Clinical trial NCT02262325
Conditions: Recurrent Non-small Cell Lung Cancer Stage IIA Non-small Cell Lung Cancer Stage IIB Non-small Cell Lung Cancer Stage IIIA Non-small Cell Lung Cancer Stage IIIB Non-small Cell Lung Cancer
Keywords: Non-small cell Lung Cancer Chemoradiation
Sponsor: Ohio State University Comprehensive Cancer Center
Start date: 2015-06-08; Completion date: 2024-04-15
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well giving a hypofractionated boost to the primary tumor before standard chemotherapy and radiation therapy works in treating patients with stage II or III non-small cell lung cancer that cannot be removed by surgery. Advances in radiation oncology have allowed better radiation targeting which may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells. Giving more precise and targeted radiation before standard chemotherapy and radiation therapy may kill more tumor cells and prevent the cancer from coming back in the location in which it started.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the primary tumor control rate at 12 months.

SECONDARY OBJECTIVES:

I. To further establish safety and tolerability of this regimen. II. To estimate the rates of regional, distant control as well as progression-free survival and overall survival.

III. To evaluate the objective response rate (ORR) to this regimen. IV. To evaluate the response of tumors to stereotactic (high-dose) radiation using magnetic resonance tumor perfusion imaging modalities (magnetic resonance \[MR\]-dynamic contrast-enhanced \[DCE\]/perfusion weighted imaging \[PWI\], MR-diffusion, blood oxygenation level dependent \[BOLD\] sequences).

OUTLINE:

Patients will receive a hypofractionated boost to the primary tumor over 2 fractions (at least 40 hours apart) during week 1. Beginning week 2, patients receive cisplatin intravenously (IV) on days 8, 15, 36, and 43; and etoposide IV over 60 minutes on days 8-12 and 36-40. If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of carboplatin (AUC=6 mg/min/mL IV on day 1, 22) and paclitaxel (200 mg/m2 IV on day 1, 22) consolidation chemotherapy are required, to be administered starting 4-6 weeks after concurrent chemoradiation has ended. Each cycle is 21 days long. If cisplatin and etoposide is administered concurrently with radiotherapy, consolidation chemotherapy is not allowed. Patients also undergo standard conformal radiation therapy once daily (QD) 5 days a week for a total of 30 fractions. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms: arm 1: Patients undergo hypofractionated radiation boost over 2 fractions (at least 40 hours apart) during week 1. Beginning week 2, patients receive cisplatin IV on days 8, 15, 36, and 43; and etoposide IV over 60 minutes on days 8-12 and 36-40. Patients also undergo standard 3-D conformal radiation therapy QD 5 days a week for a total of 30 fractions. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: hypofractionated radiation therapy intervention 2: cisplatin intervention 3: etoposide intervention 4: 3-dimensional conformal radiation therapy intervention 5: laboratory biomarker analysis
Intervention descriptions: intervention 1: Radiation boost in week 1 (days 1-5) intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo 3-dimensional conformal radiation therapy intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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OSU PROTOCOL #: 14091 
Version Date: 11/2/2020 
TITLE: 
A Phase II trial Combining 
Hypofractionated Radiation Boost with 
Conventionally- Fractionated 
Chemoradiation in Locally Advanced Non-
Small Cell Lung Cancer Not Suitable for 
Surgery 
Coordinating Center: 
Ohio State University Comprehensive Cancer 
Center/Arthur G. James Cancer Hospital 
and Richard J. Solove Research Institute 
Primary Investigator: 
Eric Miller, MD, PhD  
Department of Radiation Oncology 
460 W 10th Ave 
2nd Floor 
Columbus, OH 43210-1240 
Phone: (614) 293-8415 
Eric.Miller@osumc.edu 
Commercially 
Available Agents: 
Cisplatin & Etoposide; 
Carboplatin & Paclitaxel 


