A Phase I Trial Of Intensity-Modulated Radiation Therapy (IMRT) Using A Contralateral Esophagus Sparing Technique (CEST) In Locally Advanced Non-Small Cell Lung Cancer (NSCLC) And Limited-Stage Small Cell Lung Cancer (LS-SCLC).
Phase: NA
Conditions: Non-small Cell Lung Carcinoma, Small Cell Lung Carcinoma
Sponsor: Massachusetts General Hospital

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NCI Protocol #:
N/A
Local Protocol #:
15-023
DF/HCC Radiation Protocol Template:  August 22, 2017  
TITLE: A PHASE I TRIAL OF INTENSITY-MODULATED RADIATION THERAPY 
USING A CONTRALATERAL ESOPHAGUS SPARING TECHNIQUE IN LOCALLY 
ADVANCED NON-SMALL CELL LUNG CANCER AND LIMITED-STAGE SMALL CELL 
LUNG CANCER. 
Coordinating Center:
NA
*Principal Investigator (PI):
Henning Willers, MD
Massachusetts General Hospital (MGH)
Dept. of Radiation Oncology, Cox 3
55 Fruit Street
Boston, MA 02114
Telephone – 617-726-5184
Fax – 617-726-3603
hwillers@partners.org
Other Key Investigators:
Joanna Y. Tansky, MD PhD (Newton-Wellesley Hospital 
Site PI) 
 
MGH Radiation Oncology
Christine Olsen, MD
MGH Radiation Oncology 
Sophia Kamran, MD
Harvard Radiation Oncology Program
Gregory Sharp, PhD
MGH Radiation Physics
Peter Paetzold, BS, CMD
MGH Radiation Physics
Justin Gainor, MD, PhD
MGH Medical Oncology
NCT02394548

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Statistician:
Study Coordinator: 
Alona Muzikansky
Kelly Hill  
MGH Biostatistics Center
MGH CCPO 
NCI-Supplied Agent(s):  N/A
Other Agent(s): [F-18] FLT
Protocol Type / Version # / Version Date:
[Version 22 August 2017 ]
*Protocol types:  Original

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INDEX
SCHEMA.........................................................................................................................................5
1.
INTRODUCTION ...................................................................................................6
1.1
Study Disease...........................................................................................................6
1.2
Rationale for the use of the Contralateral Esophageal Sparing Technique 
(CEST) with IMRT..................................................................................................8
2.
OBJECTIVES........................................................................................................11
2.1
Study Design..........................................................................................................11
2.2
Primary Objectives.................................................................................................12
2.3
Secondary Objectives.............................................................................................12
3.
PARTICIPANT SELECTION...............................................................................12
3.1
Eligibility Criteria..................................................................................................12
3.2 
Exclusion Criteria ..................................................................................................13
3.3 Inclusion of Women and Minorities ............................................................................14
4.
PRETREATMENT EVALUATIONS/MANAGEMENT.....................................14
5.
REGISTRATION PROCEDURES .......................................................................14
6.
RADIATION TREATMENT PLAN.....................................................................15
6.1
Dose Specifications:...............................................................................................15
6.2
Technical Factors...................................................................................................16
6.3
CT simulation.........................................................................................................16
6.4
Treatment Planning/Target Volumes.....................................................................17
6.5
Critical Normal Structures.....................................................................................18
6.6
Treatment Verification...........................................................................................20
6.7
Quality Assurance..................................................................................................20
6.8
Radiation Quality Assurance Reviews...................................................................21
6.9
Radiation Adverse Events......................................................................................21
6.9.1
Acute esophagitis...................................................................................................22
6.10
Radiation Adverse Event Reporting ......................................................................23
6.12
Procedures for AE and SAE Recording and Reporting.........................................24
6.13
Reporting Requirements ........................................................................................25
6.14
Reporting to the Study Sponsor.............................................................................25
6.15
Reporting to the Institutional Review Board (IRB)...............................................26
6.16
Reporting to the Food and Drug Administration (FDA) .......................................26
6.17
Reporting to the NIH Office of Biotechnology Activities (OBA).........................26
6.18
Reporting to the Institutional Biosafety Committee (IBC)....................................26
6.19
Reporting to Hospital Risk Management...............................................................26
6.20
Monitoring of Adverse Events and Period of Observation....................................26
7
DRUG THERAPY.................................................................................................27
8
SURGERY.............................................................................................................27
9
CORRELATIVE STUDIES ..................................................................................27
10
TISSUE/SPECIMEN SUBMISSION....................................................................27
11
PARTICIPANT ASSESSMENTS.........................................................................29
12
DATA COLLECTION ..........................................................................................30
13
STATISTICAL CONSIDERATIONS...................................................................30

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13.1
Study Design/Endpoints Definitions......................................................................30
13.2
Sample Size, Accrual Rate and Study Duration ....................................................31
13.3
Stratification Factors..............................................................................................32
13.4
Interim Monitoring Plan ........................................................................................32
13.5
Analysis of Primary Endpoints..............................................................................32
13.6
Analysis of Secondary Endpoints..........................................................................32
13.7
Reporting and Exclusions ......................................................................................34
13.8
Evaluation of Toxicity ...........................................................................................34
13.9
Evaluation of the Primary Efficacy Endpoint........................................................35
14
REGULATORY CONSIDERATIONS.................................................................35
14.1
Data Safety Monitoring..........................................................................................35
14.2
Multicenter Guidelines...........................................................................................35
14.3
Collaborative Agreements Language.....................................................................35
15
PUBLICATION PLAN .........................................................................................37
REFERENCES ..............................................................................................................................38
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................40

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SCHEMA
NSCLC, non-small cell lung carcinoma; SCLC, small cell lung carcinoma; IMRT, intensity-
modulated radiation therapy, * high-precision therapy refers to the utilization of state-of-the-art 
techniques that ensure adequate tumor coverage and appropriate sparing of normal organs 
throughout the course of radiation therapy, including custom patient immobilization, image-
guided radiation therapy (IGRT) using daily cone beam CT, and adaptive treatment planning if 
needed, **any concurrent chemotherapy per standard of care
Locally advanced NSCLC/SCLC 
with gross tumor within 1 cm of 
the esophagus
Definitive high-precision* IMRT 
with Contralateral Esophageal 
Sparing Technique (CEST), 
with concurrent chemotherapy**
Primary Endpoint:
Rate of severe (grade 3 or higher) 
Acute Esophagitis

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1. INTRODUCTION
1.1 Study Disease 
Lung Cancer
Lung cancer is the leading cause of cancer death in men and women, and it is the second most 
common cancer. The American Cancer Society estimates 224,210 new cases in 2014 and 
159,260 deaths (27% of all cancer deaths) 1.  More than 80% of lung cancers are caused by 
exposure to tobacco smoke. Lung cancer is divided into two histologic subtypes: non-small cell 
lung cancer (NSCLC) and small cell lung cancer (SCLC).  NSCLC encompasses approximately 
87% of all lung cancer cases. The majority of NSCLC patients presents with either locally 
advanced disease or distant metastases, and are medically inoperable or have unresectable 
disease. Chemoradiation is the primary treatment for SCLC and unresectable, locally advanced 
NSCLC. It is estimated that two thirds of lung cancer patients will undergo radiation therapy. 
Locally advanced NSCLC comprises approximately 30% of all patients with NSCLC and 
includes stages IIIA and IIIB. Standard of care for this large and heterogeneous group of patients 
is multimodality therapy with chemotherapy and radiation, with the possible addition of surgical 
resection for operable candidates 2-4. Although locally advanced disease is considered curable, 
outcomes are poor with median progression-free survival of 10-13 months, median overall 
survival of 17-24 months, and a 2 year-survival rate of about 50%. In an attempt to improve 
treatment outcomes the Radiation Therapy Oncology Group (RTOG) and others have explored 
the use of higher radiation doses. The University of Michigan used a dose range of 60-100Gy 
with concurrent and adjuvant chemotherapy (Kong et al., ASTRO meeting 2011). The median 
survival was 15.5 and 41.9 months for doses less then and greater than 70Gy, respectively. 
RTOG 0617 is a randomized phase III trial comparing 74 Gy with 60 Gy using concurrent 
chemotherapy with carboplatin/paclitaxel, with or without cetuximab which is a monoclonal 
antibody directed against the epidermal growth factor receptor. Preliminary reports show higher 
toxicity for 74 Gy and the surprising finding that 74 Gy is associated with inferior survival 
outcome 5,6.  Factors predictive of worse survival on multivariate analysis included higher 
radiation dose and higher esophagitis grade 6. While final publication of this trial is awaited to 
better assess the reasons why 74 Gy fared worse, radiation doses of > 70 Gy remain 
investigational. Doses of 60-66 Gy are considered the standard of care in the community 7. The 
continued use of 70 Gy is supported by modern clinical trials such as RTOG 1308 or CALGB 
30105 8. Importantly, data show that doses of ~60-63 Gy with concurrent chemotherapy are 
associated with ~30-50% local failure rates, which is unacceptably high 3,9-11.   
SCLC is an aggressive disease that is chemosensitive yet associated with high rates of local 
relapse and metastases. SCLC is staged as limited stage (LS) or extensive stage disease: LS 
referring to disease confined to the ipsilateral hemithorax that can be safely included in a 
radiation portal while extensive stage disease includes all remaining patients. Approximately 
30% of SCLC patients present with limited stage disease 12. The standard of care in the treatment 
for SCLC is concurrent chemoradiation 13,14. One of the limitations to concurrent chemoradiation 
in many patients is the development of toxicities, one common toxicity being acute esophagitis. 
In the randomized trial by Turrisi et al, 45 Gy given at 1.5 Gy twice daily over 3 weeks was 

