Clinical trial NCT02073968
Conditions: Metastatic Malignant Neoplasm in the Brain Recurrent Non-Small Cell Lung Carcinoma Stage IIA Non-Small Cell Lung Carcinoma Stage IIB Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer
Sponsor: Albert Einstein College of Medicine
Start date: 2013-07-01; Completion date: 2020-11-01
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well intensity modulated radiation therapy adjusted by positron emission tomography (PET) scanning together with combination chemotherapy works in treating patients with stage II-IV non-small cell lung cancer (NSCLC). Radiation therapy uses high energy x rays to kill tumor cells. In intensity-modulated radiotherapy, multiple beam angles and dozens of beam segments are used to deliver highly conformal radiation therapy. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving PET-adjusted IMRT together with combination chemotherapy may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the efficacy (based on post-treatment PET findings) of dose-painted intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy for locally-advanced non-small cell lung cancer (LA-NSCLC).

SECONDARY OBJECTIVES:

I. To estimate the efficacy (based on clinical endpoints including locoregional control \[LRC\], disease-free survival \[DFS\], and overall survival \[OS\]) of dose-painted IMRT with concurrent chemotherapy for LA-NSCLC.

II. To evaluate the safety of dose-painted IMRT with concurrent and adjuvant chemotherapy for LA-NSCLC.

III. To evaluate the utility of post-treatment PET/computed tomography (CT) imaging as a predictor of clinical outcomes following treatment with this novel approach.

IV. To explore, in a preliminary manner, whether metabolomic markers in the blood and urine prior to and during the course of treatment are associated with treatment response, clinical endpoints, and treatment-related adverse events such as radiation pneumonitis.

OUTLINE:

RADIATION THERAPY: Patients undergo PET-adjusted IMRT or proton beam radiation therapy five days a week for 5 weeks.

CONCURRENT CHEMOTHERAPY: Patients receive carboplatin intravenously (IV) over 3 hours and paclitaxel IV over 1 hour once weekly for 5 weeks beginning week 1 of thoracic radiotherapy.

CONSOLIDATION CHEMOTHERAPY: Beginning approximately 4-6 weeks after the completion of all radiation therapy and when esophagitis and chemotherapy-induced neuropathy are grade 1 or less, absolute neutrophil count (ANC) \> 1500, and platelet count \> 100,000, patients may receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1. Treatment may repeat every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity at the discretion of the treating physicians.

After completion of study treatment, patients are followed up at 12-16 weeks, 19 weeks, every 3 months for 2 years, and then every 6 months for a total of 5 years.

Arms: arm 1: RADIOTHERAPY: Patients undergo PET-adjusted IMRT or proton beam radiation therapy five days a week for 5 weeks.

CONCURRENT CHEMOTHERAPY: Patients receive carboplatin IV over 3 hours and paclitaxel IV over 1 hour once weekly for 6 weeks beginning week 1 of thoracic radiotherapy.

CONSOLIDATION CHEMOTHERAPY: Beginning approximately 4-6 weeks after the completion of all radiation therapy and when esophagitis and chemotherapy-induced neuropathy are grade 1 or less, ANC \> 1500, and platelet count \> 100,000, patients may receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1. Treatment may repeat every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity at the discretion of the treating physicians.
Interventions: intervention 1: Carboplatin intervention 2: Computed Tomography intervention 3: Intensity-Modulated Radiation Therapy intervention 4: Paclitaxel intervention 5: Positron Emission Tomography intervention 6: Proton Beam Radiation Therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo PET-adjusted IMRT intervention 3: Undergo PET-adjusted IMRT intervention 4: Given IV intervention 5: Undergo PET-adjusted IMRT intervention 6: Undergo proton beam radiation therapy

Protocol documents:
Prot_SAP_000.pdf: 
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PET-Adjusted IMRT for NSCLC Trial (PAINT)
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
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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
Fax: 718-882-6914
Maury Rosenstein, MD, PhD
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
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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)
Bilal Piperdi, MD
Montefiore Medical Center
Department of Oncology, 2nd floor room 2S-51
825 Eastchester Road
Bronx, NY 10461
Phone: 718-904-2488
Fax: 718-904-2830
Email: bpiperdi@montefiore.org 
Missak Haigentz, 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
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Email: mhaigent@montefiore.org
Stuart Packer, MD
Montefiore Medical Center
Department of Oncology, Hofheimer 100
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-904-2900
Fax: 718-798-7474
Email: spacker@montefiore.org
Co-Investigators (Medical Physics)
Wolfgang Tomé, PhD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 106
Bronx, NY 10461
Phone: 718-430-3188
Fax: 718-430-8618
Email: wtome@montefiore.org
Co-Investigators (Nuclear Medicine)
Tony Abraham, DO
Montefiore Medical Park
1695A Eastchester Road
Bronx, NY 10461
Tel: 718-405-8461
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Fax: 718-824-0830
Email : toabraha@montefiore.org 
Raphaella da Silva, MD
Montefiore Medical Park
1695A Eastchester Road
Bronx, NY 10461
Tel: 718-405-8461
Fax: 718-824-0830
Email : rdasilv@montefiore.org 
Co-Investigators (Surgical Oncology)
Steven Keller, MD
Chief, Cardiothoracic Surgery
Montefiore Medical Center
111 East 210th Street
Bronx, NY 10467-2490
Phone: 718-405-8238
Fax: 718-405-8292
Email: skeller@montefiore.org
Co-Investigators (Metabolomics Core)
Irwin J. Kurland, MD, PhD
Department of Medicine (Endocrinology)
Michael F. Price Center
1301 Morris Park Avenue, Room 374
Bronx, NY 10461
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Phone: 718-678-1091
Email: irwin.kurland@einstein.yu.edu 
Research Coordinator
Alyssa Asaro
               
