Patient-Reported Outcomes Following Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer: A Randomized Trial Comparing Two Radiotherapy Schedules
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Albert Einstein College of Medicine

Title:  Patient-Reported Outcomes following 
Chemoradiotherapy for Locally Advanced Non-small Cell 
Lung Cancer
NCT03481114
IRB#:  2017-8065
IRB Approval Date:  11/22/2019
IRB NUMBER: 2017-8065
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IRB APPROVAL DATE: 11/22/2019
IRB APPROVAL DATE: 11/22/2019
IRB APPROVAL DATE: 11/22/2019

Patient-Reported Outcomes following 
Chemoradiotherapy for Locally 
Advanced Non-small Cell Lung Cancer: A 
Randomized Trial Comparing Two 
Radiotherapy Schedules
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.
Principal Investigator
Nitin Ohri, MD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 610
Bronx, NY 10461
Phone: 718-920-7750
Fax: 718-430-8618
Email: nohri@montefiore.org
Co-Investigators (Radiation Oncology)
Madhur Garg, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
William Bodner, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
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Fax: 718-882-6914
Rafi Kabarriti, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Jana Fox, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Keyur Mehta, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Co-Investigators (Medical Oncology)
Balazs Halmos, MD
Montefiore Medical Park at Eastchester
1695 Eastchester Road
Bronx, NY 10461
Phone: 718-405-8404
Fax: 718-405-8433
Email: bahalmos@montefiore.org 
Haiying Cheng, MD, PhD
Montefiore Medical Center
Montefiore Medical Park at Eastchester
1695 Eastchester Road
Bronx, NY 10461
Phone: 718-405-8505
Fax: 718-405-8501
Email: hcheng@montefiore.org 
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Roman Perez-Soler, MD
Montefiore Medical Center
Department of Oncology, Hofheimer 100
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-920-4826
Fax: 718-798-7474
Email: rperezso@montefiore.org
Rasim Gucalp, MD
Montefiore Medical Center-Moses Division
Department of Oncology, Hofheimer 100
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-920-4826
Fax: 718-798-7474
Email: rgucalp@montefiore.org
Co-Investigators (Nuclear Medicine)
Tony Abraham, DO
Montefiore Medical Park
1695A Eastchester Road
Bronx, NY 10461
Tel: 718-405-8461
Fax: 718-824-0830
Email : toabraha@montefiore.org 
Co-Investigators (Statistics)
Shankar Viswanathan, DrPH, MSc
Albert Einstein College of Medicine
1300 Morris Park Avenue, Belfer 1312D
Bronx, New York 10461
Phone: 718-430-3762
Fax: 718-430-8780
Email: shankar.viswanathan@einstein.yu.edu
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SCHEMA
50 subjects will be stratified by performance status (2 v. 0-1) and primary tumor size (>4 
cm v. ≤ 4 cm) and then will be randomized 1:1 between the two study arms.
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Abbreviations
ACRIN
American College of Radiology Imaging Network
AE
Adverse Event
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the curve
BSA
Body surface area
chemoRT
Chemoradiotherapy
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTV
Clinical Target Volume
DFS
Disease-free survival
ECOG
Eastern Cooperative Oncology Group
EQD2
Equivalent dose in 2-Gy fractions
FEV1
Forced expiratory volume
Fx
Fractions
FDG
Fludeoxyglucose
GFR
Glomerular filtration rate
GTV
Gross tumor volume
Gy
Gray
IMRT
Intensity modulated radiotherapy
ITV
Internal target volume
IV
Intravenous
LA-NSCLC
Locally-advanced non-small cell lung cancer
LRC
Locoregional control
MTV
Metabolic tumor volume
NSCLC
Non-small cell lung cancer
OS
Overall survival
PET
Positron emission tomography
PHI
Protected health information
PI
Principal investigator
PO
By mouth
PTV
Planning target volume
RECIST
Response Evaluation Criteria in Solid Tumors
RT
Radiotherapy
RTOG
Radiotherapy Oncology Group
Rx
Prescription
SAE
Serious adverse event
SUV
Standardized uptake value
ULN
Upper limit of normal
VMAT
Volumetric modulated arc therapy
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Contents
1.0 OBJECTIVES .............................................................................................................8
1.1 Primary Objective....................................................................................................8
1.2 Secondary Objectives .............................................................................................8
2.0 BACKGROUND..........................................................................................................8
2.1 Locally-advanced Non-small Cell Lung Cancer (LA-NSCLC) .................................8
2.2 PET Imaging for LA-NSCLC....................................................................................9
2.3 Patient-Reported Outcomes..................................................................................13
3.0 PATIENT ELIGIBILITY .............................................................................................14
3.1 Inclusion Criteria....................................................................................................14
3.2 Exclusion Criteria ..................................................................................................15
4.0 STUDY DESIGN.......................................................................................................15
4.1 General Design .....................................................................................................15
4.2 Study Calendar......................................................................................................16
4.3 Primary Endpoint...................................................................................................16
4.4 Secondary Endpoints ............................................................................................16
5.0 STUDY THERAPY....................................................................................................16
5.1 Radiotherapy.........................................................................................................17
5.2 Concurrent Chemotherapy....................................................................................20
5.3 Adjuvant Therapy ..................................................................................................21
5.4 Treatment Modifications........................................................................................21
6.0 RESPONSE ASSESSMENT ....................................................................................26
7.0 STATISTICAL CONSIDERATIONS..........................................................................26
7.4 Subject Accrual .....................................................................................................27
8.0 REGULATORY CONSIDERATIONS........................................................................27
8.1 Protection of Human Subjects...............................................................................28
8.2 Compliance with the Protocol and Protocol Revisions..........................................28
9.0 DATA HANDLING AND RECORD KEEPING ..........................................................28
9.1 Confidentiality........................................................................................................28
9.2 Source Documents................................................................................................29
9.3 Case Report Forms...............................................................................................29
10.0 DATA SAFETY AND MONITORING BOARDS......................................................29
11.0 ADVERSE EVENTS ...............................................................................................30
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11.1 Adverse Event Definitions ...................................................................................30
11.2 Adverse Event Reporting ....................................................................................31
12.0 REFERENCES .......................................................................................................33
13.0 APPENDICES.........................................................................................................36
13.1 Appendix A – Eligibility Checklist ........................................................................36
13.2 Appendix B – Common Toxicity Criteria..............................................................38
13.3 Appendix C – ECOG Performance Status ..........................................................39
13.4 Appendix D – AJCC Lung Cancer Staging (7th Edition) ......................................40
13.5 Appendix E – PRO-CTCAE Assessment Tool ....................................................41
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1.0 OBJECTIVES
1.1 Primary Objective

To characterize patient-reported outcomes during and after concurrent 
chemoradiotherapy for locally-advanced non-small cell lung cancer.
1.2 Secondary Objectives

To compare patient-reported outcomes observed during and after treatment with 
PET-based, dose-painted, accelerated chemoradiotherapy against patient-
reported outcomes observed during and after treatment with standard 
chemoradiotherapy for locally-advanced non-small cell lung cancer. 

To compare physician-reported adverse event rates during and after treatment 
with PET-based, dose-painted, accelerated chemoradiotherapy against 
physician-reported adverse event rates during and after treatment with standard 
chemoradiotherapy for locally-advanced non-small cell lung cancer. 

To compare clinical outcomes (local disease control, progression-free survival, 
and overall survival) following dose-painted, accelerated chemoradiotherapy 
against clinical outcomes after treatment with standard chemoradiotherapy for 
locally-advanced non-small cell lung cancer.