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associated with a > 30% incidence of severe esophagitis, with 27% grade 3 esophagitis and 5% 
of grade 4 esophagitis 14. The range of recommended doses in the standard of care for SCLC is 
60-70 Gy when given once-daily15. 
Acute Esophagitis 
Challenges for delivering an adequate radiation dose are the limitations of normal tissue 
tolerance. Acute esophagitis is a common toxicity in patients undergoing concurrent 
chemoradiation for lung cancer, often requiring treatment breaks, fluid and nutritional support, or 
even hospitalization (see Table 1). Importantly, treatment breaks can lower tumor control rates 
and reduce survival, emphasizing the need to avoid severe acute esophagitis. Concurrent 
chemoradiation generally results in a ~15-25% rate of severe esophagitis (RTOG Grade 3 or 
higher) 16. Patients undergoing concurrent chemoradiation have an approximate 5-fold increase 
in the development of esophagitis as compared to patients undergoing sequential chemoradiation. 
In addition, the development of esophagitis has been a limitation to dose-escalation of radiation. 
Of note, esophagitis rates are generally similar for different concurrent chemotherapy schedules 
17 (see Table 1).
 
Table 1. Rates of acute esophagitis in prospective trials of concurrent chemoradiation
Prospective 
trial
Radiation 
dose
2D, 3D or 
IMRT
Chemotherapy
Esophagitis 
scoring 
system
G3+ acute 
esophagitis 
(%)
Patient 
number & 
comments
Albain INT 
0139, 
Lancet 2
61.2 Gy
(1.8 Gy/day)
2D 
Cisplatin,
Etoposide
RTOG
Arm 2: 23% 
N=194 in Arm 
2 (definitive 
chemoRT* 
arm)
Curran RTOG 
94-10,
JNCI 3
Arm 2:
63 Gy  
(1.8 Gy to 
45 Gy, 2 Gy 
to 18Gy)
2D
Arm 2: 
Cisplatin,
VBL^
RTOG
Arm 2: 22%
N=204
Govindan 
CALGB, JCO 
18
70 Gy 
(2 Gy/day)
3D 
Carboplatin,
Pemetrexed
CTCAEv3.0#
Arm A: 16%
Arm B: 13%
N=48 (Arm 
A), N=53 (B) 
(Group B with 
same chemo + 
cetuximab)
Furuse, JCO 4
56 Gy 
(2Gy/day)
Split-course
2D
Cisplatin,
Vindesine,
Mitomycin
ECOG 1982
[2.6%]@
N=156 in the 
concurrent arm
Hanna
HOG, JCO 19
59.4 Gy (45 
Gy + 14.4 
Gy boost; 
1.8 Gy/day)
2D
Cisplatin,
Etoposide
CTCAEv3.0#
17.2%
N=203
Turrisi
14
45 Gy (1.8 
Gy QD or 
1.5 Gy BID)
2D
Cisplatin,
Etoposide
RTOG
16% QD&
32% BID%
N= 206 QD& 
N= 211 BID%
RTOG 0324 20
63 Gy (1.8 
Gy/fraction)
3D 
Cetuximab,
Carboplatin,
Paclitaxel
CTCAEv3.0#
8%
N=87 (phase II 
trial)
*chemoRT=chemotherapy with concurrent radiation therapy, ^VBL=vinblastin, #Common Terminology Criteria for 
Adverse Events (CTCAE), @split-course reduces esophagitis rate, &QD=once daily, %BID=twice daily

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Intensity-Modulated Radiation Therapy (IMRT)
IMRT is an advanced form of conformal radiation therapy, which delivers radiation to the patient 
via multiple fields (typically 5-7) that have non-uniform radiation fluence. IMRT uses “inverse 
planning”, meaning that the radiation oncologist specifies the dose distribution, and the plan is 
calculated to deliver it. IMRT can increase dose conformality and provide greater sparing of 
normal tissues than traditional 3D conformal forward planning 21-24. Despite this improved 
conformality around the tumor, the reported rates of grade 2 and 3 esophagitis remain relatively 
high. Jiang et al. reported toxicity outcomes in 165 inoperable NSCLC patients treated with 
definitive IMRT (median dose 66 Gy in 33 fractions) at the MD Anderson Cancer Center, of 
which 136 received concomitant chemotherapy 21. The encountered incidences of Common 
Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 esophagitis were 70% and 
18%, respectively. On long term follow-up, the development of esophagitis was associated with 
the late esophageal stricture in 15 patients (9%). Similarly, Kwint et al. assessed the esophagitis 
outcomes in 139 patients with inoperable NSCLC treated with IMRT and concomitant 
chemotherapy. Using a hypofractionated regimen of 64 Gy in 24 fractions, 38% of patients 
experienced CTCAE grade 2 esophagitis, and 22% developed grade 3 toxicity 25. Hence, IMRT 
has not been shown to reduce the toxicity to the esophagus, at least not with traditional dose 
constraints. 
  
1.2 Rationale for the use of the Contralateral Esophageal Sparing Technique (CEST) with 
IMRT 
Traditional esophagus dose constraints
The dose in definitive radiation therapy for locally advanced NSCLC and SCLC is limited by 
normal tissues and organs, most notably lungs, spinal cord, heart, and esophagus. Concurrent 
chemoradiation, as evidenced in Table 1, leads to high rates of severe acute esophagitis (15-
25%). Thus, there is an urgent need for improved radiation technologies, techniques, and 
predictors of esophagitis in the treatment of lung cancer. Many centers have tried to predict 
esophagitis rates using dose-volume histograms (DVH), that is, the dose of radiation given to a 
volume of esophagus that will result in esophagitis. The use of DVH constraints is now a 
common tool used to predict radiation toxcity to organs. In a large metaanalysis published in 
2013, Palma et al. looked at 1,082 lung cancer patients who received concurrent chemoradiation 
26. The study found that the volume of esophagus receiving 60 Gy (V60) was the most accurate 
predictor of grade 2 and 3 acute esophagitis. Patients with a very low V60 <1% had a low risk of 
esophagitis and patients with a V60 above 17% conferred a high risk. A review by Werner-
Wasik et al. summarized 11 studies that used 3D treatment planning. Unfortunately, a single best 
parameter was not identified to predict esophagitis, mainly because a variety of V(dose) 
parameters were associated with acute esophagitis 16. This suggests that the maximum dose 
limits to the esophagus may not be a reliable tool to reduce esophagitis in patients undergoing 
concurrent chemoradiation. The recent RTOG 0617 trial has collected V60 data on all patients 
and is recommending keeping the mean dose to the esophagus to less than 34 Gy. Altogether, the 
available data indicate a lack of robust dosimetric parameters that could be used to limit the rate 
of severe esophagitis. 