 
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-5636
Fax: 718-882-6914
Email: aasaro@montefiore.org
                           
Research Nurse
Hilda Haynes-Lewis, NP
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-7750
Fax: 718-231-5064
Email: hhaynes@montefiore.org 
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PET-Adjusted IMRT for NSCLC Trial (PAINT)
SCHEMA
Sample size: 39 patients
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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
BID
Twice daily
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
LD
Longest diameter
LLN
Lower limit of normal
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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
TGA
Total glycolytic activity
ULN
Upper limit of normal
VMAT
Volumetric modulated arc therapy
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Contents
1.0  OBJECTIVES ..........................................................................................................13
1.1  Primary Objective.................................................................................................13
1.2  Secondary Objectives ..........................................................................................13
2.0  BACKGROUND.......................................................................................................13
2.1  Locally-advanced Non-small Cell Lung Cancer (LA-NSCLC) ..............................13
2.2  PET Imaging for LA-NSCLC ................................................................................14
2.3  Intensity-Modulated Radiotherapy (IMRT) for LA-NSCLC ...................................17
2.4  Safety of RT Intensification ..................................................................................17
2.5  Biomarker Studies................................................................................................19
2.6  Rationale for Treating Low-risk Lesions with a Conservative RT Dose ...............19
3.0  PATIENT ELIGIBILITY ............................................................................................22
3.1  Inclusion Criteria ..................................................................................................23
3.2  Exclusion Criteria .................................................................................................24
4.0  STUDY DESIGN......................................................................................................25
4.1  General Design ....................................................................................................25
4.2  Study Calendar ....................................................................................................26
4.3  Primary Endpoint..................................................................................................26
4.4  Secondary Endpoints ...........................................................................................26
5.0  STUDY THERAPY ..................................................................................................27
5.1  Radiotherapy........................................................................................................27
5.2  Concurrent Chemotherapy...................................................................................31
5.3  Adjuvant/Consolidation Chemotherapy................................................................33
5.4  Treatment Modifications.......................................................................................35
5.5  Biospecimen Collection........................................................................................41
6.0  RESPONSE ASSESSMENT...................................................................................43
6.1  Primary Endpoint – PET Response .....................................................................43
6.2  Secondary Endpoints – Progression-free Survival...............................................43
7.0  STATISTICAL CONSIDERATIONS ........................................................................43
7.1  Sample Size Calculation ......................................................................................43
7.2  Primary Efficacy Analysis.....................................................................................44
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7.3  Secondary and Other Efficacy Analyses..............................................................44
7.4  Subject Accrual ....................................................................................................44
8.0  REGULATORY CONSIDERATIONS ......................................................................46
8.1  Protection of Human Subjects..............................................................................46
8.2  Compliance with the Protocol and Protocol Revisions.........................................46
9.0  DATA HANDLING AND RECORD KEEPING .........................................................46
9.1  Confidentiality.......................................................................................................46
9.2  Source Documents...............................................................................................47
9.3  Case Report Forms..............................................................................................47
10.0  DATA SAFETY AND MONITORING BOARDS.....................................................47
11.0  ADVERSE EVENTS..............................................................................................48
11.1  Adverse Event Definitions ..................................................................................48
11.2  Adverse Event Reporting ...................................................................................50
12.0  REFERENCES......................................................................................................52
13.0  APPENDICES .......................................................................................................55
13.1 Appendix A – Eligibility Checklist ........................................................................55
13.2 Appendix B – Common Toxicity Criteria .............................................................57
13.3 Appendix C – ECOG Performance Status ..........................................................58
13.4 Appendix D – AJCC Lung Cancer Staging (7th Edition) .....................................59
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1.0  OBJECTIVES
1.1  Primary Objective

To estimate the efficacy (based on post-treatment PET findings) of dose-painted 
intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy for 
locally-advanced non-small cell lung cancer (LA-NSCLC).
1.2  Secondary Objectives

To estimate the efficacy (based on clinical endpoints including locoregional 
control [LRC], disease-free survival [DFS], and overall survival [OS]) of dose-
painted IMRT with concurrent chemotherapy for LA-NSCLC.

To evaluate the safety of dose-painted IMRT with concurrent chemotherapy for 
LA-NSCLC.

To evaluate the utility of post-treatment PET/CT imaging as a predictor of clinical 
outcomes following treatment with this novel approach.

To explore, in a preliminary manner, whether metabolomic markers in the blood 
and urine prior to and during the course of treatment are associated with 
treatment response, clinical endpoints, and treatment-related adverse events 
such as radiation pneumonitis.