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Table of Contents  
STUDY SUMMARY and STUDY SCHEMA ............................................................8 
1 OBJECTIVES .......................................................................................................12 
1.1 PRIMARY OBJECTIVE ................................................................12 
1.2 SECONDARY OBJECTIVES .......................................................12 
2 BACKGROUND & RATIONALE ..........................................................................12 
2.1 LOCAL CONTROL IN LOCALLY-ADVANCED NSCLC ...............12 
2.2 POTENTIAL TOXICITY FROM DOSE-ESCALATION………….....13 
2.3 STEREOTACTIC BODY RADIATION THERAPY ........................13 
2.4 RADIOBIOLOGIC HIGH DOSE MODELING………...……………14 
2.5 MAGNETIC RESONANCE IMAGING BIOMARKERS .................15 
3 STUDY DESIGN ...................................................................................................15 
3.1 GENERAL DESIGN ...................................................................15 
3.2 PRIMARY STUDY ENDPOINTS ................................................16 
3.3 SECONDARY STUDY ENDPOINTS .........................................16 
3.4 IMAGING CORRELATIVE ENDPOINTS....................................16 
4 SUBJECT SELECTION AND WITHDRAWAL .....................................................18 
4.1 INCLUSION CRITERIA ..............................................................18 
4.2 EXCLUSION CRITERIA .............................................................19 
4.3 GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH ..... 21 
4.4 SUBJECT RECRUITMENT AND SCREENING .........................21 
4.5 EARLY WITHDRAWAL OF SUBJECTS ....................................21 
4.5.1 When and How to Withdraw Subjects ...............................21 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects .....21 
5 STUDY PROCEDURES .......................................................................................22 
5.1 TREATMENT OVERVIEW .........................................................22 
5.2 SCREENING..............................................................................23 
5.3 RADIATION THERAPY ..............................................................23 
5.3.1 CT simulation and Target Delineation  ..............................23 
5.3.2 Radiation Planning ............................................................25 
5.3.3 Normal Tissue Constraints ................................................27 
5.3.4 Treatment Delivery and IGRT............................................30 
5.3.5 Treatment 
Modification/Interruption/Toxicity………………………30 
5.4 CHEMOTHERAPY ......................................................................... 31 
5.4.1 Concurrent Chemotherapy 
Schedule…………………………………31 
5.4.2 Consolidation Chemotherapy 
Schedule………………………………31 
5.4.3 Cisplatin ............................................................................32 
5.4.4 Etoposide ..........................................................................32 
5.4.5 Carboplatin…………………………………………………….33 
5.4.6 Paclitaxel……………………………………………………….34 
5.4.7 Dose Modifications ............................................................35 
5.5 PERMITTED THERAPIES ...........................................................38 
5.5.1 Immunotherapy .................................................................38 


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5.6 ON TREATMENT EVALUATIONS ...............................................38 
6.0 MRI Imaging……………………………………………………………………………39 
7.0 RESEARCH BLOOD DRAWS ..........................................................................40 
8.0 ADVERSE EVENTS, COMMON TOXICITY ASSESSMENT CRITERIA AND SUPPORTIVE 
CARE .......................................................................................................................41 
8.1   Adverse Events ..........................................................................41 
8.2 Interruption and Discontinuation……………………………..........43 
8.3 Management of Toxicity and supportive care .............................43 
8.4 Followup for toxicities………………………………………….….…44 
9.0 FOLOW-UP AND OUTCOME ASSESSMENT .................................................44 
9.1 VISIT SCHEDULE......................................................................44 
9.2 EFFICACY ASSESSMENTS......................................................45 
10 DURATION OF STUDY .....................................................................................47 
11 REGULATORY AND REPORTING REQUIREMENTS ......................................47 
12 STATISTICAL CONSIDERATIONS ...................................................................47 
12.1 SAMPLE SIZE DETERMINATION .............................................47 
12.2 FEASIBILITY ..............................................................................47 
12.3 DATA ANALYSIS PLAN .............................................................47 
13 SUBJECT POPULATION(S) FOR ANALYSIS .................................................... 48 
14 STUDY CALENDAR ..........................................................................................48 
15 STUDY FINANCES ............................................................................................48 
16 REFERENCES…………………………………………………………………………49 
17 ATTACHMENTS/APPENDICES ........................................................................52 
Appendix I:  Study Schedule ...........................................................52 
Appendix II:  RECIST .......................................................................54 
Appendix III: ECOG Performance Status Scale ............................ 55 
Appendix IV: Supplementary Tables…………………………………56 
Appendix V: Covid-19 Precautions…………………………………...57