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Contralateral Esophageal Sparing Technique (CEST)
In prostate cancer, IMRT is associated with low rates of radiation-induced proctitis. Sparing of 
the posterior rectal wall with IMRT has been of great significance in reducing the rates of rectal 
toxicity, while achieving high dose to the tumor-containing prostate 27-31. At MGH, we have 
applied a similar technique for esophagus sparing in the treatment of lung cancer patients with 
IMRT since 2013. This simple technique involves outlining the half of the esophageal 
circumference that is located contralateral to the tumor on axial CT slices.  This contralateral 
esophagus (CE) contour serves as a distinct avoidance structure that is used as a guide for 
promoting a steep dose fall-off across sections of the esophagus in close proximity to tumor. 
Figure 1A,B illustrates how radiation isodose lines attempt to “curve” around the CE contour.
Figure 1: Sparing of contralateral esophagus (CE) with IMRT. A+B) Illustration of how the isodose lines 
“curve” around the contralateral esophagus (purple). In A), the tumor target is covered by the prescription 
dose of 70.2 Gy and a steep dose fall off across the esophagus allows for limiting the contralateral 
esophogus to 41 Gy. In B), the target is covered with a prescription dose of 66.6 Gy, while the 
contralateral esophagus is receiving 45 Gy. C) Summary of V45 and V55 value (i.e., volume of 
esophagus receiving 45+ Gy or 55 + Gy in 20 patients treated with this technique. Box and whiskers 
represent mean and range of data.
We recently analyzed our experience with CEST in 20 consecutive patients with locally 
advanced thoracic malignancies who received concurrent chemoradiation 32. All patients had 
gross tumor within 1 cm of the esophagus. The median total radiation dose was 70.2 Gy (range, 
63-72.15 Gy). Only one patient was treated with 63 Gy following an R1 resection of a 
paramediastinal pT3N0 NSCLC. Importantly, CEST did not compromise target coverage in any 
patient. Strikingly, no patient developed grade 3-4 esophagitis (RTOG score) (95% CL, 0-16%), 
and the rate of grade 2 esophagitis was only 20%. 
Dosimetric parameters and esophagus toxicity are summarized in Table 2. The median maximum 
dose to the CE was 62.3 Gy (range, 47-68.2Gy), which was significantly lower than the 
maximum dose to the esophagus, mean 67.5 Gy (range, 61.9-72.7Gy) (paired t-test, p<0.05). 
Similarly, the median esophageal volume receiving 60 Gy or more (V60) was 5.3% (range, 0-
23%), which was higher than the median CE V60 of 0.5% (range, 0-12.7%). The median CE 

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volume receiving 45 Gy and volume receiving 55 Gy measured 2.1 cc and 0.4 cc, respectively 
(Figure 1C). Overall, the CE had more favorable dosimetry in comparison to the whole 
esophagus, indicating effective esophagus cross section sparing. 
Table 2: Characteristics of patients treated with CEST and observed acute esophagitis 
 *Max Dose is defined as the dose received by 0.03 cc receiving the highest dose. 
To understand how CE sparing may decrease severe esophagitis, it is important to consider the 
different mechanisms of radiation-induced normal tissue injury. The reason why a large dose to a 
small length of the spinal cord may cause severe radiation injury, such as myelopathy, is that the 
inactivation of even a single functional subunit (FSU) can disrupt the function of the entire organ 
for tissues whose FSUs are arranged in a serial fashion. In contrast, a high dose to a small 
volume of the lung may have little impact because the remainder of the lung will continue to 
function normally because its FSUs are arranged in parallel 33. Assuming that the esophagus 
represents an organ with FSUs arranged in serial fashion in the longitudinal axis, high dose 
irradiation of the entire cross-section of the esophagus would be expected to result in whole 
organ dysfunction. The results suggest a model in which near-normal esophageal function is 
maintained by preserving the function of part of the esophageal cross-section, i.e., converting 
serial organ-type injury to parallel organ-type injury. 
Esophagus
Contralateral Esophagus
Patient
TN 
Stage
Gross Tumor PTV  
(Gy)
Max 
Dose 
(Gy)*
V60 (%)
Max Dose 
(Gy)*
V60 
(cc)
V55 (cc)
V45 
(cc)
RTOG 
Acute 
Esophagitis 
Grade
1
T2N2
69.9
69.5
18.2
65.0
0.82
3.56
7.38
1
2
TxN1
70.2
68.0
5.6
55.0
0.00
0.07
3.96
1
3
T3N2
72.0
72.7
14.9
64.8
0.59
2.34
6.28
0
4
T2N2 
66.6
65.5
2.5
52.3
0.00
0.00
0.20
1
5
T2N3
72.2
66.9
5.0
65.5
0.36
1.06
5.22
1
6
T3N2
70.2
70.3
12.5
65.1
0.39
0.97
3.90
2
7
T0N2
72.0
70.8
6.0
62.5
0.06
0.18
0.86
0
8
T2N3 
72.0
70.2
14.0
65.0
0.37
0.95
1.73
0
9
T3N2 
72.0
72.5
8.0
65.3
0.12
0.32
1.68
1
10
T2N3 
72.0
62.0
1.6
62.0
0.40
2.32
7.23
1
11
T1N2 
70.2
63.6
2.0
47.0
0.00
0.00
0.05
1
12
T2N3
72.2
66.6
2.8
52.8
0.00
0.00
1.48
1
13
TxN3
66.6
65.0
10.0
55.4
0.00
0.05
1.75
2
14
T0N2
70.2
70.8
22.8
68.2
1.87
2.35
3.20
0
15
T2N1
70.0
58.7
0.0
47.0
0.00
0.00
0.05
1
16
TxN3
66.6
66.9
9.7
64.8
1.36
2.00
2.68
1
17
T3N0
63.0
65.6
4.7
59.4
0.01
0.51
2.49
1
18
T2N2
70.2
70.2
2.7
56.4
0.00
0.07
1.24
2
19
T3N0
72.0
67.04
1.9
64.1
0.00
0.02
0.34
2
20
T4N0
70.0
68.7
2.3
54.9
0.15
0.50
2.63
0

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We now propose to prospectively test the utility of CEST which was developed in clinical 
practice. The rationale for using CEST is that, once we can reduce the rate of severe esophagitis 
from the published rate of 15-25% to 5% or less, we may be able to revisit the question of 
radiation dose escalation to > 70 Gy. Increasing the radiation dose is predicted to increase local 
tumor control and subsequently survival, provided that the dose increase is not associated with 
morbidity and mortality. 
2. OBJECTIVES
2.1
Study Design
Standard therapy for both inoperable, locally advanced NSCLC and LS-SCLC involves 
concurrent radiation therapy and chemotherapy. The rate of grade 3+ acute esophagitis 
associated with these treatment regimens is generally in the order of 15-25% (Table 1). We will 
thus allow both locally advanced NSCLC and LS-SCLC patients to enroll. 
Acceptable radiation doses for both lung cancer types range from 60 Gy to 70 Gy. We will select 
70 Gy for our study, which would be predicted to result in somewhat higher esophagitis rates 
than 60 Gy and is thus better suited to demonstrate the superiority of CEST in terms of 
esophagitis reduction. We note that 70 Gy is already being used as a standard at MGH, and its 
use therefore does not represent a deviation from routine clinical care (see Table 2). 
There is no prospective data to indicate that different concurrent chemotherapy regimens result 
in different rates of esophagitis. We will, therefore, allow any type of standard-of-care 
concurrent regimen at the discretion of the treating medical oncologist (this would be in the vast 
majority of cases cisplatin + etoposide, carboplatin + paclitaxel, or cisplatin/carboplatin + 
pemetrexed).
Currently, there are no established dosimetric parameters to guide appropriate esophageal 
sparing in the treatment of locally advanced lung cancer. This is highlighted by the recently 
opened RTOG 1308 protocol in which patients with locally advanced NSCLC are randomized to 
photon or proton radiation to a dose of 70 Gy. In this protocol, only a maximum esophageal dose 
is specified. At MGH, we have developed an IMRT-based technique to reduce radiation dose to 
the part of the esophagus that is located contralateral to the tumor. This approach mirrors the 
approach to sparing of the posterior rectum, used in the treatment of prostate cancer. In our 
clinical experience, esophagus sparing with IMRT-based CEST has the potential to dramatically 
reduce the rates of acute esophagitis, and in particular grade 3+ esophageal toxicity (Table 2).  
We, therefore, wish to analyze the toxicity associated with this technique in a prospective 
fashion. 
Contralateral esophageal sparing is particularly important in patients in whom there is gross 
tumor (primary tumor or involved lymph nodes) in close proximity to the esophagus. We will, 
therefore, enroll only patients with gross tumor within 1 cm of the esophagus. A steep dose 
gradient between the gross tumor (which receives 70 Gy) and the contralateral esophagus wall 
(which is limited to a maximum dose of ~55 Gy) requires high precision delivery of radiation. 