To evaluate the rate of local disease progression in lesions deemed to be low-
risk based on pre-treatment PET findings and treated with a conservative RT 
dose
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 year.1  
Approximately one-third of NSCLC patients are diagnosed with locally-advanced 
disease, which may be defined as unresectable stage II disease or stage III disease.2  
For locally-advanced non-small cell lung cancer (LA-NSCLC), the standard treatment 
approach is conventionally-fractionated (1.8-2.0 Gy/day) radiotherapy (RT) to a dose of 
approximately 60-66 Gy with concurrent, platinum-based chemotherapy.  This treatment 
approach, however, yields median survival times of only 16-23 months and local control 
rates of only 40-66%.3-7
Attempts to improve survival for LA-NSCLC patients through the extension of 
systemic therapy have yielded disappointing results in phase III trials.  Administration of 
induction chemotherapy prior to chemoradiotherapy (ChemoRT) did not decrease the rate 
of distant relapse or improve overall survival (OS).8  Similarly, addition of consolidation 
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docetaxel to conventional ChemoRT increased toxicity but did not improve survival.9  
Maintenance therapy with a targeted agent was found to decrease survival.10
The failure of intensified systemic therapy to improve survival in LA-NSCLC, in 
combination with the poor local control rates observed following conventional chemoRT, 
suggest that intensification of locoregional therapy may provide the best chance of 
improving outcomes for this patient population.  This is supported by a meta-analysis of 
6 randomized trials that compared concurrent chemoRT against sequential chemoRT.11  
Concurrent chemoRT was found to significantly improve OS and locoregional disease 
control (LRC), but it did not decrease the rate of distant progression.  This is direct 
evidence that intensification of locoregional therapy can improve overall survival in LA-
NSCLC.
Since concurrent chemoRT has been adopted as the standard of care for LA-
NSCLC, several approaches to further improving locoregional therapy have been 
explored.  Trimodality therapy, consisting of neoadjuvant ChemoRT followed by surgical 
resection, improved progression-free survival but not OS in a phase III study.12  The value 
of RT dose escalation in the setting of definitive chemoRT was evaluated in RTOG 0617, 
a large, randomized trial in which patients were randomized to conventional dose (60 Gy 
in 30 fractions) versus high dose (74 Gy in 37 fractions) RT with concurrent weekly 
carboplatin and paclitaxel.  Based on a second randomization, ½ of enrolled patients also 
received daily cetuximab.  The 74 Gy arms of that trial were closed when it was 
determined that RT dose escalation was unlikely to yield a survival benefit.13   Post-hoc 
analyses suggest that target coverage for many patients on the 74 Gy arm was 
suboptimal, possibly because treating physicians were concerned about treating large 
volumes to such a high dose.  Additionally, the fact that the RT course of the high dose 
arm was approximately 10 days longer than that of the 60 Gy arm raises the possibility 
that accelerated repopulation may counteract the benefits of dose escalation using 
standard fractionation.
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 patients.14-16  Implementation of PET imaging may alter the management of 
NSCLC patients in up to 40% of cases.15,17,18  Several reports indicate that for NSCLC 
patients, PET metrics such as maximum SUV (SUVmax), metabolic tumor volume 
(MTV), and total glycolytic activity (TGA) may be independent predictors of overall 
survival.19-22.
The clinical significance of quantitative PET findings before and after 
conventionally-fractionated chemoradiotherapy for LA-NSCLC was the subject of the 
multi-institutional ACRIN 6668 / RTOG 0235 trial.  In that Phase II study, PET imaging 
was collected before and 12-16 weeks after the completion of definitive, concurrent 
chemoRT for LA-NSCLC.  Treatment details were not specified, but the protocol 
required a RT dose of at least 60 Gy and the use of one platinum-based 
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chemotherapeutic agent with a second non-platinum agent.  In the primary analysis of 
that study, pre-treatment SUVmax and peak SUV (SUVpeak) values were not found to 
be prognostic with respect to LRC or OS.  Post-treatment SUVmax and SUVpeak, on 
the other hand, correlated with both LRC and OS.23  In exploratory analyses, an 
SUVpeak cutoff of 5.0 on post-treatment imaging effectively stratified patients into 
favorable and unfavorable groups. (Personal communication with ACRIN/RTOG 
investigators, Figure 1)
Figure 1 – Unpublished results from ACRIN 6668 / RTOG 0235.  Kaplan-Meier curves were generated 
using data from 173 patients who underwent post-treatment PET imaging.  Post-treatment SUVpeak 
predicts for OS.  An SUVpeak value of 5.0 corresponds to an SUVmax value of approximately 6.0.
Our group has been working with the ACRIN 6668 / RTOG 0235 dataset to 
evaluate additional metrics derived from pre- and post-treatment PET imaging.  We 
have found that pre-treatment MTV, defined as the composite volume of all 
hypermetabolic lesions delineated on PET imaging, is an independent predictor of both 
LRC and OS. (Figures 2a and 2b)  We have also found that for individual tumors and 
hypermetabolic lymph nodes, pre-treatment MTV correlates with the risk of persistent 
hypermetabolic activity on post-treatment imaging. (Figure 3)  Based on these results, 
we hypothesize that pre-treatment MTV identifies high-risk lesions for which RT 
intensification is likely to provide clinical benefit.
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Figure 2a – Unpublished results from ACRIN 6668 / RTOG 0235.  Kaplan-Meier curves for locoregional 
progression-free survival were generated after dividing patients into two groups based on pre-treatment 
MTV (above/below mean value of 92 cc).
Figure 2b – Unpublished results from ACRIN 6668 / RTOG 0235.  Kaplan-Meier curves for overall 
survival were generated after dividing patients into two groups based on pre-treatment MTV (above/below 
mean value of 92 cc).
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Figure 3 – Pre-treatment MTV correlates with the risk of significant (SUVmax>6) activity on post-
treatment PET imaging.  Data shown are for 434 lesions in 157 patients from ACRIN 6668 / RTOG 0235 
who underwent both pre- and post-treatment imaging.  Lesions were sorted into seven groups based on 
pre-treatment MTV.  Lesions with pre-treatment MTV above 25 cc have a >15% risk of significant 
post-treatment activity.
2.3  Intensity-Modulated Radiotherapy (IMRT) for LA-NSCLC
In intensity-modulated radiotherapy (IMRT), multiple beam angles and dozens of 
