GTV.  For this protocol, we have chosen to define the CTV as minimum 
of 4 cm proximal and distal and 1 cm lateral beyond the GTV delineated by CT 
scan and /or endoscopy (endoscopy is preferable).  However, final CTV may be 
larger to make sure that nodal regions at > 20% risk of involvement are included at 
the discretion of the radiation oncologist.  For example, for upper esophagus 
primaries (defined as tumors above the carina), the bilateral supraclavicular nodes 
should be included.  For mid-esophageal primaries (at or below the carina), the 
paresophageal nodes should be included—not the supraclavicular or celiac.  For 
distal/gastroesophageal primaries, the field should include the celiac nodes and left 
gastric nodes. The final CTV must respect anatomic boundaries of potential 
microscopic disease spread. 
 

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Planning Target Volume (PTV) will provide margin around the CTV to compensate 
for variability in treatment set up, breathing, or motion during treatment.  The PTV 
will be generated by the dosimetrist, as each beam will need its own PTV 
delineation due to the effect of differing tissue inhomogeneities and distal and 
lateral penumbra as it relates to dose coverage of the CTV. 
 
The ICRU Reference Point is to be located in the central part of the PTV.  Typically 
this point should be located on the beam axis or at the intersection of the beam axis 
(isocenter). 
 
5.2.4 Radiation Treatment Planning 
 
The normal tissues in the table below are to be contoured in their entirety. 
 
The following organs and doses are guidelines for the radiation treatment plan (see 
Table 4: Normal Tissue Volume and Tolerance).  Physician/Dosimetrist should 
make every effort not to exceed these tolerance levels.  All normal tissues assume 
treatment at 1.8 or2 Gy RBE/Fx 
 
Table 4: Normal Tissue Volume and Tolerance 
Tolerance Dose 
Organ                         Volume                       TD 5/5          End Point 
Lung  
Mean 
lung 
dose 
<21 Gy 
V20 ≤35% 
Clinical Pneumonitis 
Spinal Cord 
5 cm 
10 cm 
20 cm 
50 Gy 
50 Gy 
47 Gy 
Myelitis 
Myelitis 
Myelitis 
Heart 
1/3 
2/3 
3/3 
50 Gy 
45 Gy 
40 Gy 
Clinical Pericarditis 
Clinical Pericarditis 
Clinical Pericarditis 
Liver 
1/2 
2/2 
35 Gy 
30 Gy 
Clinical Hepatitis 
Clinical Hepatitis 
 
It is expected that the dose to the lungs, heart, spinal cord, and liver will be the 
primary dose-limiting structures.  Every effort should be made to keep the total 
lung dose to a minimum. 
 
When planning the beam arrangement to the PTV, the lungs, heart, spinal cord, and 
liver should be excluded from the radiation field to the greatest extent possible.  The 
dose per fraction to the lungs, heart, and spinal cord should be maintained at 2 Gy 
or less per fraction to the greatest extent possible.  If tolerance dose to any of the 
normal organs is exceeded, alternate beam arrangement should be used. 
 
5.3 
Surgery 
 

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Once patients are deemed eligible for surgical resection, surgery should ideally be 
performed no later than 8 to 10 weeks after completing chemoradiation.  In the post-
operative period for patients who undergo surgery, postoperative complications will be 
scored by the surgeons and/or nursing/research staff at the post-op visit with the surgeon 
and will be recorded.   
 
5.4 
Patient-Reported Outcomes Measures (PROs) 
 
Treatment-related symptom scores and QOL will be assessed by a research coordinator at 
the following time points: 
• prior to the start of therapy 
• at the end of chemoradiation (day of EOT or up to 1 week after) 
• 2 months (+/- 2 weeks) following the end of chemoradiation; this should be just 
prior to surgery for those patients undergoing surgery who have received CRT but 
not definitive chemotherapy 
• 4 months (+/- 2 weeks) following the end of chemoradiation; this should be just 
prior to surgery for those patients undergoing surgery who have received CRT + 
definitive chemotherapy and should be approximately 2 months following surgery 
for those patients undergoing surgery who have received CRT but not definitive 
chemotherapy 
• 6 months (+/- 2 weeks) following the end of chemoradiation; this should be 
approximately 2 months following surgery for those patients undergoing surgery 
who have received CRT + definitive chemotherapy 
• 9 months following the end of chemoradiation 
• 12 months following the end of chemoradiation   
 
The QOL and other PRO assessments will be conducted using a computer-assisted 
interview program, and may be done in person before/after a routine office visit or over the 
phone at the preference of the study participant. 
   