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List of Abbreviations 
 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer  
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BOLD 
blood oxygenation level dependent  
  BP 
 
  blood pressure 
CBCP 
complete blood count with platelets  
CDDP  
cisplatin 
CFR 
Code of Federal Regulations  
Cmax 
maximum concentration of drug  
CMP 
comprehensive metabolic panel  
CPK 
serum creatine phosphokinase 
CrCl 
creatinine clearance 
CRT 
chemoradiation treatment 
CT 
computed tomography 
CTV 
clinical target volume 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCE/PWI 
dynamic contrast enhanced/perfusion weighted imaging  
DLCO 
diffusion capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicities 
DSMC 
Data Safety Monitoring Committee  
DWI 
diffusion weighted imaging 
FDA 
Food and Drug Administration 
FDG PET 
fluorodeoxyglucose positron emission tomography  
FEV-1 
forced expiratory volume at 1 second 
g/dL 
grams per deciliter 
gLQ 
generalized linear quadratic 
GTV 
gross tumor volume 
Gy 
Gray (unit of radiation) 
HCT 
hematocrit 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 


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IGRT 
Image guided radiation therapy  
IMRT 
Intensity modulated radiation 
 
therapy  
IRB 
Investigational Review Board 
ITV 
internal target volume 
IV 
intravenous 
L 
liter 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LQ 
linear quadratic 
LVEF 
left ventricular ejection fraction 
mg/m2 
milligrams per square  
meter mL/min milliliter per minute 
mmHg 
millimeters of mercury 
MRI 
magnetic resonance imaging  
MSDS 
Material Safety Data Sheet  
msec 
millisecond 
MTD 
maximum tolerated dose 
MV 
megavoltage photons 
NCI 
National Cancer Institute  
ng/mL 
nanograms per milliliter  
NIH 
National Institutes of Health 
OS 
overall survival 
PET 
positron emission tomography 
PFS 
progression-free survival 
PHI 
protected health information 
PI 
primary investigator 
PK 
pharmacokinetic 
PMN 
polymorphonuclear cells 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PTV 
planning target volume 
QD 
once daily 
RECIST 
Response Evaluation Criteria In Solid Tumors  


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RT 
radiation therapy 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SBRT 
stereotactic body radiation therapy 
Tmax 
maximum body temperature 
TNM 
tumor, (lymph) nodes, metastasis (cancer staging system) 
UICC 
International Union Against Cancer  
ULN 
upper limit of normal 
VMAT 
volumetric modulated arc therapy  
VP16 
etoposide 
WOCBP 
  Women of child-bearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Summary 
Title 
A Phase II trial Combining Hypofractionated Radiation Boost with 
Conventionally-Fractionated Chemoradiation in Locally Advanced 
Non-Small Cell Lung Cancer Not Suitable for Surgery 
Short Title 
Hypofractionation Boost with Chemoradiation for Locally Advanced 
Cancer 
Protocol Number 
OSU-14091 
IRB #2014C0112 
Phase 
2 
Methodology/Study 
Design 
Open-label, single-arm, phase II study to evaluate the efficacy and 
safety of hypofractionated, stereotactic body radiation therapy 
(SBRT) boost doses in patients with Stage II-III unresectable (or 
medically-inoperable) locally-advanced non-small cell lung cancer.  
Our goal is to improve on local control of the primary tumor. We 
will deliver 2 boost doses of SBRT in Week 1 to the primary tumor 
prior to the start of conventional chemoradiation, which will begin 
Week 2. 
Study Duration 
36 months for accrual of all patients 
Study Center(s) 
Single center 
Objectives 
Primary Objectives: 
• 
To estimate the primary tumor control rate at 12 months. 
Secondary Objectives: 
• 
To further establish feasibility, safety and tolerability of this 
regimen. 
• 
To estimate the rates of objective response rates (ORR) 
and rates of regional, distant control as well as 
progression-free survival and overall survival. 
• 
To evaluate the response of tumors to stereotactic (high- 
dose) radiation using magnetic resonance tumor perfusion 
imaging modalities (MR-DCE/PWI, MR-diffusion, BOLD 
sequences). 
• 
To correlate circulating tumor DNA and miRNA biomarkers 
with response and toxicity. 
Number of 
Subjects 
34 