beam segments are used to deliver highly conformal RT.  Computerized inverse 
planning is used to identify the combination of beam segments that optimally covers the 
target volumes with the prescribed RT dose while limiting the dose to surrounding 
normal structures based on pre-specified constraints.24   IMRT is commonly used for a 
number of malignancies, including LA-NSCLC.  In a large single-institution experience, 
the adoption of IMRT for LA-NSCLC was associated with significant improvements in 
OS.25  In the aforementioned RTOG 0617 trial, approximately 50% of patients were 
treated with IMRT.13
An additional benefit of IMRT compared to older treatment techniques is that 
IMRT can be used to perform “dose painting”, also referred to as the “simultaneous 
integrated boost technique”.  This means that in a single session, various target 
volumes can be treated with different RT doses, which are generally based on historical 
failure patterns.  This approach is commonly used for head and neck cancer26 and anal 
cancer27, where dose levels are based on lesion type (primary tumor v. lymph node) 
and size.  This approach has not yet been adopted for the treatment of NSCLC, 
presumably because locoregional failure patterns have been difficult to establish using 
anatomic imaging, and distant failure remains common.
2.4  Safety of RT Intensification
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We hypothesize that pre-treatment PET imaging can be used to identify high-risk 
lesions for which RT dose escalation is likely to provide clinical benefit.  In this trial, we 
will utilize IMRT to selectively treat high-risk lesions with intensified RT dosing.  The 
safety of chemoRT dose escalation to larger volumes has already been established, as 
has the safety of modest chemoRT hypofractionation (use of daily fraction sizes > 2.0 
Gy).  Therefore we are confident that our regimen will be well-tolerated.
In RTOG 0617, patients on the experimental arm were treated with high-dose 
concurrent chemoRT.  They received an RT dose of 74 Gy in 37 fractions over 7 ½ 
weeks, along with weekly carboplatin (AUC=2) and paclitaxel (45 mg/m2).13  This RT 
schedule was based on previous phase I and II studies demonstrating the safety of 
chemoRT dose escalation up to 74 Gy.28-30  Preliminary results from RTOG 0617 
indicate that high-dose chemoRT was well-tolerated, and treatment-related toxicities did 
not account for the study’s negative results.
Several single-institution reports indicate that gentle chemoRT hypofractionation 
is well-tolerated.  In a Japanese study, 10 patients with stage III NSCLC were treated 
with daily RT fraction sizes of 2.5 Gy to a median dose of 65 Gy.31  All patients received 
concurrent chemotherapy consisting of weekly carboplatin and paclitaxel.  Treatment 
was extremely well-tolerated, with no reported acute or late grade ≥ 3 toxicities.  In a 
second trial, 14 patients were treated with 52.5 Gy in 15 fractions (3.5 Gy/fraction) with 
concurrent liposomal doxorubicin and vinorelbine.32  No grade ≥ 3 nonhematologic 
toxicities were observed.  At the University of Michigan, over 50 LA-NSCLC patients 
have been treated with hypofractionated RT along with carboplatin and paclitaxel.  Daily 
fraction sizes were based on predicted complication probabilities, and patients were 
treated to biologically equivalent doses of 80-100 Gy over 30 fractions.  Based on 
encouraging toxicity and efficacy results from the Michigan group, the RTOG has 
opened a phase II study using a similar design. (RTOG 1106 protocol)
Table 1 describes our proposed RT dosing schema along with RT schedules 
used in other studies.  Time-adjusted biologically equivalent doses are also provided, 
using the Linear Quadratic Model and published estimates for model parameters.33,34  
Based on the data summarized above, “high-risk” lesions shall be defined as tumors or 
lymph nodes with MTV greater than 25 cc on pre-treatment PET imaging.
Regimen
Description
EQD2 – Tumor
EQD2 - Normal Tissues
RTOG 0617: Control Arm
2.0 Gy x 30 fx = 60 Gy
(6 weeks)
55.5 Gy
60.0 Gy
RTOG 0617: High-dose Arm
2.0 Gy x 37 fx = 74 Gy
(7.5 weeks)
67.8 Gy
74.0 Gy
Current Trial: Low-risk lesions 
(MTV<25 cc)
2.28 Gy x 25 fx = 57 Gy
(5 weeks)
56.4 Gy
60.2 Gy
Current Trial: High-risk lesions 
(MTV>25 cc)
2.6 Gy x 25 fx = 65 Gy
(5 weeks)
68.3 Gy
72.8 Gy
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Table 1 – Proposed dosing schedules for high- and low-risk lesions, defined by MTV on pre-treatment 
PET/CT imaging.  fx=fractions.  EQD2 refers to biologically equivalent dose, calculated using the Linear 
Quadratic Model (α/β=10 Gy and potential doubling time=5.6 days for tumor, α/β=3 Gy for normal tissues)
2.5  Biomarker Studies
Metabolomics is the "systematic study of the unique chemical fingerprints that 
specific cellular processes leave behind".35  The metabolome represents the collection 
of all metabolites in a biological cell, tissue, organ or organism.36  The tools most 
commonly used to quantify metabolite levels are nuclear magnetic resonance (NMR) 
spectroscopy and mass spectroscopy (MS).  Metabolomics is an emerging discipline 
that may one day change medical practice in fields such as nutrition, toxicology, 
endocrinology, and oncology.37-40
A number of biomarkers are theorized to have implications in the detection, 
prognosis, and post-treatment evaluation of NSCLC patients.41,42   Reported metabolite 
derangements in NSCLC include changes in plasma levels of Krebs cycle components 
and certain amino acids.42  Urine markers for NSCLC have also been identified.43  
Metabolomics may also prove helpful for the early detection of radiation-induced lung 
injury.44
Our group is fortunate to collaborate closely with Dr. Irwin J. Kurland, who is an 
Associate Professor in the Department of Medicine and Director of the Stable Isotope 
and Metabolomics Core Facility of the Diabetes Research Center.  Blood and urine 
samples collected as part of this protocol we be used to study of the metabolomics of 
lung cancer and how they evolve during chemoradiotherapy.  These exploratory 
analyses will identify promising subjects for future prospective study.
2.6  Rationale for Treating Low-risk Lesions with a Conservative RT Dose
This protocol is being amended such that tumors or lymph nodes deemed to be 
low-risk (based on having pre-treatment MTV < 25 cc) will be treated with a total RT 
dose of 52.5 Gy (2.1 Gy per fraction).  This is a modest decrease compared to the initial 
study design, where such lesions were treated with 57 Gy (2.28 Gy per fraction).  This 
change is supported by a number of studies whose results have become available since 
the initial design of this trial as well as older studies that can now be viewed in a 
different context: 