Regardless of whether the patient had surgery, clinical outcomes and treatment-related 
toxicity will continue to be captured at each follow-up visit after Month 12 along with 
standard clinical assessments.  Follow-up visits are typically are done at intervals of 3-4 
months for the first 2 years after completion of last treatment procedure, and every 6 
months for the 3 years thereafter.   
 
5.5 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 7 days prior to study entry.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the 
study.  

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If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 3 months after the last study treatment, the investigator must be notified in order to 
facilitate outcome follow-up. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, PBT may continue for 6 weeks 
and QOL assessments for one year after the end of CRT or until one of the following 
criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol (if the patient is noncompliant with 
their recommended treatment, rendering his/her QOL data not usable) 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
5.7 
Duration of Follow-up 
 
Follow-up visits are typically done at intervals of 3-4 months for the first 2 years after 
completion of last treatment procedure, and every 4-6 months thereafter for the next 3 
years. 
 
 
6.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 

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The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 6.2. 
 
6.1 
Definitions 
 
6.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.03 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
6.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
6.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
6.1.4 Life-Threatening Adverse Experience 
 

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Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
6.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
6.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
6.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
6.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
6.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 

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• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
6.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
6.4 
Timeframe for Reporting Required Events  
 
Only AE’s grade 3 or greater which are at least possibly related to the proton beam radiation 
therapy and listed in Appendix D, will be tracked Grade 3 or higher AE’s possibly related 
to PBRT and found in Appendix D will be documented in clinical notes and the relatedness 
will be assessed in a timely fashion for the first year. After 12 months, the AE’s will be 
reviewed at the 5 year follow-up time point through chart review and they will be assessed 
at that time. Please review Appendix D for a list of reportable adverse events. SAEs will 
be reported for 30 days after the end of concurrent chemoradiation regardless of the 
attribution. Thereafter, SAEs, which are possibly, probably, or definitely related will be 
reported for up to one year after the end of concurrent chemoradiation. 
 
 

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7.0 
STUDY CALENDAR 
 
 
Screening 
/ Baseline 
On-
treatment 
RT visits 
End of 
CRT 
First post-CRT 
visit (8 wks after 
end of CRT)2 
4 mos 
after end 
of CRT2 
6 mos 
after end 
of CRT2 
9 mos 
after end 
of CRT2 
12 mos 
after end 
of CRT2 
Follow-
up3 
Informed consent 
X 
 
 
 
 
 
 
 
 
ACE-27 comorbidity index4 
X 
 
 
 
 
 
 
 
 
History and physical, vitals 
X1 
X 
 
X 
 
 
 
 
 
Performance status 
X1 
X 
 
X 
 
 
 
 
 
Proton beam therapy approval 
X 
 
 
 
 
 
 
 
 
CBC w/diff 
X1 
 
 
 
 
 
 
 
 
BMP9 
X1 
 
 
 
 
 
 
 
 
LFTs10 
X1 
 
 
 
 
 
 
 
 
CT chest/abdomen or PET/CT 
X8 
 
 
X6 
 
 
 
 
 
EGD/EUS +/- biopsy 
X 
 
 
X 
 
 
 
 
 
Adverse events collection 
(MD-reported CTCAE v 4.0) 
X1 
X 
 
X 
X 
X 
X 
X 
X7 
MDASI-plus 
X1 
 
X 
X 
X 
X 
X 
X 
 
EQ-5D 
X1 
 
X 
X 
X 
X 
X 
X 
 
SF-12 
X1 
 
X 
X 
X 
X 
X 
X 
 
MOS Social Support Survey 
X1 
 
X 
X 
X 
X 
X 
X 
 
4-item CES-D 
X1 
 
X 
X 
X 
X 
X 
X 
 
Post-op complication eval5 
 
 
 
 
 
 
 
 
 