To explore associations between radiotherapy doses delivered to normal 
structures and declines in patient-reported outcomes.
2.0 BACKGROUND
2.1 Locally-advanced Non-small Cell Lung Cancer (LA-NSCLC)
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in 
the United States and worldwide, causing nearly one million deaths each year1.  
Approximately one-third of NSCLC patients are diagnosed with locally-advanced 
disease, which may be defined as unresectable stage II disease or stage III disease2.  
For locally-advanced non-small cell lung cancer (LA-NSCLC), the standard treatment 
approach is conventionally-fractionated (1.8-2.0 Gy/day) radiotherapy to a dose of 
approximately 60-66 Gy with concurrent, platinum-based chemotherapy. This treatment 
approach, however, yields median survival times of only 16-30 months. Randomized 
trials have tested changes or additions to systemic therapy3-7, radiotherapy dose 
escalation6, and the addition of surgical resection8 but have failed to improve outcomes 
for this patient population.
Toxicities of thoracic chemoradiotherapy include acute esophagitis, radiation 
pneumonitis, and increased risk of cardiac events. The risk and severity of these 
complications is directly related to the extent of normal tissue irradiation9-12. Acute 
esophagitis can dramatically impair patients’ quality of life and lead to hospitalizations 
and treatment interruptions that reduce treatment efficacy13,14.  Recent high-profile 
analyses demonstrate that, even when modern radiotherapy planning techniques are 
utilized, incidental cardiac irradiation significantly increases the risk of death following 
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treatment of LA-NSCLC with chemoradiotherapy6,15,16. Strategies to reduce irradiation of 
normal tissues during the treatment of LA-NSCLC can therefore be expected to improve 
patients’ quality of life and prolong survival.
2.2 PET Imaging for LA-NSCLC
FDG-PET/CT imaging is recommended as part of the staging workup for most 
patients with suspected or newly-diagnosed NSCLC.  Depending on the presumed 
stage based on clinical findings and anatomic imaging, PET leads to upstaging in 12-
21% of patients17-19.  Implementation of PET imaging may somehow alter the 
management of NSCLC patients in up to 40% of cases18,20,21.  
Beyond its use as a staging tool, PET may provide meaningful prognostic 
information for LA-NSCLC patients treated with chemoradiotherapy. In a multi-
institutional trial (ACRIN 6668 / RTOG 0235), post-treatment PET findings (maximum or 
peak SUV) were found to predict locoregional disease progression and overall 
survival22. In a secondary analysis of that study, we found that pre-treatment disease 
burden, measured as total metabolic tumor volume (MTV), was also a powerful 
predictor of clinical outcomes23.  Additionally, we found that individual tumors or lymph 
nodes with high MTV before treatment were most likely to retain high levels of activity 
after chemoradiotherapy. Using data from Montefiore/Einstein, we found that MTV may 
be used to identify specific tumors or lymph nodes at risk for progression following 
chemoradiotherapy24. We then validated these findings in a separate patient cohort25.  
Of note, we found no evidence that the use of relatively high radiotherapy doses would 
improve local control rates for large lesions and no evidence that the use of relatively 
low doses would reduce local control rates for small lesions.
Cumulative incidence rates of local disease progression in lesions with low MTV (left) and high MTV 
(right) in 89 LA-NSCLC subjects treated with concurrent chemoradiotherapy at Montefiore/Einstein.
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Scatterplot of radiation therapy dose 
(PTV D90, or minimum dose that 
encompassed at least 90% of target 
volume) versus MTV. MTV is plotted 
on a logarithmic scale. Squares 
represent primary tumors, and circles 
denote lymph nodes. Lesions that 
were the first site of disease 
progression are shaded in black
.
Based on our findings that in-field disease progression nearly always occurs in 
lesions with high MTV, we performed a prospective study entitled “The PET-Adjusted 
IMRT for NSCLC Trial (PAINT, NCT02073968)”. Patients with inoperable stage IIB-III 
NSCLC and ECOG performance status 0-2 who underwent staging PET were eligible 
for this single-arm study.  All patients were treated with a 25-fraction course of dose-
painted IMRT over 5 weeks. Tumors or lymph nodes with MTV exceeding 25 cc were 
deemed “high risk” and received 65 Gy.  Lesions smaller than 25 cc were considered 
“low risk” and treated with 57 Gy until November 2014, when the study was amended to 
reduce the prescription dose for such lesions to 52.5 Gy.  All patients received 
concurrent weekly carboplatin (AUC 2) and paclitaxel (45-50 mg/m2) during 
radiotherapy, and adjuvant chemotherapy with the same agents was optional.  Patients 
underwent post-treatment PET 12-16 weeks after completion of IMRT.  The primary 
study endpoint was the absence of high residual metabolic activity (maximum SUV > 6) 
in the lungs and regional lymph nodes on post-treatment PET. Thirty-five enrolled 
subjects with 116 hypermetabolic tumors and lymph nodes were eligible for analysis.  
The primary endpoint was met for 24/30 patients (80%) who underwent post-treatment 
PET, satisfying our pre-specified efficacy objective. Median overall survival duration for 
all subjects was 22.5 months, and median survival for subjects with performance status 
0-1 has not yet been reached. Treating progression in other sites and death without 
disease progression as competing risks, the two-year cumulative incidence rate of local 
disease progression in the 25 high-risk lesions was 9%. The two-year cumulative 
incidence rate of local disease progression in the 91 low-risk lesions that were treated 
with a low radiotherapy dose was only 3%. These results will be reported in an oral 
presentation at the ASTRO 2017 Annual Meeting.
In this study, we will shorten the radiotherapy course for patients receiving dose-
painted IMRT to 20 fractions over 4weeks. A 20 fraction radiotherapy course is standard 
in some countries26. This shortened course will be more convenient for our patients and 
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can be expected to improve treatment compliance14,27. Accelerated radiotherapy may 
also be ideal for future studies incorporating radiotherapy and immunotherapy, as long 
radiotherapy courses are expected to suppress antitumor immune responses28. We will 
define high v. low-risk lesions using a slightly more conservative MTV cutoff (20 cc) than 
we previously used, based on tumor control probability modeling results25 and the fact 
that we have observed local progression in 2/14 lesions with MTV between 20 and 25 
cc (unpublished data from our 93 patient LA-NSCLC database).
Rationale for 2019 Amendment Lowering the Radiotherapy Dose for Low-Risk Lesions
Based on promising interim study results as well as emerging literature 
supporting selective radiotherapy de-intensification for LA-NSCLC, we are amending 
this protocol to reduce the dose delivered to low-risk tumors and lymph nodes from 48 
Gy to 44 Gy.
As of July 2019, 24 study subjects have completed radiotherapy. Ten of those 
subjects were randomized to receive dose-painted IMRT.  Three of those subjects have 
experienced disease recurrence. One subject developed small bilateral lung metastases 
seven months after completing radiotherapy, one subject was found to have brain 
metastases ten months after completing radiotherapy, and one developed rib 
metastases two months after completing radiotherapy. Local disease progression in a 
tumor or lymph node targeted with dose-painted radiotherapy has not occurred. Only 
one subject on the dose-painted IMRT arm has died. He experienced a fatal stroke 20 
months after completing radiotherapy and had no evidence of recurrent lung cancer at 
that time. The 12-month actuarial progression-free survival rate for the dose-painted 
IMRT arm is 55%, which compares favorably to the 25% 12-month progression-free 
survival rate that was seen in our PAINT trial29.
The excellent disease control rates observed so far in the present study are likely 
related to the recent introduction of adjuvant immunotherapy (durvalumab) after 
chemoradiotherapy. In a landmark randomized trial, durvalumab was shown to 
significantly improve rates of distant metastasis, local disease recurrence, overall 
disease progression, and death30,31. This development strengthens the argument for 
selective radiotherapy de-intensification in the modern era. In fact, recent data from our 
institution demonstrates that durvalumab may be particularly beneficial for subjects who 
receive conservative doses of radiotherapy, which has known immunosuppressive 
effects32-34:
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0
2
4
6
8
10
12
Time after RT Completion (months)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival (%)
12
10
7
# at Risk:
27
18
15
# at Risk:
Logrank p = 0.0187
Adjuvant durvalumab, Low EDRIC (n=18)
No durvalumab, Low EDRIC (n=33)
0
2
4
6
8
10
12
Time after RT Completion (months)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival (%)
11
5
1
# at Risk:
23
14
9
# at Risk:
Logrank p = 0.755
Adjuvant durvalumab, High EDRIC (n=14)
No durvalumab, High EDRIC (n=36)
Montefiore-Einstein data suggesting that adjuvant durvalumab may be particularly beneficial for patients 
who receive a low Estimated Dose of Radiation to Immune Cells (EDRIC).  EDRIC is a function of 
radiotherapy course duration and the dose delivered to the heart, lungs, and whole body35.
As expected, we are observing that reducing the radiotherapy dose delivered to 
thoracic organs is associated with improved patient-reported outcomes (examples 
below). These gains should be enhanced by reducing the dose-painted radiotherapy 
dose for low-risk lesions to 44 Gy.
0
5
10
15
20
25
30
35
Esophagus Mean Dose (Gy)
None
Mild
Moderate
Severe
Very Severe
Worst Score
In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its WORST?
Control Arm
Dose Painting Arm
2
4
6
8
10
12
14
16
18
20
22
Lung Mean Dose (Gy)
Not at all
A little bit
Somewhat
Quite a bit
Very Much
Worst Score
In the last 7 days, how much did your SHORTNESS OF BREATH INTERFERE with your usual or daily activities?
Control Arm
Dose Painting Arm
 