Updated results of RTOG 0617 have been presented.45  In this randomized study 
testing high-dose RT (74 Gy) against a standard RT dose (60 Gy), dose 
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escalation unexpectedly led to a statistically and clinically significant decrease in 
overall survival.  Median survival was 29 months in the control arm and only 20 
months in the high-dose arm.  Rates of Grade 5 treatment-related toxicity were 
2% and 4% in the control and experimental arms, respectively.  Although this 
difference does little to explain the large difference in outcomes between the two 
arms, multivariable analysis revealed that the occurrence of severe acute 
radiation esophagitis and the RT dose received by the heart were independently 
predictive of inferior overall survival.46  This suggests that the additional RT 
delivered to thoracic organs in the high-dose arm may directly lead to decreased 
patient survival.  Decreasing the dose delivered to these organs, conversely, may 
be expected to improve outcomes.

A large National Cancer Database analysis of over 30,000 locally-advanced 
NSCLC patients who underwent potentially-curative resection demonstrated that 
the use of postoperative RT with a dose above 54 Gy was associated with 
significantly lower 5-year survival than the use of a dose between 45 and 54 Gy 
(28% v. 38%).47  The use of high RT doses remained statistically significantly 
associated with inferior overall survival on multivariable analysis.

A retrospective review performed at our institution has demonstrated that, 
although locoregional progression is common following definitive 
chemoradiotherapy for locally-advanced NSCLC, the specific site of tumor 
progression can be predicted based on pre-treatment PET.48  We found that the 
2-year cumulative incidence rate for progression in lesions larger than 25 cc was 
45%, compared to only 5% for lesions under 25 cc (p < 0.001).  Many of the 
lesions smaller than 25 cc were treated with doses below 55 Gy, and only one 
such lesion progressed following treatment (Figures 4 and 5).
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Figure 4 – Scatter plot of PTV D90 versus MTV for 82 lesions. MTV is plotted on a 
logarithmic scale. Squares represent primary tumors, while circles denote lymph nodes. 
Lesions that were the first site of disease progression are shaded in black.
Figure 5 – Cumulative incidence of local disease progression in individual lesions after
grouping by pre-treatment MTV. Death and progression at any other disease site were 
treated as competing risks.  Gray’s test p-value is less than 0.001.

RTOG 73-01 was a randomized trial testing four RT schedules for locally-
advanced NSCLC.49  Its results are often cited as the rationale for the “standard” 
dose of 60 Gy.  Review of the results from that study, however, demonstrates 
that there was no difference in overall survival between patients who were 
treated with 50 Gy and those who received 60 Gy (Figure 6).  In light of this, 
reducing the RT dose for lesions deemed to be at low risk for disease 
progression to 52.5 Gy is unlikely to detract from patients’ outcomes.
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Figure 6 – Overall survival curves from RTOG 73-01, a randomized study that tested 
four radiotherapy schedules for patients with locally-advanced NSCLC
The data summarized above support reduction of the RT dose administered to 
low-risk tumors and lymph nodes.  While de-escalation of therapy for a patient 
population where cure rates are limited seems counterintuitive, it is important to note 
that we are only scaling back therapy for lesions whose local control has been excellent 
(Figure 5).  The new dose of 52.5 Gy for these lesions was chosen because it exceeds 
the 50 Gy dose studied in RTOG 73-01 but remains within the acceptable range of 
doses suggested by the National Cancer Database study.47  If patients enrolled on this 
study develop disease progression in low-risk lesions treated with 52.5 Gy, we will 
revise this amendment.
Figure 7 – Rationale for pursuing risk-adjusted dose painted RT for locally-advanced 
NSCLC
3.0  PATIENT ELIGIBILITY
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Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. This checklist must be photocopied, completed and 
maintained in each patient’s chart.
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 D):
o
Stage IIIA or IIIB 
o
Stage II NSCLC with medical contraindication to curative surgical 
resection
o
Stage IV disease 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 