1. At the time of initial Radiation Oncology consultation (within 4 weeks prior to start of protocol therapy), recognizing that some of these patients will go on to receive induction 
therapy prior to enrollment in the trial 
2. +/- 2 weeks 
3. Typically every 3-4 months for the first 2 years and every 6 months for the next 3 years; patients will be tracked for toxicity for the first year and for survival for the remaining 4 
years 
4. From tumor board; need not be available for data capture at baseline, but comorbidity index must be derived from patient status prior to initiation of CRT 
5. Assessed at 4-6 weeks after surgery (which will be at different time points dependent on receipt of definitive chemotherapy) 
6. Must be PET/CT 
7. Grade 3 events or higher, at least possibly related to PBRT and found in Appendix D, for the first year only 
8. Within 8 weeks of start of protocol therapy 
9. BMP = Na+, K+, Cl-, CO2, BUN, creatinine, glucose 
10. LFTs = bili, AST, ALT, ALP 
 

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8.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Chemotherapy Form 
Radiation Form 
End of CRT 
EQ-5D* 
MDASI-plus* 
SF-12* 
MOS Social Support Survey* 
4 item CES-D* 
Baseline 
End of CRT 
8 weeks after end of CRT 
4 months after end of CRT 
6 months after end of CRT 
9 months after end of CRT 
12 months after end of CRT 
Adverse Events Form** 
Baseline 
At each on-treatment RT visit 
End of CRT 
Every 3-4 months during Year 1 
Post-Op Form 
4-6 weeks post-op 
Follow Up Form 
Every 3-4 months during Years 1-2 
Every 6 months during Years 3-5 
 
* The QOL forms will be entered via a computer-assisted interview program and will be stored on 
the computer’s hard drive.  The data will then be transferred via encrypted email, Dropbox, or 
encrypted flash drive and dumped into a password-protected database for data accumulation and 
merging.  The other forms will be entered directly into the study REDCap database. 
** MD-reported AE’s will be obtained from clinical note and chart review. 
 
 
9.0 
MEASUREMENT OF EFFECT 
 
9.1 
Toxicity 
 
Toxicities related to radiation therapy, both acute (< 90 days from RT start) and late (> 90 
days from RT start) will be documented and graded according to the NCI CTCAE v 4.0 
 
9.2 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 

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10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities separated by cohorts 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This is a single arm clinical trial to evaluate proton beam radiation therapy (PBT) for treatment of 
stage II/III esophageal cancer in two clinical settings; a.) definitive chemoradiation and b.) 
neoadjuvant chemoradiation followed by esophagectomy.  While we will report and provide 
descriptive statistics between the two clinical settings, analyzing the differences is not our main 
concern.  The main endpoints are to determine the patient-reported outcomes and physician-
reported toxicities of proton beam therapy for esophagus cancer at 6 months.  Additional endpoints 
in the setting of definitive chemoradiation are to assess the progression-free and overall survival 

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rates at 2 and 5 years.  
  
11.1 
Sample Size 
 
Due to the novel nature of this study, standard sample size and power calculations are not 
possible. Therefore, we plan to enroll 20 patients to both the operative and non-operative 
treatment arms (40 patients total) because we believe that we have the ability to accrue this 
number of patients in a timely and clinically relevant manner.  This is NOT a randomized 
trial between these two therapy strategies. This number of patients is intended to obtain 
preliminary data upon which to base subsequent studies.   
 
11.2 
Toxicity Analysis 
 
Although this is not a randomized trial where the number of patients on each treatment arm 
is controlled, we will capture that information and hope that these two groups will be 
relatively the same size. Early stopping rules would cease accrual to the trial if ≥Grade 4 
CTCAEv4 gastrointestinal or pulmonary toxicity rates exceed 10% (2), or if ≥ grade 3 
CTCAEv4 gastrointestinal or pulmonary toxicity rates exceed 30% (6) for the first 20 
patients enrolled. In order to assess the overall toxicity of this treatment method we will 
compare the proportion of ≥Grade 3 gastrointestinal or pulmonary toxicity events against 
historical controls utilizing Binomial tests for proportion.  
 