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Regimen
Description
EQD2 – Tumor
EQD2 - Normal Tissues
RTOG 0617: Control Arm
2.0 Gy x 30 = 60 Gy
(6 weeks)
55.5 Gy
60.0 Gy
PAINT: Low-risk lesions 
(MTV<25 cc)
2.1 Gy x 25 = 52.5 Gy
(5 weeks)
49.9 Gy
53.6 Gy
PAINT: High-risk lesions 
(MTV>25 cc)
2.6 Gy x 25 = 65 Gy
(5 weeks)
68.3 Gy
72.8 Gy
Present Trial: Low-risk lesions 
(MTV<20 cc)
BEFORE 2019 AMENDMENT
2.4 Gy x 20 = 48 Gy
(4 weeks)
48.8 Gy
51.8 Gy
Present Trial: Low-risk lesions 
(MTV<20 cc) 
AFTER 2019 AMENDMENT
2.2 Gy x 20 = 44 Gy
(4 weeks)
43.0 Gy
45.8 Gy
Present Trial: High-risk lesions 
(MTV>20 cc)
2.75 Gy x 20 = 55 Gy
(4 weeks)
59.4 Gy
63.3 Gy
Proposed dosing schedules for high- and low-risk lesions, defined by MTV on pre-treatment PET/CT 
imaging. EQD2 refers to biologically equivalent dose, calculated using the Linear Quadratic Model36,37 
(α/β=10 Gy and potential doubling time=5.6 days for tumor, α/β=3 Gy for normal tissues)
2.3 Patient-Reported Outcomes
Patient-reported outcomes are becoming the standard tool for evaluating health-
related quality of life, treatment preferences, and treatment quality assessment38. They 
may be particularly important in studies involving radiotherapy for NSCLC. This is 
exemplified by the results of RTOG 0617, which was a multi-institutional randomized 
trial testing uniform radiotherapy dose escalation (including all tumors and regional 
lymph nodes) with concurrent chemotherapy for LA-NSCLC. Dose escalation from 60 
Gy to 74 Gy was unexpectedly found to increase the risk of mortality, with median 
overall survival durations of 29 months with the standard dose of 60 Gy and only 20 
months for subjects treated with 74 Gy6. Investigators found no statistically significant 
differences in serious (grade ≥ 3) adverse events between radiotherapy dose groups, 
demonstrating the disconnect between physician-scored toxicity and important clinical 
outcomes. Impairments in patient-reported quality of life, on the other hand, occurred 
more frequently in the high dose radiotherapy arm39. Additionally, baseline quality of life 
score was found to be a powerful predictor of overall survival.
The National Cancer Institute recently developed the Patient-Reported Outcomes 
Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)40. The 
PRO-CTCAE item library is comprised of 78 symptomatic adverse events, each of 
which is elicited using between one and three questions (representing frequency, 
severity, and/or interference), for a total of 124 individual questions. For any given 
clinical trial, relevant PRO-CTCAE items can be selected from the online library to 
create a concise patient questionnaire that has been validated in several languages. 
This promising tool has not yet been utilized extensively in chemoradiotherapy trials for 
NSCLC. One recent study demonstrated the extent to which CTCAE and PRO-CTCAE 
findings may differ in this setting41.  As an example, clinicians using CTCAE reported 
that high-level anxiety occurred in 0/130 subjects.  PRO-CTCAE demonstrated that 
28/120 subjects had high-level anxiety. Large differences between CTCAE and PRO-
CTCAE were observed for several other adverse events, including anorexia, cough, 
dysphagia, fatigue, and pain.
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We have developed a concise PRO-CTCAE tool that includes the elements that 
are likely most relevant to LA-NSCLC patients who are treated with chemoradiotherapy 
(Appendix). Patient-reported outcomes for each of these elements might be improved 
with the use of dose-painted radiotherapy compared to standard radiotherapy in this 
setting. 
3.0 PATIENT ELIGIBILITY
3.1 Inclusion Criteria

Pathologically proven (either histologic or cytologic) diagnosis of NSCLC with any 
of the following stages (according to the AJCC Staging Manual, 7th edition, 
Appendix):
o
Stage IIIA or IIIB 
o
Stage II NSCLC with contraindication to curative surgical resection
o
Stage IV disease with solitary brain metastasis that has been treated 
radically (eg: with surgical resection and/or stereotactic radiosurgery) and 
thoracic disease that would be classified as stage II-III 

Appropriate diagnostic/staging workup, including:
o
Complete history and physical examination
o
PET/CT within 42 days prior to study entry demonstrating hypermetabolic 
pulmonary lesion(s) and/or thoracic lymph node(s). If PET/CT was 
obtained more than 42 days prior to study entry and is not repeated, chest 
CT within 28 days prior to study entry demonstrating stable disease is 
required.
o
MRI of the brain or head CT with contrast within 42 days prior to study 
entry
o
Biopsy confirmation of suspected metastatic disease identified by PET/CT 
is recommended.
o
PFTs within 6 weeks of study entry are recommended but not required.

No prior chemotherapy or thoracic radiotherapy for lung cancer

ECOG Performance Status 0-2 (Appendix)

Age > 18

Able to read and write in one of the following languages, in which the PRO-
CTCAE tool is available: English, Danish, German, Italian, Japanese, Korean, 
Spanish

Laboratory studies obtained within 28 days prior to study entry demonstrating 
adequate bone marrow and end organ function defined as:
o
Absolute neutrophil count (ANC) >1,500 cells/µl
o
Platelets > 100,000 cells/µl
o
Hemoglobin > 9.0 g/dl (Note: The use of transfusion or other intervention 
to achieve Hgb > 9.0 g/dl is acceptable.)
o
Total bilirubin < 3.0 times the institutional Upper Limit of Normal (ULN)
o
AST and ALT < 3.0 x the ULN
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o
Serum creatinine < 1.5 x ULN or calculated creatinine clearance ≥ 50 
ml/min (by Cockroft-Gault formula)

Women of childbearing potential must:
o
Have a negative serum or urine pregnancy test within 72 hours prior to the 
start of study therapy
o
Agree to utilize an adequate method of contraception throughout 
treatment and for at least 4 weeks after study therapy is completed 
o
Be advised of the importance of avoiding pregnancy during trial 
participation and the potential risks of an unintentional pregnancy.

All patients must sign study specific informed consent prior to study entry.
3.2 Exclusion Criteria

Pleural or pericardial effusion
o
A patient with pleural effusion may be enrolled the effusion is sampled by 
thoracentesis and cytology is negative or the effusion is seen on axial 
imaging but not on chest x-ray and deemed too small to tap under CT or 
ultrasound guidance.

Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) 
for treatment of either a psychiatric or physical (e.g., infectious) illness

Women who 
o
are unwilling or unable to use an acceptable method to avoid pregnancy 
for the entire study period and for at least 4 weeks after cessation of study 
therapy
o
have a positive pregnancy test at baseline
o
are pregnant or breastfeeding

Poorly controlled diabetes (defined as fasting glucose level > 200 mg/dL) despite 
attempts to improve glucose control by fasting duration and adjustment of 
medications.  Patients with diabetes will preferably be scheduled for PET/CT 
imaging in the morning, and instructions for fasting and use of medications will be 
provided in consultation with the patients’ primary physicians
4.0 STUDY DESIGN
4.1 General Design
Subjects will undergo standard evaluations, detailed in the Study Calendar, prior 
to enrollment, during treatment, and after treatment. Additionally, patient-reported 
outcomes will be assessed periodically using the PRO-CTCAE tool.
Upon study enrollment, subjects will be randomized to receive PET-based, dose-
painted, accelerated chemoradiotherapy versus standard chemoradiotherapy. Patients 
receiving standard radiotherapy will receive a total dose of 60 Gy in 30 fractions over 6 
weeks, delivered to all involved lesions (tumors and lymph nodes). For patients 
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receiving PET-based, dose-painted, accelerated chemoradiotherapy, lesions with MTV 
exceeding 20 cc will be treated with 55 Gy in 20 fractions over 4 weeks, while lesions 
with MTV below 20 cc will receive 44 Gy in 20 fractions over the same 4 weeks.
All subjects will receive standard weekly doses of carboplatin (AUC 2) and 
paclitaxel (50 mg/m2) during radiotherapy.  This may be followed by adjuvant systemic 
therapy, at the discretion of the treating physicians. The recommended adjuvant 
chemotherapy regimen is 3 cycles of full dose adjuvant carboplatin (AUC 6) and 
paclitaxel (200mg/m2) every 3 weeks, but another regimen may be selected by the 
treating physicians. 
4.2 Study Calendar
* - Approximate     
^ - May be replaced by CT
** - Only for subjects receiving standard radiotherapy
^^ - Optional
For subjects receiving adjuvant immunotherapy after radiotherapy completion or salvage therapy for 
disease recurrence, the type and timing of restaging imaging studies will be left to the discretion of the 
treating physicians and may deviate from the Study Calendar.
4.3 Primary Endpoint

PRO-CTCAE adverse events with score ≥ 3, observed 6 weeks after initiation of 
chemoradiotherapy
4.4 Secondary Endpoints

Locoregional progression-free survival: the interval from study registration to date 
of local or regional disease progression or death, censored at the date of data 
collection

Progression-free survival: the interval from study registration to date of disease 
progression or death, censored at the date of data collection

Overall survival: the interval from study registration to death, censored at the 
date of data collection

Grade 3-5 adverse events, scored using CTCAE v. 4

PRO-CTCAE adverse events with score ≥ 3 at any time

PRO-CTCAE adverse events with any score
5.0 STUDY THERAPY
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5.1 Radiotherapy
5.1.1 Immobilization, Simulation, and Localization
Patients will be positioned in a stable position capable of allowing accurate 
reproducibility of the target position from treatment to treatment. A variety of 
immobilization systems may be used, including stereotactic frames that surround the 
patient on three sides and large rigid pillows (conforming to patients’ external contours) 
with reference to the stereotactic coordinate system.  Patient immobilization must be 
reliable enough to ensure that the gross tumor volume (GTV) does not deviate beyond 
the confines of the planning treatment volume (PTV) with any significant probability (i.e., 
< 5%).
Special considerations will be made to account for the effect of internal organ 
motion (e.g., breathing) on target positioning and reproducibility. Acceptable maneuvers 
include reliable abdominal compression, accelerator beam gating with the respiratory 
cycle, active breath-holding techniques, and use of 4D simulation CT to generate 
internal target volumes (ITVs).  Internal organ inhibition maneuvers must be reliable 
enough to ensure that the GTV does not deviate beyond the confines of the PTV with 
any significant probability (i.e., < 5%).
Computed tomography will be the primary image platform for targeting and 
treatment planning. Axial acquisitions with gantry 0 degrees and spacing ≤ 3.0 mm 
between scans in the region of the tumor are required Images will be transferred to the 
treatment planning system for radiotherapy planning.
Isocenter or reference point port localization images (anterior/posterior and 
lateral) should be obtained immediately before each treatment to ensure proper 
alignment of the geometric center (isocenter) of the simulated fields.  Verification CT 
scans and portal films following each treatment may be taken at the discretion of the 
treating physician but are not required.
5.1.2 Target Volumes and Treatment Planning
Target lesions will be drawn on simulation CT imaging, using lung or mediastinal 
window levels as appropriate.  PET imaging may be fused to simulation CT scans to aid 
with localization of hypermetabolic lesions. If 4D CT simulation is used, gross tumor 
volumes (GTVs) should be generated on each CT phase that will be used for treatment 
(typically 4/10 phases if respiratory gating is employed or 10/10 phases if the patient will 
be treated while breathing freely).  GTVs will be combined to form internal target 
volumes (ITVs).
For patients treated with dose-painted radiotherapy, the low-risk GTV 
(GTV_4400) shall include the pulmonary tumor(s) as well as any suspicious lymph 
nodes (based on appearance, size ≥ 1cm in short axis, or pathologic data).  A high-risk 
gross tumor volume (GTV_5500), will also be defined and will include only lesions with 
MTV > 20 cc on pre-treatment PET imaging.  MTV calculations will be performed on 
PET imaging using a semiautomatic gradient-based contouring algorithm (“PET Edge”, 
MIMvista Corp, Cleveland, OH) or using a thresholding tool to encompass all voxels 
with SUV > 40% of the SUVmax42.  GTV_5500 will be contained within GTV_4400.
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Each GTV (or ITV) will be expanded by 7-10 mm to form a CTV (CTV_4400 and 
CTV_5500).  CTVs may be trimmed to exclude anatomic boundaries to microscopic 
tumor spread.  CTV_5500 will contained within CTV_4400.
Each CTV will be expanded to form a PTV. PTV expansions will be 5 mm in all 
directions if respiratory motion has been accounted for (eg: with beam gating, breath 
hold, or use of 4D-CT to form internal target volumes).  Otherwise, PTV expansions will 
be 5 mm radially and approximately 10 mm in the superior and inferior directions.  
PTV_5500 will be a subset of PTV_4400.
For subjects treated with standard radiotherapy, a single set of target volumes 
(GTV_6000, CTV_6000, and PTV_6000) will be created following the same procedures 
utilized to generate the low-risk volumes described above.
Adaptive radiotherapy (adjustment of target volumes during the course of 
radiotherapy) is not allowed in this protocol, unless difficulties with daily patient setup 
require repeating the CT simulation procedure.
Megavoltage equipment is required with effective photon energies of 6-18 MV. 
Use of IMRT or volumetric modulated arc therapy (VMAT) should be used for dose-
painting in this protocol. If these treatment techniques are not available for some reason 
(eg: a subject’s insurance company refuses to authorize IMRT), treatment will be 
delivered using a sequential boost technique (2.75 Gy x 16 to the low-risk PTV followed 
by 2.75 Gy x 4 to the high-risk PTV). All treatment planning will be performed using 
tissue heterogeneity corrections.
5.1.3 Target Coverage
The goal is to deliver conformal treatment that minimizes normal tissue 
irradiation.  As a guideline, a conformity index (ratio of the volume of the prescription 
isodose surface to the PTV) of < 1.5 is desirable.  The prescription isodose surface 
should encompass at least 95% of each PTV.  The minimum PTV dose (to 0.3 cm3) 
must not fall below 90% of the prescription dose.  The maximum dose must not exceed 
a value that is 115% of the highest prescribed dose, and the hot spot must be located 
within the PTV. 
5.1.4 Critical Structures
Lung, spinal cord, esophagus, brachial plexus, and heart/pericardium should be 
contoured based on atlases published on the RTOG web site. Dosimetric constraints for 
organs at risk are listed below.  These have been adopted from recent RTOG LA-
NSCLC protocols.
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Structure
Metric
No Deviation
Deviation Acceptable
Deviation Unacceptable
Lungs-CTV
Max Dose
Mean Dose
Volume>20 Gy
Volume>5 Gy
≤110% Rx Dose
≤20 Gy
≤35%
≤50%
≤113% Rx Dose
≤21 Gy
≤36%
≤55%
>113% Rx Dose
>21 Gy
>36%
>55%
Heart & 
Pericardium
Max Dose
Mean Dose
Volume>40 Gy
Volume>60 Gy
≤65 Gy
≤30 Gy
≤80%
≤30%
≤67 Gy
≤31 Gy
≤85%
≤33%
>67 Gy
>31 Gy
>85%
>33%
Esophagus
Mean Dose
≤34 Gy
≤35 Gy
>35 Gy
Spinal Cord
Max Dose (30 fractions)
Max Dose (20 fractions)
≤50 Gy
≤44 Gy
≤52 Gy
≤46 Gy
>52 Gy
>46 Gy
Brachial 
Plexus
Max Dose
≤63 Gy
≤65 Gy
>65 Gy
Dosimetric Constraints
5.1.5 Radiotherapy Adverse Events
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy.  Radiation induced 
myocarditis or transverse myelitis rarely occur when the pericardium and spinal cord 
receive doses lower than 50 Gy. Radiographic evidence of radiation change and 
subsequent fibrosis of the lung may occur, typically within lung volumes receiving≥ 20 
Gy and within the first six months after treatment. It is important to spare as much 
normal lung as possible to avoid symptomatic lung injury.  
Esophageal complaints are common with combined modality therapy. 
Esophagitis does not constitute a reason to interrupt or delay radiotherapy or 
chemotherapy, provided oral intake is sufficient to maintain hydration.  Patients should 
be advised to avoid alcoholic, acidic, or spicy foods or beverages.  Viscous Xylocaine, 
Carafate, or other medications should be used for symptomatic relief.  Occasionally, 
narcotics may be required.  It is not necessary to biopsy acute esophagitis in the first 2 
weeks of combined therapy since it is rarely due to underlying viral or fungal disease. 
Acute esophagitis may persist for 4-6 weeks.  Esophagitis should be graded using 
CTCAE v.4.0.  If high grade esophagitis occurs, and a treatment interruption is being 
considered, every effort should be made to minimize the treatment break duration. 
Acute esophageal toxicity, which typically manifests as dysphagia, odynophagia, and 
reflux symptoms, should be pharmacologically managed with the following approach: 
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5.2 Concurrent Chemotherapy
5.2.1 Concurrent Chemotherapy Dosing
Chemotherapy will be administered weekly concurrent with radiation on the same 
day each week.  Carboplatin (AUC 2, IV) and Paclitaxel (50 mg/m2, IV) will be started on 
week 1 of thoracic radiotherapy and will be continued weekly during the course of 
radiotherapy. Patients may receive chemotherapy on any day of the week from Monday 
to Friday, but the day of administration should remain constant during the course of 
chemoradiotherapy. A 1-day shift in the day of weekly chemotherapy infusion will be 
allowed if necessary. Paclitaxel 50 mg/m2 IV will be given by one hour infusion. 
Paclitaxel is mixed in non-PVC containers per the usual guidelines of the pharmacy.  
Carboplatin will be given at AUC 2 (calculated using the Calvert formula) over 1/2 hour 
immediately after paclitaxel. GFR will be calculated using the Cockroft-Gault formula.  A 
> 10% change in the serum creatinine will warrant a recalculation of the carboplatin and 
paclitaxel doses.
Calvert Formula
Calculated dose of carboplatin (mg) = target AUC x (glomerular filtration rate (GFR) + 25)
Cockroft-Gault Formula
GFR = (140 – Age) x Weight (in kg) x 0.85 (females only) ÷ (72 x Serum Creatinine (in mg/dL))
Prior to receiving carboplatin and paclitaxel, all patients should receive standard 
premedication. One standard that is recommended is:

Dexamethasone 20 mg orally 12 and 6 hours before paclitaxel or 20 mg IV just 
prior to paclitaxel

Diphenhydramine 25 or 50 mg IV (or equivalent) prior to paclitaxel

Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or famotidine 20 mg) prior 
to paclitaxel

Granisetron 1 mg orally (or equivalent) prior to chemotherapy
Dose modifications are outlined in section 5.4.2.
5.2.2 Chemotherapy Adverse Events
Adverse events caused by carboplatin may include:

Hematologic: Myelosuppression

Gastrointestinal: Nausea and vomiting; hepatic toxicity; electrolyte imbalance; 
hypomagnesemia; hypercalcemia

Neurological: Peripheral neuropathy, ocular changes

Other: Ototoxicity, myalgia, fatigue, allergic reaction
Adverse events caused by paclitaxel may include:
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
Hematologic: Myelosuppression

Gastrointestinal: Nausea and vomiting; diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis, increased liver 
function tests (AST, ALT, bilirubin, alkaline phosphatase); hepatic failure, hepatic 
necrosis 

Cardiac: Arrhythmias, heart block, ventricular tachycardia, myocardial infarction 
(MI), bradycardia, atrial arrhythmia, hypotension, hypertension, lightheadedness

Neurological: Sensory (taste), peripheral neuropathy, seizures, mood swings, 
hepatic encephalopathy, encephalopathy, sensation of flashing lights; blurred 
vision, scintillating scotoma

Allergic: Anaphylactoid and urticarial reactions (acute); Stevens-Johnson 
Syndrome flushing, rash, pruritus

Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, 
induration, tenderness, rarely ulceration); radiation recall reaction.
Required dose modifications for adverse events are detailed in sections 5.4.2 and 5.4.3.
5.3 Adjuvant Therapy
5.3.1 Adjuvant Chemotherapy Dosing
Adjuvant systemic therapy may start approximately 4-6 weeks after the 
completion of all radiotherapy. The recommended regimen is carboplatin and paclitaxel 
(detailed below). However, another standard regimen may be selected, at the discretion 
of the treating physicians.
Adjuvant carboplatin and paclitaxel may be started when esophagitis and 
chemotherapy-induced neuropathy are grade 1 or less, ANC > 1500, and platelet count 
> 100,000.  If the ANC and platelet count are not at the required levels, chemotherapy 
should be delayed until the following week.  Carboplatin (AUC 6, IV, over ½ hour) and 
Paclitaxel (200 mg/m2, IV, over 3 hours) will be given on day 1.  This will be repeated 
every 21 days for a total of 3 cycles, on the same day of the week for each cycle.  
Patients should receive standard premedication as outlined above.  
Dose modifications are outlined in section 5.4.3.
Potential complications of carboplatin and paclitaxel are detailed in section 5.2.2.
5.4 Treatment Modifications
If treatment is interrupted due to a non-dose-limiting adverse event or any reason 
other than toxicity, such as a holiday, bad weather, or a transportation problem, the 
duration of therapy will be extended accordingly. If a patient misses a day of radiation 
and chemotherapy, then the weekly chemotherapy should be delivered the next day 
and the missed radiation fraction will be given after the completion of planned 
treatments.
Patients who exhibit distant tumor progression will discontinue study procedures 
and will be managed at the discretion of their treating physicians. These patients will 
continue to be followed as specified in the protocol. Tissue confirmation to confirm 
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progressive disease is recommended in cases where this might affect patient 
management.
5.4.1 RT Interruption
Recommended treatment modifications for in-field RT toxicities are detailed 
below.  If treatment is interrupted for > 2 weeks, protocol treatment should be 
discontinued. Follow up and data collection will continue as specified in the protocol. RT 
should be held for all Grade 4 nonhematologic toxicity in or outside the treatment field 
and resumed only when toxicity is ≤ Grade 2.  Further treatment off protocol is at the 
discretion of the treating physician. RT should be discontinued if Grade 4 pulmonary 
toxicity occurs.  
5.4.2 Concurrent Chemotherapy Modifications
Recommended dose modifications for hematologic toxicity are detailed below.  
Dose levels are relative to the starting dose in the previous cycle.  For concurrent 
therapy, chemotherapy doses will not be adjusted.  Doses that are missed during 
weekly schedule concurrent with radiotherapy will not be made up but will be 
documented.  If either chemotherapeutic agent is withheld for greater than two 
consecutive weeks, that drug will be held for the duration of concurrent therapy.
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Recommended dose modifications for non-hematologic toxicity are detailed 
below.  For CTCAE Grade ≤ 2 non-hematologic toxicity, maintain dose levels.  Dose 
levels are relative to the starting dose in the previous cycle. For concurrent therapy,
paclitaxel and carboplatin doses will not be adjusted.  Note that concurrent 
chemotherapy will also be held for certain in-field RT toxicities (see section 5.4.1).
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5.4.3 Adjuvant Chemotherapy Modifications
The use of adjuvant systemic therapy is allowed but not required by the protocol. 
The decision to administer adjuvant therapy for a particular subject will be left to the 
discretion of the treating physicians. The recommended regimen is carboplatin and 
paclitaxel (detailed below). However, another standard regimen may be selected, at the 
discretion of the treating physicians.
Patients receiving adjuvant carboplatin/paclitaxel will be treated at the following 
chemotherapy dose levels:
Recommended dose modifications for hematologic toxicity are detailed below.  
Dose levels are relative to the levels in the previous cycle.  For adjuvant therapy, dose 
reductions of paclitaxel and carboplatin below the –1 dose level will not be allowed.  
Dose delays greater than 2 weeks will warrant discontinuation of chemotherapy for the 
adjuvant cycles.  When a chemotherapy dose reduction is required during the adjuvant 
therapy, reescalation of the chemotherapy dose will not be allowed for subsequent 
doses during that specific course.
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Recommended dose modifications for non-hematologic toxicity are detailed 
below.  Dose levels are relative to the dose levels in the previous cycle.  If paclitaxel 
doses must be withheld for greater than 2 consecutive weeks, the drug will be held 
permanently for the duration of adjuvant therapy. 
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5.4.4 Allergic Reactions
If a subject is deemed to develop an allergic reaction to carboplatin or paclitaxel, 
carboplatin/paclitaxel chemotherapy can be discontinued at the discretion of the treating 
physicians. This regimen can be replaced by another platinum doublet (eg: 
carboplatin/nab-paclitaxel) that will be administered using a standard dosing schedule.  
Radiotherapy and other protocol-specified procedures will proceed as planned.  These 
patients will be followed for primary and secondary endpoints, in keeping with the “intent 
to treat” principle. 
6.0 RESPONSE ASSESSMENT
Secondary endpoints of this study include locoregional progression-free survival 
and progression-free survival.  Evaluation for progressive disease will follow RECIST 
criteria43:
7.0 STATISTICAL CONSIDERATIONS
At the time of study registration, subjects will be stratified by performance status 
(2 v. 0-1) and primary tumor size (>4 cm v. ≤ 4 cm) and then will be randomized 1:1 
between the two study arms with the aid of the study statistician, using a modified 
permuted block treatment allocation scheme44. We are using tumor size to stratify 
patients because it can be determined easily at the time of study registration and is 
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highly correlated with total disease burden, which is a prognostic factor for both disease 
control and treatment-related toxicity.
The primary objective of this study is to explore patient-reported outcomes using 
the PRO-CTCAE tool in LA-NSCLC patients who are treated at our institution with 
standard or dose-painted thoracic chemoradiotherapy. The primary endpoint is the 
occurrence of patient-reported adverse event(s) with score ≥ 3, observed 6 weeks after 
initiation of chemoradiotherapy. For each study arm, we will report the distribution of 
PRO-CTCAE scores at each time point data is collected. As this is an exploratory study, 
no formal power calculation is performed. We plan to accrue 25 subjects to each arm. 
The following table describes the precision with which we will be able to characterize 
true event rates based on the frequency of observed events.
# of Events (%)
90% CI for Event Rate
95% CI for Event Rate
5/25 (20)
8-38%
7-41%
6/25 (24)
11-42%
9-45%
7/25 (28)
14-46%
13-49%
8/25 (32)
17-50%
15-54%
9/25 (36)
20-54%
18-57%
10/25 (40)
24-58%
21-61%
11/25 (44)
27-62%
24-65%
12/25 (48)
31-66%
28-69%
13/25 (52)
34-69%
31-72%
Toxicity outcomes and patterns of failures will be summarized and tabulated 
along with Clopper-Pearson exact confidence intervals. 
Exploratory comparisons of continuous variables will be performed using Student 
t-tests. If data are not normally distributed, appropriate non-parametric tests (Wilcoxon 
rank-sum test or van Elteren test) will be used. Categorical variables will be presented 
using frequencies and percentages, and comparisons may be performed using the chi-
square test or Fisher’s exact test. Time-to-event outcomes will be analyzed using the 
Kaplan-Meier method. Exploratory comparisons may be made using logrank tests.
As patient-reported outcomes will be assessed repeatedly over the follow-up 
period, exploratory analyses of differences between groups will be analyzed using 
generalized linear mixed effects modeling.
7.4 Subject Accrual
In the Einstein/Montefiore Department of Radiation Oncology, approximately five 
patients are treated with definitive chemoradiotherapy for LA-NSCLC each month.  We 
expect that 40-50% of such patients will be enrolled on this study, for an average of 2 
patients per month.  Thus, we anticipate that enrollment will span over a period of 
approximately 25 months.
8.0 REGULATORY CONSIDERATIONS
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8.1 Protection of Human Subjects
The Investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and 
other critical issues regarding clinical trials in which they volunteer to participate.  
Preparation of the consent form is the responsibility of the Investigator and must include 
all elements required by CFR 21 Part 50.25 and the local IRB.
8.2 Compliance with the Protocol and Protocol Revisions
The study must be conducted as described in this approved protocol.  All 
revisions to the protocol must be provided to the PI.  The PI should not implement any 
deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an Amendment, except where 
necessary to eliminate an immediate hazard(s) to study patients.
The investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and 
other critical issues regarding clinical trials in which they volunteer to participate.  
Preparation of the consent form is the responsibility of the PI.
9.0 DATA HANDLING AND RECORD KEEPING
9.1 Confidentiality
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:

What protected health information (PHI) will be collected from subjects in this 
study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.

In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period.
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9.2 Source Documents
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial.
9.3 Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the individual 
case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect 
entry and enter the correct data above it.  All such changes must be initialed and dated.  
DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it.  
10.0 DATA SAFETY AND MONITORING BOARDS
The Albert Einstein College of Medicine/Albert Einstein Cancer Center Data Safety 
Monitoring Committee (DSMC) has the responsibility for ensuring data and safety 
monitoring along with the PI who is ultimately responsible for the ongoing monitoring 
and safety of clinical protocols.  The primary functions of the AECC DSMC are as 
follows:
1. To review and ensure protocol compliance with dose escalation in phase I trials 
2. To review/assure protocol compliance for all trials that have two-stage phase II 
designs, 
3. Reviewing all internal and external serious adverse reports, investigator alerts, 
action letters, and other safety reports for trials being performed at AECC-
affiliated institutions and; 
4. To implement and to determine the adequacy of DSM plans of all approved 
protocols. 
The DSMC is an independent committee and meets on a bimonthly basis.  During its 
bimonthly meeting, the DSMC will review serious (grade 3 or higher) adverse events 
from this study.  In the event that the DSMC decides that a revision is warranted, the 
committee will immediately notify the principal investigator of this study.  The DSMC has 
the authority to close trials to patient accrual should the risk to patients be excessive or 
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outweigh the potential benefits of the study.  All study suspensions and closures will be 
forwarded to the IRB/CCI and study sponsor from the DSMC.
11.0 ADVERSE EVENTS
An adverse event (AE) is defined as any untoward medical occurrence in a 
patient or clinical investigation subject and does not necessarily have to have a causal 
relationship with study treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of treatment.  During clinical trials, AEs can be 
spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. 
AEs will be recorded in the case report form for the duration of the trial, 
regardless of whether or not the event(s) are considered related to trial intervention or 
medication. All AEs considered related to trial intervention or medication will be followed 
until resolution, even if this occurs post-trial.
11.1 Adverse Event Definitions
Adverse Event (AE):  any new, undesirable medical experience or change of an existing 
condition that occurs during or after treatment, whether or not considered product-
related.
Serious Adverse Event (SAE):  An AE occurring at any dose that results in any of the 
following outcomes (CFR 312.32)