Appropriate diagnostic/staging workup, including:
o
Complete history and physical examination
o
Whole body 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.
o
MRI of the brain or CT Scan of the head 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 highly recommended but not 
required.

No prior chemotherapy or thoracic radiotherapy for lung cancer

ECOG Performance Status 0-2 (Appendix C)

Age > 18

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
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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
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 
thoracentisis 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 
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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
Treatment
This will be a single stage phase II study testing the efficacy and feasibility of 
hypofractionated, dose-painted IMRT (based on target lesion volumes on pre-treatment 
PET/CT imaging) with standard concurrent chemotherapy (low dose weekly carboplatin 
and paclitaxel) for the treatment of LA-NSCLC.  Any lesions with pre-treatment MTV 
greater than 25 cc will be prescribed the higher dose (2.6 Gy per fraction), and lesions 
with MTV less than 25 cc will be treated with the lower dose (2.28 Gy per fraction).  All 
patients will be treated with 25 daily fractions over 5 weeks. 
All patients will receive standard weekly dosing of carboplatin (AUC 2) and 
paclitaxel (45 mg/m2) chemotherapy weekly for five weeks during RT.  This may be 
followed by 3 cycles of full dose adjuvant carboplatin (AUC 6) and/ paclitaxel 
(200mg/m2) every 3 weeks, at the discretion of the treating physicians.  Adjuvant 
chemotherapy should be started 4-6 weeks after completion of radiotherapy.  Patient 
will have restaging PET/CT scan after completion of adjuvant chemotherapy or 12-16 
weeks from completion of chemoradiation.
Follow-up
Patients will be evaluated with a history and physical examination at least once 
each week during the course of RT.  Patients will be seen four weeks after completion 
of RT for toxicity evaluation.  Patients may be seen more frequently to manage 
treatment-related toxicities if needed.  Patients will be evaluated for response with post-
treatment PET/CT imaging 12-16 weeks after completion of RT.  Subsequent follow-up 
visits will occur every three months for the first two years and then every six months for 
a total of five years.  Chest imaging with CT or PET/CT is recommended every three 
months over the first two years.  Patients will be followed for survival and recurrence 
every 3 months for the first two years and every 6 months thereafter, and this data will 
be recorded on follow-up forms.
4.2  Study Calendar
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A:  Pre-enrollment laboratory tests should be performed within 28 days of study entry.  HCG is required 
only for women with childbearing potential and must be done within 72 hours prior to start of study 
therapy.
B:  PFTs within 6 weeks of study entry are highly recommended but not required.
C:  Additional imaging of the brain may be obtained at any point if clinically indicated.
D:  Adjuvant chemotherapy is optional, at the discretion of the treating physicians.  Clinic visits and 
evaluations, including blood tests, can be skipped at weeks 12 and 15 for subjects who are not receiving 
adjuvant chemotherapy.
E:  After Week 19 visit, patients will be seen every three months (+/- 2 weeks) for two years and then 
every six months (+/- 4 weeks) for a total of five years
4.3  Primary Endpoint

The primary endpoint of this study is the metabolic response of all pulmonary 
lesions and thoracic lymph nodes on post-treatment PET/CT imaging.  For the 
purposes of this study, response will be defined as having maximum SUV less 
than 6.0 on post-treatment PET/CT, which will be obtained 12-16 weeks after 
completion of RT.  Persistent metabolic activity above this threshold in a single 
lesion will qualify the subject as a nonresponder.
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
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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

Lung cancer cause-specific survival: the interval from study registration to death 
directly from lung cancer, censored at the date of data collection (a patient will be 
considered to have died from lung cancer if he or she had evidence of disease 
progression at any site and no direct evidence of other cause of death)