11.3 
Progression-Free Survival and Overall Survival Rates 
 
PFS and OS will be assessed using the Kaplan-Meier estimate.  Since we don’t have enough 
patients on either arm for a firm comparison to the literature, we plan to simply provide 
descriptive statistics and projected 2-year and 5-year PFS and OS estimates for the 
following two arms: 
A. Definitive chemoradiation – We completed an internal Phase II trial that used 
intensity-modulated radiation therapy (IMRT) to a dose of 60 Gy with concurrent 
chemotherapy.  The 2-year PFS and overall survival rates (OS) from that experience 
are 25% (95% CI of 11 - 62%) and 36% (95% CI of   7 - 49%), respectively. These 
results are consistent with the literature.  
B. Neoadjuvant chemoradiation followed by esophagectomy – The two-year PFS and 
OS rates for patients with adenocarcinoma of the esophagus or gastroesophageal 
junction treated with neoadjuvant chemoradiation followed by esophagectomy on 
CALGB 9781 was 60% and 70%, respectively (taken from PFS and OS curves). 
(Tepper, Krasna, Mayer et al. 2008: 26:1086) 
 
11.4 
Patient Reported Outcomes 
 
We will calculate descriptive statistics (mean, standard deviation, etc.) for all QOL data 
(EQ-5D, SF-12) in addition to other PROs (depressive symptoms, social support) at each 
evaluation period.  Univariate tests will explore the associations among QOL and PROs 
using analysis of variance (ANOVA) and Fisher’s exact test for correlation. Changes over 
time in QOL and PROs will be analyzed utilizing repeated-measures modeling techniques 

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(repeated measures analysis of covariance).  
 
12.0 
REFERENCES 
 
Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, Okawara G, Rosenthal 
SA, Kelsen DR. INT 0123 (RTOG 94-05) phase III trial of combined-modality therapy for 
esophageal cancer: high-dose versus standard-dose radiation therapy. JCO 2002; 20(5):1167-74. 
 
Berkman LF, Vaccarino V, Seeman T. Gender differences in cardiovascular morbidity and 
mortality: The contribution of social networks and support. Ann Behav Med 1993; 15:112-118. 
 
Berkman L, Syme S. Social networks, host resistance, and mortality: A nine-year follow-up study 
of Alameda county residents. Am J Epidemiol 1979; 109:186-204. 
 
Cleeland, C. S., T. R. Mendoza, et al. (2000). "Assessing symptom distress in cancer patients; The 
M.D. Anderson Symptom Inventory." Cancer 89(7): 1634-1646. 
 
 
Gold, M. (1996). "Panel on cost-effectiveness in health and medicine." Med Care 34(12 suppl): 
197-199. 
 
 
Jeffe DB, Perez M, Liu Y, Collins KK, Aft RL, Schootman M. Quality of life changes over time 
in women diagnosed with ductal carcinoma in situ, early-stage invasive, breast cancer, and age-
matched controls. Breast Cancer Res Treat. 2012;134(1):379-391. 
 
Kaplan GA, Salonen JT, Cohen RD, Brand RJ, Syme SL, Puska P. Social connections and 
mortality from all causes and cardiovascular disease: Prospective evidence from Eastern Finland. 
Am J Epidemiol 1988; 128:370-380. 
 
Lian M, Jeffe DB, Schootman M. Racial and geographic differences in mammography screening 
in St. Louis City: A multilevel study. J Urban Health. 2008;85:677-92 
 
Lin, S. H., R. Komaki, et al. (2012). "Proton Beam Therapy and Concurrent Chemotherapy for 
Esophageal Cancer." International Journal of Radiation Oncology*Biology*Physics 83(3): e345-
e351. 
 
 
Lin, S. H., L. Wang, et al. (2012). "Propensity Score-based Comparison of Long-term Outcomes 
With 3-Dimensional Conformal Radiotherapy vs Intensity-Modulated Radiotherapy for 
Esophageal Cancer." International Journal of Radiation Oncology*Biology*Physics 84(5): 1078-
1085. 
 
 
Longman AJ, Braden CJ, Mishel MH. Side effects burden in women with breast cancer. Cancer 
Prac 1996; 4:274-280. 
 