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We will, therefore, require custom immobilization and daily image-guidance with cone beam CT 
in every patient, in order to ensure adequate tumor coverage and esophageal sparing. In addition, 
if changes in esophagus position are detected during the course of radiation therapy, for example 
due to regressing tumor which had pushed the esophagus aside, repeat (adaptive) radiation 
planning will be required.
Therefore, we propose to undertake a phase I study to analyze the impact of CEST on rates of 
acute esophagitis in patients with locally advanced NSCLC and LS-SCLC receiving definitive 
radiation with concurrent chemotherapy. We anticipate that sparing the contralateral esophagus 
from full prescription dose will result in a reduction of grade ≥3 acute esophagitis compared to 
historical rates of 15-25%. We will test this technique in a cohort of 20 patients with 
NSCLC/SCLC treated to a radiation dose of 70 Gy.   
 
2.2 Primary Objectives
To describe the rate of grade ≥3 acute esophagitis using CTCAE v4 in patients with locally 
advanced NSCLC or LS-SCLC, located in close proximity to the esophagus, who undergo 
concurrent IMRT with CEST and chemotherapy. 
2.3 Secondary Objectives
As a main secondary objective we will describe the rates of acute esophagitis using the historical 
RTOG scoring scale, in order to facilitate comparisons with published clinical trials. We will 
describe the general toxicities of treatment, which, because combined radiation/chemotherapy is 
the standard of care, will reflect routine clinical practice. Because reducing the dose to parts of 
the esophagus in close proximity to the tumor can theoretically lead to underdosing of tumor 
during the course of treatment, we will also assess local and regional failure rates.
Secondary objectives are thus:
1)
To describe the rates of acute esophagitis using the historical RTOG scoring system 
2)
To describe general toxicities of radiation treatment using CTCAE v4.0
3)
To analyze local and regional failure rates
4)
To determine overall survival time 
3.
PARTICIPANT SELECTION
3.1 Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study. 
3.1.1 Histologically or cytologically proven diagnosis of NSCLC or SCLC. In cases where 
the histology and cytopathology results are consistent with a carcinoma but 
immunohistochemistry stains are indeterminate and unable to support the lungs as the most 

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likely site of origin, the diagnosis of NSCLC or SCLC may be established in conjunction 
with the radiographic and clinical picture.
3.1.2 For NSCLC, patients with clinical stage IIB-IV patients (AJCC, 7th ed.) are eligible, 
and for SCLC, limited-stage patients are eligible, if documented to be a candidate for 
definitive radiation and concurrent chemotherapy in the radiation oncologist or medical 
oncologist clinic note.

Stage IV NSCLC patients are eligible only if they have a solitary brain metastasis

Patients with non-malignant pleural effusion are eligible.
o
If a pleural effusion is present, the following criteria must be met to exclude 
malignant involvement: 

When pleural fluid is visible on both the CT scan and on a chest x-ray, a 
pleuracentesis is required to confirm that the pleural fluid is cytologically 
negative. 

Exudative pleural effusions are excluded, regardless of cytology;

Effusions that are minimal (ie, not visible on chest x-ray) that are too 
small to safely tap are eligible.
3.1.3 Gross tumor (primary tumor or involved lymph node) must be within 1 cm of 
esophagus on the most recent chest CT scan.
3.1.4 ECOG performance status 0-1 within 30 days prior to registration; 
3.1.5 Age ≥ 18 
3.1.6 Women of childbearing potential must indicate that there is not a possibility of being 
pregnant at the time of enrollment or have a negative serum pregnancy test prior to the 
initiation of radiation therapy. 
3.1.7 Women of childbearing potential and male participants must practice adequate 
contraception. 
3.1.8
Patient must provide study-specific informed consent prior to study entry.
3.2 
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study.
3.2.1
Greater than minimal, exudative, or cytologically positive pleural effusions
3.2.2
Tumor suspected or known to invade the esophagus
3.2.3
Prior chemotherapy if this precludes administration of concurrent chemotherapy for 
protocol treatment. Note that induction chemotherapy is allowed as long as 
concurrent chemotherapy is possible.
3.2.4
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields

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3.2.5
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; 
note, however, that HIV testing is not required for entry into this protocol. The need 
to exclude patients with AIDS from this protocol is necessary because the treatments 
involved in this protocol may be significantly immunosuppressive. Protocol-specific 
requirements may also exclude immuno-compromised patients.
3.2.6
Pregnancy or women of childbearing potential and men who are sexually active and 
not willing/able to use medically acceptable forms of contraception; this exclusion is 
necessary because the treatment involved in this study may be significantly 
teratogenic.
3.2.7
Any history of allergic reaction to chemotherapies used
3.3 Inclusion of Women and Minorities
We do not expect that the inclusion or exclusion criteria will impact the enrollment of women, 
minorities, or other underrepresented populations as lung cancer affects people of all genders, 
races, and socioeconomic classes.
4. PRETREATMENT EVALUATIONS/MANAGEMENT
Baseline studies include the following minimum diagnostic workup, which is standard-of-care: 

History/physical examination, including vital signs with weight, blood pressure, heart 
rate, oxygen saturation, documentation of smoking history, alcohol use, acid reflux, and 
pre-chemotherapy laboratory tests as per standard-of-care within 30 days prior to 
registration; 

FDG-PET scan for staging within 90 days prior to registration. 

CT chest/abdomen scan with IV contrast for staging within 90 days prior to registration. 
o
MRI scan with IV contrast of the brain (preferred) or CT scan of the brain with iv 
contrast within 90 days prior to registration.PET and CT may be combined in a 
single study. If a subject has an allergy to IV dye or refuses, non-contrast scans 
will be acceptable.

Optional FLT-PET Scan (Refer to Section 9)
o
A pregnancy test will be conducted before the scan for women of child-bearing 
potential.
5. REGISTRATION PROCEDURES
5.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registration must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied. 

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An investigator will confirm eligibility criteria and a member of the study team will complete 
the protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a 
participant does not receive protocol therapy following registration, the participant’s on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as 
possible.
5.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
5.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the Coordinating Center by the 
Multi-center Coordinator. All sites should contact the Multi-center Coordinator to verify dose 
level availabilities prior to consent. 
Following registration, participants should begin protocol therapy within 5 weeks. Issues that 
would cause treatment delays should be discussed with the Overall PI. If a participant does 
not receive a protocol therapy following registration, the participant’s registration on the 
study must be canceled. The Study Coordinator should be notified of cancellation as soon as 
possible.
6. RADIATION TREATMENT PLAN
Radiation therapy will consist of high-precision IMRT that utilizes custom patient 
immobilization, 4D CT planning, daily image guidance, and adaptive planning as needed. A total 
dose of 70 Gy at 2 Gy per fraction over 7 weeks will be delivered to all gross tumor using a 
shrinking field technique. 
6.1 Dose Specifications: 