Death

Life-threatening adverse experience

Inpatient hospitalization or prolongation of existing hospitalization excluding  
those for study therapy administration, transfusional support, disease staging/re-
staging procedures, thoracentesis / paracentesis, or placement of an indwelling 
catheter, unless associated with other serious events

Persistent or significant disability or incapacity

Congenital anomaly / birth defect. 
The definition of SAE also includes important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.  A new diagnosis of cancer during the course of treatment 
should be considered an important medical event.
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The definition of “related” is that there is a reasonable possibility that the drug or the 
study intervention caused the adverse experience.
Unexpected Adverse Event:  An AE that is not mentioned in the Investigator's Brochure 
or package insert or the specificity or severity of which is not consistent with the 
investigator's brochure or package insert.
Life-threatening:  Any adverse experience that places the patient or subject, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death.
AEs will use the descriptions and grading scales found in the revised Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix). A list of AEs 
that have occurred or might occur can be found in sections above.  
11.2 Adverse Event Reporting
Study site personnel must notify the PI and the sponsor immediately of any SAE 
experienced by a patient.  In general, SAEs assessed as clearly being due to disease 
progression, and not due to study drug(s), should be excluded from AE reporting.  
Study-specific clinical outcomes of death because of disease progression are exempt 
from SAE reporting, unless the investigator deems them related to use of the study 
drug.  Hospitalization for study drug administration is not an SAE.
The following steps will be taken to report promptly and document accurately any SAE, 
even if it may not appear to be related to the study treatment:

Report the SAE to the PI and the treating physician by email, telephone or fax 
within 24 hours of becoming aware that a patient has experienced an SAE.

Record the SAE accurately on the AE page of the patient’s CRF.