Grade ≥ 2 radiation-induced lung toxicity, scored using CTCAE, v. 4

Any grade ≥ 3 treatment-related toxicity, scored using CTCAE, v. 4
5.0  STUDY THERAPY
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. Positions 
uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments. 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 must 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 insure 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.  The planning CT scans should be performed with IV contrast 
unless the patient has allergic problems with contrast or has renal insufficiency.  
Contrast will allow better distinction between target lesions and adjacent vessels or 
atelectasis.  Axial acquisitions with gantry 0 degrees will be required with spacing ≤ 3.0 
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mm between scans in the region of the tumor.  Images will be transferred to the 
treatment planning computers for treatment planning.
Isocenter or reference point port localization images (anterior/posterior and 
lateral) should be obtained at each treatment on the treatment unit (or patients should 
undergo a tomographic imaging study using the linear accelerator couch, if available) 
immediately before treatment to ensure proper alignment of the geometric center (i.e., 
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.  The low-risk gross tumor volume 
(GTV_5250) 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_6500), will also be defined and will include only lesions with 
MTV > 25 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 SUVmax.50  By definition, GTV_6500 will be a subset of 
GTV_5250.
If 4D CT simulation is used, 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).
Each GTV (or ITV) will be expanded by 7-10 mm to form a CTV (CTV_5250 and 
CTV_6500).  CTVs may be trimmed to exclude anatomic boundaries to microscopic 
tumor spread.  CTV_6500 will be a subset of CTV_5250.
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 10 mm in the superior and inferior directions.  PTV_6500 will be a 
subset of PTV_5250.
For high-risk lesions that are in close proximity to a dose-limiting structure (eg: 
large supraclavicular lymph node abutting brachial plexus), the prescription dose will be 
2.4 Gy x 25 fractions = 60 Gy.  A GTV_6000, CTV_6000, and PTV_6000 shall be 
generated for those lesions as described above.
Adaptive RT (adjustment of target volumes during the course of RT) is not 
allowed in this protocol, unless difficulties with daily patient setup require repeating the 
CT simulation procedure.
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Megavoltage equipment is required with effective photon energies of 6-18 MV. 
Use of IMRT or volumetric modulated arc therapy (VMAT) is required for this protocol.  
All fields must be individually shaped to minimize structures and lung not within the 
target volume. Divergent custom-made blocks or multi-leaf collimation will be used. All 
treatment planning will be performed using tissue heterogeneity corrections.
Treatment may alternatively be delivered using proton beam therapy.  In that 
case, all of the dosimetric guidelines described herein must be followed after converting 
physical dose to gray-equivalent (GyE).
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 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 
based on the published atlases available on the RTOG web site 
(http://www.rtog.org/CoreLab/ContouringAtlases.aspx).  Dosimetric constraints for 
organs at risk are listed in Table 2.  These have been adopted from the ongoing RTOG 
1106 protocol for LA-NSCLC.
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
Max Dose
Mean Dose
≤72 Gy
≤34 Gy
≤74 Gy
≤35 Gy
>74 Gy
>35 Gy
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Spinal Cord
Max Dose
≤50 Gy
≤52 Gy
>52 Gy
Brachial 
Plexus
Max Dose
≤63 Gy
≤65 Gy
>65 Gy
Table 2 – 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 when the pericardium and spinal cord receive 
doses lower than 50 Gy.  Radiographic evidence of radiation change and subsequent 
fibrosis of the lung will occur within lung volume receiving  ≥ 20 Gy, usually within the
first six months after initiation of treatment.  It is essential to spare as much normal lung 
as possible in order 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 according 
to the CTCAE v.4.0.  If Grade 4 esophagitis occurs, and a treatment interruption is 
being considered, every effort should be made to limit the treatment break to 3 days or 
less.  Patients requiring hospitalization because of esophagitis may have their treatment 
interrupted.  In this event, please notify the principal investigator (PI).
Treatment should be interrupted for grade 4 or greater dysphagia or 
odynophagia.  Acute esophageal toxicity, which typically can occur within two weeks of 
the initiation of treatment and manifests as dysphagia, odynophagia, and reflux 
symptoms, should be pharmacologically managed with the following approach and 
should be initiated at the first signs or symptoms of esophageal toxicity.  Recommended 
treatments are listed in the table below.  In cases where the treating physicians are 
concerned that inanition will occur due to disease burden and/or chemoradiotherapy 
(eg, based on the patient’s RT plan), prophylactic feeding tube placement may be 
considered.
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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 (45 mg/m2, IV) will be started 
on week 1 of thoracic radiotherapy and will be continued weekly for 5 weeks. 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 45 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
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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.
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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:

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/Consolidation Chemotherapy
5.3.1  Adjuvant/Consolidation Chemotherapy Dosing
Consolidation chemotherapy will start approximately 4-6 weeks after the 
completion of all radiotherapy when esophagitis and chemotherapy-induced neuropathy 
are grade 1 or less, ANC > 1500, and platelet count > 100,000.  If the ANC and platelet 
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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.
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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 all study 
procedures and will be medically managed. These patients will continue to be followed 
as specified in the protocol.  These patients may be treated with other agents. Patients 
who exhibit local-regional tumor progression will complete radiation as described in 
Section 6.0. Tissue confirmation is recommended to confirm the progressive disease in 
locoregional or metastatic sites.
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. If the patient experiences esophagitis so that IV fluid 
support is needed, insertion of a feeding tube should be considered.  RT should be 
discontinued if Grade 4 pulmonary toxicity occurs.  
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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/Consolidation Chemotherapy Modifications
Patients 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 consolidation 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 consolidation cycles.  When a chemotherapy dose reduction is 
required during the consolidation 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 consolidation therapy. 
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5.4.4 Allergic Reactions
If, at any point in the course of study therapy, 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: cisplatin/etoposide) that will be administered using a 
standard dosing schedule.  Radiotherapy and other protocol-specified procedures, 
including the post-treatment PET/CT, will proceed as planned.  These patients will be 
followed for primary and secondary endpoints, in keeping with the “intent to treat” 
principle. 
5.5  Biospecimen Collection
Blood (less than 10 mL in an EDTA tube) and urine (less than 15 mL) samples 
will be collected from patients prior to therapy, and at week 3, at week 9, and at the time 
of response evaluation (at approximately week 19).  These collections are included in 
the Study Calendar (section 4.2).  Blood tests are routinely performed on a weekly basis 
for patients receiving chemotherapy, so only the week 19 collection will cause patient 
inconvenience outside of standard clinical care.  Urine samples will also be collected at 
the same time points.
Instructions for the handling of blood and urine samples are described in detail 
on the Albert Einstein Stable Isotope & Metabolomics Core website. 
(http://www.einstein.yu.edu/uploadedFiles/Research/Shared-Facilities/stable-isotopes-
metabolics/Sample%20preparation%20guideline.pdf)  Samples will be directed to:
Hardik Shah
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Einstein Metabolomics Core Facility
c/o Albert  Einstein College of Medicine
1301 Morris Park Ave, Price Bldg 368
Bronx, NY 11743
Each specimen will be analyzed in the Stable Isotope & Metabolomics Core 
Facility of the Diabetes Research Center, which is directed by Dr. Irwin Kurland.  We will 
test each sample for over 150 metabolites that are involved in pathways such as the 
urea cycle, fatty acid metabolism, and spermidine and spermine metabolism.  Additional 
information about these tests is available at http://www.einstein.yu.edu/research/shared-
facilities/stable-isotope-metabolomics-core/services/.
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6.0  RESPONSE ASSESSMENT
6.1  Primary Endpoint – PET Response
The primary endpoint of this study is achieving metabolic response in the primary 
tumor and all thoracic lymph nodes on post-treatment PET/CT imaging, which will be 
obtained 12-16 weeks after completion of RT.  For the purposes of this study, metabolic 
response will be defined as having maximum SUV less than 6.0 on post-treatment 
imaging.  Persistent metabolic activity above this threshold in a single lesion will qualify 
the subject as a nonresponder.
This assessment will be performed by the PI and co-investigators from the 
Department of Nuclear Medicine.  For each patient, every hypermetabolic thoracic 
lesion visible on post-treatment PET/CT imaging will be contoured 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 SUVmax.  The maximum SUV for each lesion will be recorded, as will the maximum 
SUV for each study subject.
6.2  Secondary Endpoints – Progression-free Survival
Secondary endpoints of this study include locoregional progression-free survival 
and progression-free survival.  Evaluation for progressive disease will follow RECIST 
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7.0  STATISTICAL CONSIDERATIONS
7.1  Sample Size Calculation
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Based on data we have generated from the ACRIN 6668 / RTOG 0235 dataset, 
approximately 35% of patients can be expected to have significant (SUVmax>6.0) 
residual hypermetabolic activity on post-treatment PET/CT after chemoRT for LA-
NSCLC.  We hypothesize that this rate will be less than or equal to 15% for patients 
treated on this protocol.  Based on this assumption, 31 post-treatment PET/CT scans 
will be required to provide 80% power to detect an improvement in PET response rate 
at a target error rate of 5% and actual error rate of 0.046.  If 7 or fewer out of 31 patients 
have significant residual activity, we will accept the hypothesis that the rate of residual 
activity is less than or equal to 15%.  Adjusting for a 10% dropout rate, a total of 39 
patients will be accrued to this study. 
 
7.2  Primary Efficacy Analysis
Descriptive statistics of baseline demographic and clinical characteristics will be 
presented. The demographic and clinical characteristics will be compared between 
responders and non-responder’s using chi-square statistics or Fishers exact test for 
categorical variable and t-test or Wilcoxon Mann-Whitney U test for continuous 
variables. The efficacy analysis of the primary endpoint, which is the metabolic 
response of all pulmonary lesions and thoracic lymph nodes on post-treatment PET/CT 
imaging, will be performed using single sample pre-post proportion test. 
7.3  Secondary and Other Efficacy Analyses
Secondary endpoints of this study include locoregional progression-free survival, 
progression-free survival and overall survival.  Kaplan-Meier survival plots will be 
produced for disease-free survival and overall survival.  The survival probabilities will be 
presented.  Log-rank testing will be used to compare the survival probabilities between 
categorical predictors.  A Cox regression model will be used to estimate the hazard 
rates for progression free survival and overall survival among the predictor variables.  In 
addition, for patients who are assessed as responders, time to objective response and 
objective response duration will be summarized.  The safety parameters will be 
presented as frequency and percentages.  The relationship of metabolic markers during 
the course of time with treatment response and clinical endpoints will be assessed using 
logistic regression and time-dependent Cox regression models.
7.4  Subject Accrual
In the Einstein/Montefiore Department of Radiation Oncology, approximately five 
patients are treated with definitive chemoRT for LA-NSCLC each month.  We expect 
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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 
18 months.
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8.0  REGULATORY CONSIDERATIONS
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.
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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.
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 
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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 monthly basis.  During its 
monthly 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 
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)
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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.
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 B). A list of 
AEs that have occurred or might occur can be found in sections above.  
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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
o
Intervention, including concomitant medications used to treat SAE
o
Pertinent laboratory data/diagnostic tests conducted and date
o
Pertinent medical history of patient
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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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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
-Whole body 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)
IRB NUMBER: 2013-252
IRB APPROVAL DATE: 02/16/2017