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Initial fields: 44 Gy at 2 Gy/fraction
At least 99% of the CTV (clinical target volume, see 6.4 below) will be covered with 
100% of prescription dose (i.e., 44 Gy). At least 99% of the CTV plus margin (PTV1, 
see 6.4 below) will be covered by at least 90% of prescription dose (i.e., 39.6 Gy).
Boost fields: 26 Gy at 2 Gy/fraction
At least 99% of the ITV (internal target volume, see 6.4 below) will be covered with 
100% of prescription dose (i.e., 26 Gy, for a total dose of 70 Gy). At least 99% of the 
ITV plus margin (PTV2) will be covered by at least 90% of the prescription dose (i.e., 
23.4 Gy).
Target coverage may not be compromised in order to spare normal organs at risk 
(OAR). If OAR sparing cannot be achieved with the above coverage specifications, the 
study PI will decide on a case-by-case basis whether the gross tumor can be covered at 
least in part by a lower dose that remains within the standard of care, such as 22 Gy to 
the PTV2 boost volume (for a total 66 Gy) (i.e., ~94% of 70 Gy). 
6.2 Technical Factors
a.
IMRT will be delivered with megavoltage equipment at 6 MV energy.
b. IMRT will be planned and carried according to standard institutional practice and 
guidelines. Typically no more than 5 beams should be used in order to minimize low 
dose lung exposure. 
c.
IMRT planning may not use multicriteria optimization (MCO) so that techniques and 
results of this study will be applicable to institutions that do not have MCO planning 
capability in future trials. However, in cases where only MCO-planned IMRT would 
provide adequate esophagus and OAR sparing without compromising target coverage, 
the study PI will make a determination as to whether this will be allowable. 
d. In patients where respiratory peak-to-peak motion of the tumor exceeds 1.5 cm or if 
needed to meet lung DVH constraints, respiratory gating is permissible and will be 
performed according to institutional practice.
6.3 CT simulation
Custom patient immobilization is required to ensure precise and reproducible positioning. 
All simulations will be done on CT scanners capable of acquiring 4D CT image data sets. 
The slice thickness through tumor-containing regions should be 2.5 mm. The imaging 
session will consist of acquisition of a free-breathing treatment planning CT image data set 
and a 4D CT image data set consisting of 0% to 90% phase CT sets representative of a 
single respiratory cycle, as per individual institutional practice. 

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CT images should be acquired with the application of intravenous contrast for the free 
breathing scan component, unless medically contraindicated. Omission of intravenous 
contrast for non-medical reasons is discouraged but permissible if a diagnostic chest CT 
scan with IV contrast is available to guide the delineation of mediastinal target volume and 
critical normal tissue structures. Oral esophageal contrast may not be used as it can 
interfere with dosimetric calculations. 
Repeat 4D CT scanning during the treatment course to take advantage of tumor regression 
or adjust for anatomical changes including changing esophagus position for adaptive 
purposes is strongly recommended.
6.4 Treatment Planning/Target Volumes
Visible gross tumor should be outlined on each CT slice. For the identification of 
parenchymal lung tumor, lung windows should be used. For the identification of tumor in 
the mediastinum including lymph nodes, an appropriate soft tissue window should be used. 
Interpolation is allowed. 
The use of the average intensity projection of the 4D CT data set as reference scan is 
recommended.
For the purpose of this protocol, the following target volumes are defined:
GTV
The gross tumor volume (GTV) is all known gross disease visible on the 50% 
(exhale) phase of the 4D planning CT modified as necessary based on diagnostic 
CT and PET images. Mediastinal lymph nodes are considered involved if they are 
FDG-avid on PET or biopsy-proven (for example, on mediastinoscopy). Suspicious 
lymph nodes that are PET negative may also be included at the treating physician’s 
discretion, for example if they are > 1 cm in short axis diameter, lie in a predicted 
path of lymphatic spread, or have a necrotic center.
ITV
For the purpose of this protocol, the internal target volume (ITV) will be defined as 
GTV plus internal margin for respiratory tumor motion. Generation of the ITV will 
be performed as per institutional practice. The ITV should encompass all gross 
disease on all respiratory phase and maximum intensity projection (MIP) scans. 
CTV The clinical target volume (CTV) is derived by adding an automatic 5-8 mm margin 
around the ITV for microextension of tumor.  The CTV should be extended beyond 
the automatic margin to include areas of likely subclinical disease, including 
atelectatic lung, postobstructive changes, and likely lymphatic drainage routes. 
However, comprehensive elective nodal irradiation (ENI) is not allowed and careful 
consideration must be given to any increase in lung V5 or V20 that may result from 
an increase in the CTV volume that could limit delivery of the prescription dose to 
the gross tumor. The CTV should be manually constricted if it extends into normal 
tissue structures that do not contain microscopic spread such as lumen of a vessel, 
vertebral body, and esophagus.
PTV1 The planning target volume (PTV) entails a margin that accounts for variations in 
treatment delivery, including variations in setup between treatments. The PTV1 
should be 5 mm around the CTV. Manual editing of PTV is not allowed even if this 

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were to minimize overlap with critical normal tissue structures such as the 
esophagus. 
PTV2  The planning target volume 2 (PTV2) is obtained by adding a 5 mm margin around 
the ITV.  Manual editing of PTV is not allowed even if this were to minimize 
overlap with critical normal structures. 
6.5 Critical Normal Structures 
The following normal tissue structures should be generated for every subject except where 
indicated: 

right and left lung

combined lungs minus ITV

thoracic spinal cord

spinal cord + 5 mm margin

esophagus (entire length),

heart (contour the pericardial sac from the apex of the heart to a level of ~1 cm 
inferior to the pulmonary artery bifurcation), unless all disease is located above the 
heart

left ventricle, unless all disease is located above the left ventricle

ipsilateral brachial plexus, if there is disease above the aortic arch that would 
potentially put the brachial plexus at risk

contralateral esophagus (CE) from 2 cm above the most superior slice that contains 
PTV1/2 to 2 cm inferior to the most inferior slice that contains PTV1/2 – see below
The CE should be contoured as a distinct avoidance structure that will be used as a guideline 
for promoting a steep dose fall-off across sections of the esophagus in close proximity to tumor. 
This is illustrated in Figures 2 and 3 below. On an axial slice, identify the cross-sectional half 
of esophagus that is opposite to the gross tumor. This can be the posterior half, left or right 
half, or oblique half. Figure 2 illustrates examples of CE contours. Figure 3 shows examples 
of CE contours in patients. On slices where the esophagus is located within 1 cm of the ITV, 
the CE should be contoured at least 5 mm away from the ITV edge. This is helpful in order to 
allow a sufficient gap for adequate dose fall-off to occur beyond the ITV. As a result, the CE 
may be reduced to a quarter or less of the esophagus’ cross section in cases where the 
esophagus abuts the ITV. To facilitate planning, it is recommended that the CE does not 
overlap with any PTV. Thus, after creating the 5 mm PTV expansion, the CE may be modified 
by subtracting the PTV volume. There is no minimum size for the CE on an axial slice, hence, 
if after subtracting out the PTV there is only a small sliver of CE or no CE left on a given slice, 
that is allowable though not desirable. The rationale underlying this approach is that tumor 
coverage has always priority over esophagus sparing.

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A
B
C
D
E
F
Figure 2. Illustrated above are examples of the contralateral esophagus contour (solid black outline) in 
relation to gross tumor (red).  In A and B, the CE is drawn opposite to the tumor, resulting in right and left 
lateral contours. In C and D, the CE is drawn posteriorly and anteriorly, respectively. In E and F, the CE is 
drawn in obliquely, given that the tumor “wraps” around the esophagus (gray). In the latter (E/F), the CE 
may be edited to introduce a gap of ~ 5 mm for a steep dose gradient between tumor (70 Gy) coverage and 
the CE (max 55 Gy) (additional black line). Note that the PTV extension around the gross tumor is 5 mm 
and that the minimum dose to the PTV2 is 63 Gy. The PTV should not overlap with the CE. Note that a 
minimum cross section area of the esophagus is not defined as target coverage must be ensured at all times.
Figure 3: This figure illustrates contouring of the CE contours (yellow) in relation to the internal target 
volume (red) and esophagus (green).

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Every effort must be made to respect dose constraints to critical organs at risk (OAR) as outlined 
below. 
Table 3. OAR Dose Constraints 
OARs
Constraints
Deviations 
Combined Lungs 
V5 ≤ 65%
V20 ≤ 35%
V20 ≤ 40%, acceptable if subject 
has excellent lung function
Spinal Cord
max 45 Gy
 No deviations permitted
Spinal Cord + 5mm
V45 ≤ 1%
max 50 Gy
The V45 constraint may only be 
exceeded in cases where gross 
tumor is in close vicinity to the 
spinal cord. 
Brachial Plexus
max 60 Gy
max 66 Gy, acceptable if there is 
gross tumor in close proximity
Heart
V40 ≤ 40%
guideline only
 
max 70 Gy
Left Ventricle
V40 ≤ 10%
max 45 Gy
guideline only
Esophagus
max 72 Gy
V40 ≤ 40%
V60 ≤ 15%
guideline only
Contralateral 
Esophagus (CE)
max 60 Gy 
V55 ≤ 0.5cc
V45 ≤ 2.5cc
max 63 Gy 
V55 ≤ 3.0cc
V45 ≤ 7.5cc
 
deviations from these constraints 
are permitted if otherwise tumor 
coverage would be compromised
All max doses refer to a dose to a 0.03 cc volume
V(dose) refers to the volume that receives at least the indicated dose 
6.6 Treatment Verification
Daily pre-treatment cone beam CT (CBCT) must be obtained. CBCT should be matched 
using the planning CT as reference. Preportal orthogonal kV images are allowed if CBCT is 
not available. Physician review of soft tissue anatomy and target matching at least once per 
week is recommended.
 