Melchior LA, Huba GJ, Brown VB, Reback CJ. A Short Depression Index for Women. Education 
and Psychological Measurement. 1993, 53 
 

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Monjazeb, A. M. and A. W. Blackstock (2013). "The Impact of Multimodality Therapy of Distal 
Esophageal and Gastroesophageal Junction Adenocarcinomas on Treatment-Related Toxicity and 
Complications." Seminars in Radiation Oncology 23(1): 60-73. 
 
 
Orth-Gomer K, Johnson JV. Social network interaction and mortality: A six-year follow-up of a 
random sample of the Swedish population. J Chronic Diseases 1987; 4:944-957. 
 
Rabin, R. and F. deCharro (2001). "EQ-5D: ameasure of health status from the EuroQol Group." 
Annals of Medicine 33(5): 337-343. 
 
 
Ramsey SD, Berry K, Moinpour C, Giedzinska A, Andersen MR. Quality of life in long term 
survivors of colorectal cancer. Am J Gastroenterol. May 2002; 97(5):1228-34. 
 
Scarpa M, Erroi F, Ruffolo C, et al. Minimally invasive surgery for colorectal cancer: quality of 
life, body image, cosmesis, and functional results. Surgical Endoscopy. 2009;23(3):577-82. 
 
Sherbourne CD, Stewart AL. The MOS social support survey. Soc Sci Med. 1991;32(6):705-14 
 
Siassi MMD, Weiss MPD, Hohenberger WMD, Losel FPD, Matzel KMD. Personality Rather 
Than Clinical Variables Determines Quality of Life After Major Colorectal Surgery. Diseases of 
the Colon & Rectum April. 2009;52(4):662-8 
 
Trovo, M., J. Bradley, et al. (2008). "Esophageal Carcinoma with Celiac Nodal Metastaes; 
Curative or Palliative?" Journal of Thoracic Oncology 3(7): 751-755. 
 
 
Wang, X., L. Williams, et al. (2010). "Validation and application of a module of the M.D. 
Anderson Symptom Inventory for measuring multiple symptoms in patients with gastrointestinal 
cancer (the MDASI-GI)." Cancer 116(8): 2053-2063. 
 
 
Ware J, Kosinski M, Keller S. SF-12: How to Score the SF-12 Physical and Mental Health 
Summary Scales. Second ed. Boston: The Health Institute, New England Medical Center; 1995 
 
Ware J, Kosinski M, Keller S. A 12-Item Short-Form Health Survey: Construction of scales and 
preliminary tests of reliability and validity. Med Care 1996;34:220-33 
 
Waters, E.A., Liu, Y., Schootman, M., & Jeffe, D.B. (2013). Worry about cancer progression and 
low perceived social support: Implications for quality of life among early-stage breast cancer 
patients. Annals of Behavioral Medicine, 45, 57-68. 
 
Zhang, X., K.-l. Zhao, et al. (2008). "Four-Dimensional Computed Tomographyâ€“Based 
Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal 
Esophageal Cancer." International Journal of Radiation Oncology*Biology*Physics 72(1): 278-
287. 
 
APPENDIX A: ECOG Performance Status Scale 
 

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Grade 
 
 
Description 
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. 
5 
 
Dead. 
 
 
 
 

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APPENDIX B: MD Anderson Symptom Inventory (MDASI)-Plus 
 

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APPENDIX C: EuroQol (EQ-5D) 
 
Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems in walking about 
 
 
I have slight problems in walking about 
 
 
I have moderate problems in walking about 
 
 
I have severe problems in walking about 
 
 
I am unable to walk about 
 
 
SELF-CARE 
I have no problems with self-care 
 
 
I have SLIGHT problems washing or dressing myself 
 
 
I have moderate problems washing or dressing myself 
 
 
I have severe problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
USUAL ACTIVITIES (e.g., work, study, housework, family or leisure activities) 
I have no problems doing my my usual activities 
 
 
I have slight problems doing my usual activities 
 
 
I have moderate problems doing my usual activities 
 
 
I have severe problems doing my usual activities 
 
 
I am unable to do my usual activities 
 
 
 

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PAIN/DISCOMFORT 
I have no pain or discomfort 
 
 
I have slight pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have severe pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
I am slightly anxious or depressed 
 