Using the standard IRB-SAE report form, submit all known patient information 
within 24 hours of SAE occurrence to the clinical trial office to submit to IRB and 
DSMB.  Date and sign each report before submission.  Include the following 
information (or as much as possible to obtain and still report the event within 24 
hours): 
o
Study protocol number and indication
o
Study site and investigator’s identification
o
Patient’s ID (patient number and initials), age or date of birth, and sex
o
Date of enrollment
o
Description of SAE, including date of onset and duration, severity, and 
outcome
o
Date of first and most recent (last) dose administered
o
Action taken regarding study treatment
o
Relationship of SAE to study treatment
o
Concomitant medications, including regimen and indication
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o
Intervention, including concomitant medications used to treat SAE
o
Pertinent laboratory data/diagnostic tests conducted and date
o
Pertinent medical history of patient
o
Date of hospital admission/discharge
o
Date of death (if applicable)
Within 10 days of initial IRB notification, the PI is required to submit a completed 
Adverse Event Report to the IRB.  The treating physicians should perform appropriate 
diagnostic tests and therapeutic measures and submit all follow-up substantiating data, 
such as diagnostic test reports and autopsy report to the PI, IRB, and DSMB.
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12.0 REFERENCES
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Journal for Clinicians 61:69-90, 2011
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Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) 
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Vokes EE, Herndon JE, Kelley MJ, et al: Induction chemotherapy followed by 
chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced 
unresectable stage III non–small-cell lung cancer: Cancer and Leukemia Group B. Journal of 
clinical oncology 25:1698, 2007
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Hanna N, Neubauer M, Yiannoutsos C, et al: Phase III study of cisplatin, 
etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients 
with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. 
Oncology. J Clin Oncol 26:5755-60, 2008
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Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or 
placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III 
non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450-6, 2008
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Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose 
conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or 
without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a 
randomised, two-by-two factorial phase 3 study. The Lancet Oncology 16:187-199, 2015
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Senan S, Brade A, Wang L-h, et al: PROCLAIM: Randomized phase III Trial of 
pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by 
consolidation chemotherapy in locally advanced nonsquamous non–small-cell lung cancer. 
Journal of Clinical Oncology 34:953-962, 2016
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Albain KS, Swann RS, Rusch VW, et al: Radiotherapy plus chemotherapy with or 
without surgical resection for stage III non-small-cell lung cancer: a phase III randomised 
controlled trial. Lancet 374:379-86, 2009
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Palma DA, Senan S, Oberije C, et al: Predicting esophagitis after chemoradiation 
therapy for non-small cell lung cancer: an individual patient data meta-analysis. International 
Journal of Radiation Oncology* Biology* Physics 87:690-696, 2013
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Marks LB, Bentzen SM, Deasy JO, et al: Radiation dose–volume effects in the 
lung. International Journal of Radiation Oncology* Biology* Physics 76:S70-S76, 2010
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Gagliardi G, Constine LS, Moiseenko V, et al: Radiation dose–volume effects in 
the heart. International Journal of Radiation Oncology* Biology* Physics 76:S77-S85, 2010
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Werner-Wasik M, Yorke E, Deasy J, et al: Radiation dose-volume effects in the 
esophagus. International Journal of Radiation Oncology* Biology* Physics 76:S86-S93, 2010
13.
Bar-Ad V, Ohri N, Werner-Wasik M: Esophagitis, treatment-related toxicity in 
non-small cell lung cancer. Reviews on recent clinical trials 7:31-35, 2012
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Ohri N, Rapkin BD, Guha C, et al: Radiation Therapy Noncompliance and 
Clinical Outcomes in an Urban Academic Cancer Center. International Journal of Radiation 
Oncology* Biology* Physics 95:563-570, 2016
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Chun SG, Hu C, Choy H, et al: Impact of intensity-modulated radiation therapy 
technique for locally advanced non–small-cell lung cancer: A secondary analysis of the NRG 
oncology RTOG 0617 randomized clinical trial. Journal of Clinical Oncology:JCO691378, 2016
16.
Wang K, Eblan MJ, Deal AM, et al: Cardiac Toxicity After Radiotherapy for Stage 
III Non–Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 
Gy. Journal of Clinical Oncology:JCO. 2016.70. 0229, 2017
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17.
Maziak DE, Darling GE, Inculet RI, et al: Positron emission tomography in 
staging early lung cancer: a randomized trial. Ann Intern Med 151:221-8, W-48, 2009
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Fischer B, Lassen U, Mortensen J, et al: Preoperative staging of lung cancer with 
combined PET-CT. N Engl J Med 361:32-9, 2009
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Weder W, Schmid RA, Bruchhaus H, et al: Detection of extrathoracic metastases 
by positron emission tomography in lung cancer. Ann Thorac Surg 66:886-92; discussion 892-3, 
1998
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Fischer BM, Mortensen J, Hojgaard L: Positron emission tomography in the 
diagnosis and staging of lung cancer: a systematic, quantitative review. Lancet Oncol 2:659-66, 
2001
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Subedi N, Scarsbrook A, Darby M, et al: The clinical impact of integrated FDG 
PET-CT on management decisions in patients with lung cancer. Lung Cancer 64:301-7, 2009
22.
Machtay M, Duan F, Siegel BA, et al: Prediction of Survival by 
[18F]Fluorodeoxyglucose Positron Emission Tomography in Patients With Locally Advanced 
Non-Small-Cell Lung Cancer Undergoing Definitive Chemoradiation Therapy: Results of the 
ACRIN 6668/RTOG 0235 Trial. J Clin Oncol 31:3823-30, 2013
23.
Ohri N, Duan F, Machtay M, et al: Pretreatment FDG-PET Metrics in Stage III 
Non–Small Cell Lung Cancer: ACRIN 6668/RTOG 0235. Journal of the National Cancer 
Institute 107:djv004, 2015
24.
Ohri N, Piperdi B, Garg MK, et al: Pre-treatment FDG-PET predicts the site of in-
field progression following concurrent chemoradiotherapy for stage III non-small cell lung 
cancer. Lung Cancer 87:23-27, 2015
25.
Ohri N, Bodner WR, Halmos B, et al: 18 F-Fluorodeoxyglucose/Positron 
Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for 
Locally Advanced Non-Small Cell Lung Cancer. International Journal of Radiation Oncology* 
Biology* Physics 97:372-380, 2017
26.
Prewett S, Aslam S, Williams M, et al: The management of lung cancer: a UK 
survey of oncologists. Clinical Oncology 24:402-409, 2012
27.
Ohri N, Rapkin BD, Guha D, et al: Predictors of radiation therapy noncompliance 
in an urban academic cancer center. International Journal of Radiation Oncology* Biology* 
Physics 91:232-238, 2015
28.
Formenti SC, Demaria S: Combining radiotherapy and cancer immunotherapy: a 
paradigm shift. Journal of the National Cancer Institute:djs629, 2013
29.
Ohri N, Bodner WR, Kabarriti R, et al: Positron Emission Tomography–Adjusted 
Intensity Modulated Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. 
International Journal of Radiation Oncology* Biology* Physics, 2017
30.
Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in 
stage III non–small-cell lung cancer. New England Journal of Medicine 377:1919-1929, 2017
31.
Antonia SJ, Villegas A, Daniel D, et al: Overall Survival with Durvalumab after 
Chemoradiotherapy in Stage III NSCLC. New England Journal of Medicine, 2018
32.
Tang C, Liao Z, Gomez D, et al: Lymphopenia association with gross tumor 
volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. International 
Journal of Radiation Oncology* Biology* Physics 89:1084-1091, 2014
33.
Crocenzi T, Cottam B, Newell P, et al: A hypofractionated radiation regimen 
avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline 
resectable and locally advanced pancreatic adenocarcinoma. Journal for immunotherapy of 
cancer 4:45, 2016
34.
Shiraishi Y, Fang P, Xu C, et al: Severe lymphopenia during neoadjuvant 
chemoradiation for esophageal cancer: A propensity matched analysis of the relative risk of 
proton versus photon-based radiation therapy. Radiotherapy and Oncology 128:154-160, 2018
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35.
Ladbury C, Rusthoven C, Camidge DR, et al: Impact of Radiation Dose to the 
Host Immune System on Tumor Control and Survival for Stage III Non-Small Cell Lung Cancer 
Treated with Definitive Radiotherapy. International Journal of Radiation Oncology• Biology• 
Physics, 2019
36.
Fowler JF: The linear-quadratic formula and progress in fractionated 
radiotherapy. The British journal of radiology 62:679-694, 1989
37.
Machtay M, Bae K, Movsas B, et al: Higher biologically effective dose of 
radiotherapy is associated with improved outcomes for locally advanced non-small cell lung 
carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. 
Int J Radiat Oncol Biol Phys 82:425-34, 2012
38.
Gotay CC, Kawamoto CT, Bottomley A, et al: The Prognostic Significance of 
Patient-Reported Outcomes in Cancer Clinical Trials. J Clin Oncol 26:1355-1363, 2008
39.
Movsas B, Hu C, Sloan J, et al: Quality of life (QOL) analysis of the randomized 
radiation (RT) dose-escalation NSCLC trial (RTOG 0617): the rest of the story. Int J Radiat 
Oncol Biol Phys 87:S1-S2, 2013
40.
Basch E, Reeve BB, Mitchell SA, et al: Development of the National Cancer 
Institute’s patient-reported outcomes version of the common terminology criteria for adverse 
events (PRO-CTCAE). Journal of the National Cancer Institute 106:dju244, 2014
41.
Fogh S, Deshmukh S, Berk LB, et al: A Randomized Phase II Trial of 
Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis 
During the Treatment of Lung Cancer: Results of Trial. International Journal of Radiation 
Oncology* Biology* Physics, 2016
42.
Werner-Wasik M, Nelson AD, Choi W, et al: What is the best way to contour lung 
tumors on PET scans? Multiobserver validation of a gradient-based method using a NSCLC 
digital PET phantom. International Journal of Radiation Oncology* Biology* Physics 82:1164-
1171, 2012
43.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the 
response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000
44.
Zelen M: The randomization and stratification of patients to clinical trials. Journal 
of chronic diseases 27:365-375, 1974
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13.0 APPENDICES
13.1 Appendix A – Eligibility Checklist
Inclusion Criteria
Must be answered YES for eligibility
1. Does the patient have pathologically proven NSCLC?
Yes / No
2. Is the patient’s disease stage one of the following? (using AJCC 7th edition):
 - Stage IIIA or IIIB
 - Stage II with medical contraindication to curative surgical resection
 - Stage IV with solitary brain metastasis that has been treated radically (eg: with 
surgical resection or stereotactic radiosurgery) and thoracic disease that would 
be classified as stage II-III
Yes / No
3. Has the patient had an appropriate staging workup, including:
- Complete history and physical examination
- PET/CT Scan within 42 days prior to study entry demonstrating hypermetabolic 
pulmonary lesion(s) and/or thoracic lymph node(s), with a maximum SUV > 6 for 
at least one lesion.  If PET/CT was obtained more than 42 days prior to study 
entry and is not repeated, CT scan of the chest within 28 days prior to study 
entry demonstrating stable disease is required.
 - MRI of the brain or CT Scan of the head with contrast within 42 days prior to 
study entry
Yes / No
4. Does the patient have ECOG Performance Status 0-2?
Yes / No
5. Is the patient at least 18 years old?
Yes / No
6. Does the patient have laboratory studies obtained within 28 days prior to study 
entry demonstrating adequate bone marrow and end organ function defined as:
 - Absolute neutrophil count (ANC) >1,500 cells/µl
 - Platelets > 100,000 cells/µl
 - Hemoglobin > 9.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb > 9.0 g/dl is acceptable.)
 - Total bilirubin < 3.0 times the institutional Upper Limit of Normal (ULN)
 - AST and ALT < 3.0 x the ULN
 - Serum creatinine < 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min 
(by Cockroft-Gault formula)
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Yes / No
7. Is either of the following true?:
 - The patient is not a woman of childbearing potential.
 - The patient has undergone negative serum or urine pregnancy test within 72 
hours prior to the start of study therapy, agrees to utilize an adequate method of 
contraception throughout treatment and for at least 4 weeks after study therapy is 
completed, and has been advised of the importance of avoiding pregnancy 
during trial participation and the potential risks of an unintentional pregnancy.
Yes / No
8. Has the patient signed study-specific informed consent?
Yes / No
Exclusion Criteria
Must be answered NO for eligibility
1. Has the patient had prior chemotherapy or thoracic radiotherapy for lung cancer?
Yes / No
2. Does the patient have a pleural or pericardial effusion that can be sampled using 
CT or ultrasound guidance but has not yet been sampled?
Yes / No
3. Is the patient compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (e.g., infectious) illness?
Yes / No
4. Is the patient pregnant or breastfeeding?
Yes / No
5. Does the patient have poorly controlled diabetes (defined as fasting glucose level 
> 200 mg/dL) despite attempts to improve glucose control by fasting duration and 
adjustment of medications.  
Yes / No
If patient is eligible, fax eligibility checklist to Hilda Haynes, NP: 718-231-5064
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13.2 Appendix B – Common Toxicity Criteria
NCI CTCAE Version 4.0
Toxicity will be scored using NCI CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov).  All appropriate treatment areas have access to a 
copy of the CTC Version 4.0
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13.3 Appendix C – ECOG Performance Status
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13.4 Appendix D – AJCC Lung Cancer Staging (7th Edition)
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13.5 Appendix E – PRO-CTCAE Assessment Tool
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