6.7 Quality Assurance
Documentation Requirements: per institutional standard, no specific requirements
Compliance Criteria: N/A

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6.8 Radiation Quality Assurance Reviews 
Treatment on protocol follows the standard-of-care for IMRT treatments including physics 
checks and phantom-based verification of monitoring units prior to first treatments. 
6.9 Radiation Adverse Events
Radiation side effects are divided into those that occur acutely (during course of radiation 
therapy and up to 3 months after completion of treatment) and those that occur later (>3 
months post-radiation). Acute side effects are typically common and transient, while late 
normal tissue complications are generally rare but they can be severe and/or permanent. All 
participants will be seen weekly by their treating radiation oncologist while undergoing 
therapy. IMRT with CEST is not expected to be associated with any more side effects than 
normally observed. These are:
 
>10%:
Fatigue
Mild to moderate dermatitis
Mild, moderate, or severe esophagitis
Dry cough
Mild to moderate pneumonitis
1-10%:
Moist desquamation of skin
Stricture of the esophagus
Severe pneumonitis, requiring oxygen support
Severe or permanent dyspnea or hypoxia
Fracture of ribs or vertebral body
Decreased neutrophil count
<1% (serious or life-threatening):
Esophageal obstruction or perforation
Fistula formation
Severe hemoptysis
Pneumonitis requiring ventilation
Myocardial infarction
Constrictive pericarditis
Severe congestive heart failure
Cardiac arrhythmias
Transverse myelitis
Brachial plexopathy
Skin ulceration
Radiation-induced cancer
All adverse events experienced by participants will be collected from the time of the first dose of 

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study treatment, through the study, and until the final study visit. Participants continuing to 
experience toxicity at the off-study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible.
Radiation-related side effects will be managed per clinical standard-of-care.
Consider holding radiation therapy for neutropenia (ANC < 500 cells/mcl) as per routine clinical 
care, because radiation can theoretically lower counts further. Hold radiation therapy for any 
febrile neutropenia. If neutropenia-related treatment break is > 3 days, subject will be removed 
from the primary endpoint analysis because prolonged treatment breaks will reduce the risk of 
severe esophagitis.
Treatment should not be interrupted for grade 2 dermatitis. However, in the case of impending or 
actual grade 3 dermatitis (moist desquamation), treatment breaks cumulatively of up to 3 days 
are allowable. However, should treatment breaks exceed 3 days the subject will be removed from 
the primary endpoint analysis because prolonged treatment breaks will reduce the risk of severe 
esophagitis. The subject may resume radiation once the skin toxicity has resolved to grade 2 or 
less.
6.9.1
Acute esophagitis
Esophagitis is common with combined radiation therapy and chemotherapy. Esophagitis should 
not be reason enough to interrupt or delay daily radiation treatment provided that oral intake is 
sufficient. Subjects will be advised to follow diet restrictions that include avoiding alcoholic, 
acidic, or spicy foods. Subjects should refrain from smoking. Medications for the treatment of 
esophagitis include proton pump inhibitors, a mixture of 2% viscous lidocaine, 
diphenhydramine, aluminum hydroxide/magnesium hydroxide/simethicone, narcotic pain 
medications as needed, and sucralfate suspension on a case-by-case basis. 
Esophagitis will be graded according to the CTCAE v4 as well as the RTOG scoring system. We 
will use both scoring systems to facilitate comparisons with published esophagitis rates.
CTCACE v4
Grade
1
2
3
4
5
Esophagitis
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated
Symptomatic; 
altered 
eating/swallowing; 
oral supplements 
indicated
Severely altered 
eating/swallowing; 
tube feeding, TPN 
or hospitalization 
indicated
Life-
threatening 
consequences; 
urgent 
operative 
intervention 
indicated
Death

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RTOG Scale
Grade
1
2
3
4
5
Esophagitis
Mild 
dysphagia or 
odynophagia, 
requiring 
topical 
anesthetic, 
non-narcotic 
agents or soft 
diet
Moderate 
dysphagia or 
odynophagia, 
requiring 
narcotic agents 
or liquid diet
Severe 
dysphagia or 
odynophagia 
with 
dehydration or 
weight loss 
(>15% of pre-
treatment 
baseline), 
requiring 
nasogastric 
feeding
Complete 
stricture, 
ulceration, 
perforation, or 
fistula
Death
6.10
Radiation Adverse Event Reporting
6.11
Definitions
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment, even if the event is not considered to be related to the study. Abnormal 
laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests. 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that: 

Results in death

Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form.

Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of 
stay). 

Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.

Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to 
prevent one of the outcomes listed above. 
Events not considered to be SAE are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not worsen

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
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

respite care
The severity of the AE should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Expectedness 
Adverse events can be ‘Expected’ or ‘Unexpected.’

Expected Adverse Event 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse 
event list or is included in the Informed Consent as a potential risk. 

Unexpected Adverse Event 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information provided in 
the current adverse event list or is not included in the Informed Consent as a 
potential risk. 
Attribution 

Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment, radiation therapy. Attribution will be assigned 
as follows: 
Definite – The AE is clearly related to the study treatment.
Probable – The AE is likely related to the study treatment.
Possible – The AE may be related to the study treatment.
Unlikely - The AE is doubtfully related to the study treatment.
Unrelated - The AE is clearly NOT related to the study treatment
For the purpose of this study protocol, we will assess all toxicities and events that a 
subject experiences irrespective of etiology, but we will only report AE that are 
possibly, probably, or definitely related to radiation therapy.
6.12 Procedures for AE and SAE Recording and Reporting
Reporting participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study. 
All AEs and SAEs, whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-specific 
case report forms. 
The descriptions and grading scales found in the CTEP Active Version of the NCI 

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Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. The CTEP Active Version of the CTCAE is identified and located on the CTEP 
website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Active Version 
of CTCAE.
6.13 Reporting Requirements
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator. 
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below. 
6.14 Reporting to the Study Sponsor
SAE Reporting
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the 
DF/HCC Overall Principal Investigator on the local institutional SAE form. 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 24 hours of learning of the occurrence. In the 
event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to:
Henning Willers, MD, PI
Tel. 617-726-5184
Fax. 617-726-3603
hwillers@partners.org
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study participation.
Non-SAE Reporting 

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Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.
6.15 Reporting to the Institutional Review Board (IRB)
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS).
6.16 Reporting to the Food and Drug Administration (FDA)
N/A
6.17 Reporting to the NIH Office of Biotechnology Activities (OBA)
N/A
6.18 Reporting to the Institutional Biosafety Committee (IBC)
N/A
6.19 Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy.
6.20 Monitoring of Adverse Events and Period of Observation
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs 
and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report). 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 