 
I am moderately anxious or depressed 
 
 
I am severely anxious or depressed 
 
 
I am extremely anxious or depressed 
 
 
 
 

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• 
We would like to know how good or bad your health is 
TODAY 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
      0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is 
TODAY. 
• 
Now, please write the number you marked on the scale in 
the box below 
 
                     YOUR HEALTH TODAY = 
 
 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
 The worst health 
you can imagine 
0 
The best 
health 
you can 
i
i
Your own 
health 

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APPENDIX D: Reportable Adverse Events from CTCAE version 4.03 
 
Cardiac AEs 
 
 
 
 
 

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Gastrointestinal AEs 
 
 
 
 
 

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Metabolism and Nutrition AEs 
 
 
 
 

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Respiratory, Thoracic and Mediastinal AEs 
 
 
 
 

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Skin and Subcutaneous AEs 
 
 
 
 

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APPENDIX E: SF-12 
 
Date ________________ 
  
Instructions:  This questionnaire asks for your views about your health.  This 
information will help keep track of how you feel and how well you are able to do 
your usual activities.  Please answer every question by marking one box.  If you 
are unsure about how to answer, please give the best answer you can. 
 
1.  In general would you say your health is: 
 
 
 
 
 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
The following items are about activities you might do during a typical day.   
Does your health now limit you in these activities?  If so, how much? 
 
 
 
Yes, 
Limited 
A Lot 
Yes, 
Limited 
A Little 
No, Not 
Limited 
At All 
2. 
Moderate activities, such as moving a 
table, pushing a vacuum cleaner, bowling, 
or playing golf. 
 
 
 
 
3. 
Climbing several flights of stairs 
 
 
 
 
During the past 4 weeks, have you had any of the following problems with your 
work or other regular daily activities as a result of your physical health? 
 
 
 
YES 
NO 
4. 
Accomplished less than you would like 
 
 
5. 
Were limited in the kind of work or other 
activities 
 
 
 

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During the past 4 weeks, have you had any of the following problems with your 
work or other regular daily activities as a result of any emotional problems (such as 
feeling depressed or anxious)? 
 
 
YES 
NO 
6. 
Accomplished less than you would like 
 
 
7. 
Didn’t do work or other activities as 
carefully as usual 
 
 
 
8.  During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
 
 
 
 
 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
These questions are about how you feel and how things have been with you during 
the past 4 weeks.  For each question, please give the one answer that comes closest 
to the way you have been feeling.  How much of the time during the past 4 weeks - 
 
 
 
All of 
the Time 
Most of 
the Time 
A Good 
Bit of 
the Time 
Some of 
the Time 
A Little 
of the 
Time 
None of 
the Time 
9. 
Have you felt calm 
and peaceful? 
 
 
 
 
 
 
10. 
Did you have a lot 
 of energy? 
 
 
 
 
 
 
11. 
Have you felt 
downhearted and 
blue? 
 
 
 
 
 
 
 
12.  During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with friends, 
relative, etc.)? 
 
 
 
 
 
 
All of the time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 

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APPENDIX F: MOS Social Support Survey 
 
 
 
 

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APPENDIX G: 4-Item CES-D 
 
Date: _____________________ 
 
Instructions: Darken the circle next to each statement which best describes how often you felt or 
behaved this way—DURING THE PAST WEEK. 
 
1. I felt depressed 
○ Rarely or none of the time (less than 1 day) 
○ Some or a little of the time (1-2 days) 
○ Occasionally or a moderate amount of the time (3-4 days) 
○ Most or all of the time (5-7 days) 
2. I felt lonely 
○ Rarely or none of the time (less than 1 day) 
○ Some or a little of the time (1-2 days) 
○ Occasionally or a moderate amount of the time (3-4 days) 
○ Most or all of the time (5-7 days) 
3. I had crying spells. 
○ Rarely or none of the time (less than 1 day) 
○ Some or a little of the time (1-2 days) 
○ Occasionally or a moderate amount of the time (3-4 days) 
○ Most or all of the time (5-7 days) 
4. I felt sad. 
○ Rarely or none of the time (less than 1 day) 
○ Some or a little of the time (1-2 days) 
○ Occasionally or a moderate amount of the time (3-4 days) 
○ Most or all of the time (5-7 days)