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unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study. 
7
DRUG THERAPY
All patients will receive standard concurrent chemotherapy as prescribed by their treating 
medical oncologist. Most common regimens include cisplatin and etoposide, carboplatin and 
paclitaxel and cisplatin/carboplatin and pemetrexed. These regimens when combined with 
radiation are associated with comparable rates of esophagitis (Table 1). Induction chemotherapy 
prior to concurrent chemotherapy and radiation is allowed. Side effects in relation to 
chemotherapy will be managed per standard of care and are not reportable as AE for purposes of 
this trial. In addition, adjuvant therapies within or outside a separate clinical trial are allowed and 
include chemotherapy and immune checkpoint inhibitor therapy at the discretion of the treating 
physicians.
8
SURGERY 
Patients will undergo definitive radiation/chemotherapy. Surgery is not allowed on this protocol
9
CORRELATIVE STUDIES 
9.1 18F-Fluorothymidine-PET (FLT-PET/CT)
 In addition to the study requirements, we would like to include 2 optional FLT-PET/CT scans, 1 
baseline scan within 1 week before treatment start and a mid-treatment scan during treatment 
week 3 (+/- 1 week). The injection dose for 18F- FLT will be not more than 10mCi.  The 
baseline FLT-PET/CT will include an attenuation correction chest CT and the week 3 FLT-
PET/CT will include a diagnostic chest CT.  The total radiation dose from the FLT-PET/CT 
imaging will be approximately 37.51 mSv, equivalent to approximately 12.1 years of normal 
background radiation. 
The difference between these FLT-PET/CT scans and the standard FDG-PET is that the FLT 
tracer has been introduced to specifically image tumor proliferation, while FDG is not 
intrinsically tumor specific and is also taken up by inflammatory cells. FLT is phosphorylated by 
thymidine kinase 1, a key enzyme in the salvage pathway of DNA synthesis. Thymidine Kinase 
1 is up-regulated during the S-phase of the cell cycle; therefore FLT uptake is dependent on cell 
proliferation. It has been shown in lung cancer that FLT correlates better than FDG with the 
proliferation activity, and multiple studies have reported that FLT-PET is useful to measure early 
tumor response to chemotherapeutic agents.  
We hypothesize that FLT-PET/CT can also be used as an early response indicator to concurrent 
chemo-radiation for lung cancer, which could enable personalized treatment approaches 
depending on changes in tumor proliferation.
10 TISSUE/SPECIMEN SUBMISSION

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N/A

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11 PARTICIPANT ASSESSMENTS
Baseline evaluation tests and scans are to be conducted as outlined in Section 4. Assessments 
during radiation therapy should be made once per week. Follow-up assessments should be 
done per routine clinical care as detailed below and obtained within 4 weeks of the protocol-
specified date.
Pre-
Stud
Concurrent radiation/chemotherapy
 
Follow-upef
Weeks
1
2
3
4
5
6
7
Radiation Therapy
X---------------------------------------------------------
Tissue diagnosis
X
Informed consent
X
Historya
X
Physical examb
X
X
X
X
X
X
X
X
X
ECOG performance status 
X
X
X
X
X
X
X
X
X
Laboratory studies c
X
X
X
X
X
X
X
X
X
Toxicity and adverse event 
monitoringd
X
X
X
X
X
X
X
X
Xf
CT chest/abdomen
  X
Xe
FDG-PET scan
X
As clinically 
indicated
FLT-PET/CT scan (optional) 
g
X
X
Brain MRI, or Head CT
X
As clinically 
indicated
a.
History must include smoking status/history, alcohol use, and acid reflux history
b.
Including weight and vital signs include blood pressure, heart rate, oxygen saturation
c.
Laboratory tests may include complete blood count with differential, basic metabolic panel (Na, K, Cl, CO2, 
BUN, creatinine, glucose, calcium), magnesium, liver function tests (albumin, total protein, alkaline 
phosphatase, total and direct bilirubin, ALT, AST). These tests will be up to the discretion of the treating 
medical oncologist depending on chemotherapy regimen and tolerance. These may be obtained only in part or 
less often than once per week. During long-term follow up after chemotherapy laboratory tests are at the 
discretion of the treating physician.
d.    Toxicity assessment must include smoking status, alcohol use, GERD/reflux, supportive medications including 
pain medications needed, intravenous fluids needed.
e.
Follow up visits and scans per routine standard of care. CT scan of the chest generally includes upper abdomen 
with liver and adrenal glands and thus does not require a separate CT abdomen during follow-up. Continue CT 
scans every 3 months (+/- 4 weeks) for year 1 and every 3-4 months for year 2 (+/- 4 weeks), which reflects 
standard-of-care. CT scans outside this schedule, will be allowed if needed per standard of care and will not be 
marked as a minor deviation.
f. 
Subjects who have at least grade 2 esophagitis at the end of the radiation therapy course should be seen at least 
every other week until esophagitis is resolved.
g.    The optional FLT-PET/CT scan will be completed at baseline, within 1 week prior to treatment start and during 
treatment week 3 (+/- 1 week). A pregnancy test will be conducted before the scan for women of child-bearing 
potential.

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12 DATA COLLECTION
The Office of Data Quality (ODQ) will collect, manage, and monitor data for this study. 
The schedule for completion and submission of case report forms (paper or electronic) to the 
ODQ is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with OnCore 
On Study Form
Within 14 days of registration
Treatment Form
Within 10 days of completion of treatment
Toxicity and Adverse 
Event Report Form
Within 10 days of completion of treatment and within 10 days 
of protocol specified follow up visit
Off Treatment/Off Study 
Form
Within 14 days of completing treatment or being taken off 
study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined follow up visit date or 
call
13 STATISTICAL CONSIDERATIONS
13.1
 Study Design/Endpoints Definitions
The historical rate of severe (grade 3+) acute esophagitis in the treatment of locally advanced 
NSCLC or LS-SCLC with radiation and concurrent chemotherapy is in the order of 15-25% 
(Table 1). Grade 3 esophagitis is a serious effect of treatment that can be associated with hospital 
admission, treatment interruptions, and reduced local tumor control and survival. Here, we will 
test a novel esophagus sparing technique (CEST) to reduce the rate of grade 3+ esophagitis. 
Specifically, we hypothesize that CEST will reduce the rate of grade 3+ esophagitis to 5% or less 
in a study cohort of 20 patients with locally advanced NSCLC or LS-SCLC treated with 
definitive IMRT to 70 Gy at 2 Gy/fraction using CEST and concurrent standard-of-care 
chemotherapy. 
Primary endpoint: 
Rate of grade 3+ acute esophagitis occurring during and up to 3 months after the last day of 
radiation therapy using CTCAEv4 
Secondary endpoints:

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1. Rates of acute esophagitis using the historical RTOG scoring scale
2. General toxicities of treatment using CTCAEv4
3. Two-year local and regional failure rates
4. Two-year overall survival rate 
13.2
 Sample Size, Accrual Rate and Study Duration 
In our clinical experience with CEST, the observed rate of grade 3+ acute esophagitis has been 
0%. In contrast, the published rate of grade 3+ esophagitis in this patient population is 15-25%, 
With the primary goal of estimating the rate of grade 3+ acute esophagitis in this study 
population a sample size of 20 subjects was chosen to guarantee that if no more than one subject 
is observed with grade 3+ esophagitis, the one-sided upper limit of the 90% confidence interval 
(CI) would not exceed 20% (exact value 18%). In addition, a sample size of 20 subjects provides 
a two-sided exact binomial 90% CI of (0.25%, 21.6%) for a good grade 3+ esophagitis rate of 
5%.This means that even if we were to observe as many as 3-5 cases of severe esophagitis out of 
20 participants results would still be in keeping with the extent of toxicity that standard-of-care 
treatment produces. Because CEST is designed to reduce the rate of acute esophagitis it is not 
expected that this technique would lead to a rate of grade 3+ esophagitis that is higher than what 
is observed with standard-of-care treatment. Therefore, grade 3+ esophagitis is not defined as a 
dose-limiting toxicity in this protocol.
At MGH and NWH, we see approximately 60 patients with locally advanced, inoperable NSCLC 
or LS-SCLC every year. At least 80% of patients receive concurrent chemotherapy/radiation. We 
anticipate that up to 10 patients may be enrolled onto other high-priority national treatment 
protocols. Of the remaining patients, we estimate that ~50% will be eligible for this study, in 
particular due to the requirement of having gross tumor within 1 cm of the esophagus. We expect 
that 75% of these patients will enroll onto the protocol. Hence, we will accrue ~14 subjects per 
year. We expect that no more than 25% of participants may have unplanned treatment 
interruptions of > 3 days for reasons other than grade 3+ esophagitis, which would lead to 
removal from primary endpoint analysis (see below). These participants will thus have to be 
replaced for the purpose of analyzing the primary endpoint based on a sample size of 20 subjects. 
Therefore, we may need up to ~25 participants, so that up to 2 years will be required to complete 
enrollment. An additional 2-year follow up will be necessary after the last participant enrolled to 
assess locoregional control and survival rates, for a total study duration of 4 years. 
Participants will be removed from study when any of the criteria listed below applies. The reason 
for study removal and the date the participant was removed must be documented in the study-
specific case report form (CRF). Alternative care options will be discussed with the participant. 

Disease progression

Illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant decides to withdraw from the study, or

General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator.
Any subject removed from the study for any of the reasons above will be replaced in order to 

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maintain the sample size of 20 subjects required for the primary endpoint. 
In addition, subjects will be excluded from primary endpoint analysis in the following scenarios:

Treatment interruption for any reason other than acute esophagitis resulting in a break of 
> 3 radiation treatment days. This includes treatment-associated toxicity other than 
esophagitis.

Less than full chemotherapy given concurrently with radiation therapy:
- only 1 cycle of cisplatin and etoposide (given every 3 or 5 weeks) received concurrently
- only 1 cycle of  cisplatin or carboplatin and pemetrexed (given every 3 weeks) received 
concurrently
- only 1-4 cycles of carboplatin/paclitaxel (once weekly) received concurrently
Subjects removed from primary endpoint analysis for these reasons will remain on study and will 
still be analyzable for secondary endpoints 2-4. Subjects will be replaced in order to maintain the 
sample size of 20 subjects. Based on our own clinical experience, it is estimated that no more 
than 1 in 4 subjects will experience treatment toxicity other than esophagitis (such as severe 
neutropenia) that warrants treatment interruption or will receive less than full dose chemotherapy 
or have any other reasons for withdrawal from protocol therapy.
13.3
Stratification Factors
Not applicable
13.4
Interim Monitoring Plan
Not applicable 
13.5
Analysis of Primary Endpoints
Determination of number of patients with grade 3 or higher acute esophagitis according to 
CTCAEv4. Exact binomial confidence intervals will be calculated for grade 3+ esophagitis and 
other toxicities of interest.
13.6
Analysis of Secondary Endpoints
1. Rates of acute esophagitis using the historical RTOG scoring scale:
Determination of number of patients with grade 3 or higher acute esophagitis according to 
RTOG. 
2. General toxicities of treatment using CTCAEv4
Determination of number of patients with grade 3 or higher toxicities according to 
CTCAEv4. 
3. Two-year local and regional failure rates 

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Crude frequencies and rates of isolated local and regional recurrence, as defined below, will 
be calculated. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline. Changes in 
the diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria.
Measurable disease: Measurable disease is the presence of at least 1 lesion that can be 
accurately measured in at least one dimension with longest diameter > 10 mm with spiral CT 
scan. Measurable lesions must be at least 2 times the slice thickness in mm. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Target lesions: The primary lung tumor and the hilar/mediastinal lymph nodes judged as 
involved should be identified as the target lesions and recorded and measured at baseline and 
with each follow-up imaging evaluation. The longest diameter (LD) of the target lesions will be 
calculated from the pre-treatment diagnostic chest CT scan with IV contrast, using pulmonary 
windowing for the primary tumor soft tissue windowing for involved lymph nodes, and reported 
as the baseline LD. The baseline LD will be used as a reference by which to characterize the 
objective tumor response. Local treatment effects in the vicinity of the tumor target may make 
determination of tumor dimensions difficult. For example, bronchial or bronchiolar damage may 
cause patchy consolidation around the tumor that over time may coalesce with the residual 
tumor. In cases in which it is indeterminate whether consolidation represents residual tumor or 
treatment effect, a PET/CT scan should be obtained for further characterization. If findings 
remain indeterminate, it should be assumed that the observed abnormalities represent residual 
tumor.
Non-target lesions: All other lesions, including small lesions < 10 mm and truly non-
measurable lesions.
Response Criteria: 
Complete Response (CR): Disappearance of all target lesions; this will be made based on CT 
image evaluation.
Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD; ideally, this will be made based on CT image evaluation.
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions  (new lesions must be > slice thickness). Ideally, this determination will be 
made based on CT image evaluation. If the criteria for PD are met, the patient should undergo 
either PET scan imaging and/or a direct biopsy of the targeted tumor for evaluation as to whether 
local or regional failure exists as defined below. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started.
Local failure (LF): Refers to the primary treated tumor after protocol therapy and corresponds to 
meeting both of the following two criteria: 
(1) Increase in tumor dimension of 20% as defined as an increase in the sum of diameters of 

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target lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study) following RECIST criteria. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance 
of one or more new lesions within the ITV is also considered progression). 
(2) The measurable tumor with criteria meeting PD should be avid on PET imaging with uptake 
of a similar intensity as the pretreatment staging PET, or the measurable tumor should be 
biopsied confirming viable carcinoma. 
Marginal failure, i.e., PET-positive or biopsied measurable tumor within 1 cm of the PTV, will 
be counted as LF. The EORTC criteria for post-treatment PET evaluation may be used as a basis 
for evaluation in cases more difficult to assign as to whether the uptake is pathologic for cancer 
recurrence vs. inflammation. It will be necessary to measure the distance of site of failure from 
the esophagus. 
Regional failure (RF): This is defined as progression of nodal target lesions or the appearance 
of non-target lesions in either hilum, the mediastinum, or supraclavicular fossa. The measurable 
tumor with criteria meeting PD should be avid on PET imaging with uptake of a similar intensity 
as the pretreatment staging PET, or the measurable tumor should be biopsied confirming viable 
carcinoma. It will be important to measure the distance the failure occurs from the esophagus. 
Distant failures (DF): This will be disease progression in sites not included as LF or RF above. 
Diagnosis will be made by CT, PET, or MRI as per clinical protocol. If imaging findings are not 
definitive biopsy confirmation is recommended. 
4. Two-year overall survival (OS) rate 
Follow-up time will be calculated from the date of registration to the date of death or the last 
follow-up date on which the patient was reported alive. OS rates will be estimated using the 
Kaplan-Meier method. 
State of patient at last follow up – This refers to the state of the patient at the last follow up on 
the study. This will be scored as alive, dead (if dead, state cause of death), or lost to follow up. 
13.7
Reporting and Exclusions
Reporting will take place at two separate time points. Initially, reporting on esophagitis will 
occur within 3 months of the last study patient completing radiation therapy. After two years of 
minimum follow up, an additional report will include local failure, regional failure, and overall 
survival. 
Participants who never start protocol therapy are excluded (“inevaluable”) from analyses. 
Participants who are removed from primary endpoint analysis for reasons specified above will be 
eligible for secondary endpoint analyses. 
13.8
Evaluation of Toxicity
All participants will be evaluable for toxicity from the time of their first treatment.

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13.9
Evaluation of the Primary Efficacy Endpoint
Not applicable
14
REGULATORY CONSIDERATIONS
14.1
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
14.2
Multicenter Guidelines
NA
14.3
Collaborative Agreements Language
NA
14.4
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant
information related to the study (e.g., advertisements used to recruit participants) and
any other necessary documents must be submitted, reviewed and approved by a
properly constituted IRB governing each study location.
Any changes made to the protocol must be submitted as amendments and must be
approved by the IRB prior to implementation. Any changes in study conduct must be
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair)
will disseminate protocol amendment information to all participating investigators.

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All decisions of the IRB concerning the conduct of the study must be made in
writing.
14.5
Informed Consent 
All participants must be provided a consent form describing this study and
providing sufficient information for participants to make an informed decision
about their participation in this study. The formal consent of a participant, using
the IRB approved consent form, must be obtained before the participant is
involved in any study-related procedure. The consent form must be signed and
dated by the participant or the participant ’s legally authorized representative, and
by the person obtaining the consent. The participant must be given a copy of the
signed and dated consent document. The original signed copy of the consent
document must be retained in the medical record or research file.
14.6 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice:

E6 Good Clinical Practice: Consolidated Guidance
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf

US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki
Title 21 Part 11 – Electronic Records ; Electronic Signatures
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html
Title 21 Part 50 – Protection of Human Subjects
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html
Title 21 Part 54 – Financial Dis closure by Clinical Investigators
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html
Title 21 Part 56 – Institutional Review Boards
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html
Title 21 Part 312 – Investigational New Drug Application
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html

State Laws

DF/HCC research policies and procedures
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unitcru/policies-
and-procedures/
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.

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14.7
Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified.
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.
14.8 
Records Retention 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.
15 PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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NCI Protocol #:
DF/HCC Protocol #: 15-023
Protocol Version Date:  22 August 2017  
40 
22 August 2017 
APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.