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Diagnosis and 
Main Inclusion 
Criteria 
Male and female patients > 18 years old with Stage II or III locally 
advanced non-small cell lung cancer, who are unresectable or 
medically inoperable. 
Key Inclusion Criteria: 
• 
Non-small cell lung cancer (NSCLC), histologically and/or 
cytologically proven. 
• 
Clinical AJCC stage IIA-IIIB NSCLC (T1-4N0-3M0), deemed 
unresectable or medically inoperable. 
• 
Patients must have primary tumor ≤ 10 cm as defined by CT 
largest axial dimension. 
• 
ECOG performance status of 0-1. 
• 
Estimated life expectancy ≥ 12 weeks. 
• 
Able to undergo two MRI scans, one before study treatment 
begins and one shortly after first dose of radiation (optional study) 
Study Regimen 
Patients will be registered on trial, followed by blood-work, and CT 
simulation. For ten patients who consent for correlative MRI studies, 
baseline MR imaging will be obtained during Weeks -2 to 0. During 
Week 1, the patient will receive 2 SBRT boost doses (with optional MR 
imaging performed within 24 hours after SBRT boost dose 1). Following 
this, patients will be treated with standard conventionally-fractionated 
chemoradiation during Weeks 2-7 (60 Gy in 30 fractions, with cisplatin & 
etoposide or carboplatin & paclitaxel chemotherapy). 
Duration of 
Treatment 
7 weeks (with 2 additional consolidation cycles of carboplatin & paclitaxel 
chemotherapy for those receiving carboplatin & paclitaxel concurrent with 
radiation at the discretion of the medical oncologist) 
Reference therapy 
Standard chemoradiation for 6 weeks (60 Gy in 2 Gy fractions) over 
6 weeks with cisplatin & etoposide or carboplatin & paclitaxel. 
 
 
Statistical 
Methodology 
 
Analytic plan for Primary Objective: Primary tumor control rate at 
12 months, as well its 95% confidence interval, will be reported for 
all eligible subjects who received treatment. In addition, the local 
control failure over time will be plotted using Kaplan-Meier survival 
analysis. Rates of primary tumor control and local control at 1, 2 years 
and 3 years will also be summarized 
(a) Analytic plan for Secondary Objectives: Rates of all 
adverse agents, with special attention to grade 3-5 
esophagitis, cardiac, and pneumonitis adverse events, and 
death during or within 30 days of discontinuation of protocol 
treatment will be calculated. Rates of tolerability will be 
determined at the end of study. 
 
Regional and distant failure, PFS, and OS will be 
measured from date of treatment initiation to the event of 


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interest or otherwise censored at last follow-up. Kaplan-
Meier (K-M) analysis will be used to estimate PFS and OS. 
PFS will include any failure (local, regional, or distant) or 
death from any cause. 
 
For MRI correlative studies, all 3 metrics 
(perfusion/diffusion/oxygenation measurements) will be 
tested by comparing mean values pre- and post-SBRT using 
a paired t-test. Should there be concern for outliers, we will 
determine the median for each metric and compare medians 
using a corresponding non-parametric procedure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.1 OBJECTIVES 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
1.2 PRIMARY OBJECTIVE 
The primary objective of this work is: 
• 
To estimate the primary tumor control rate at 12 months after a combined regimen of 
stereotactic body radiation therapy (SBRT) with conventionally-fractionated 
chemoradiation in unresectable or medically-inoperable non-small cell lung cancer 
(NSCLC). 
 
1.3 SECONDARY OBJECTIVES 
The secondary objectives of this work are: 
• 
To further establish safety and tolerability of this regimen. 
• 
To estimate the rates of regional, distant control as well as progression-free survival and 
overall survival. 
• 
To evaluate the objective response rate (ORR) to this regimen. 
• 
To evaluate the response of tumors to stereotactic (high-dose) radiation using magnetic 
resonance tumor perfusion imaging modalities (MR-DCE/PWI, MR-diffusion, BOLD 
sequences). 
 
2.0 BACKGROUND AND RATIONALE 
2.1 Local Control in Locally-advanced NSCLC 
Concurrent chemoradiation (CRT) is the standard of care for ECOG PS 0-1 patients with 
unresectable tumors or medically-inoperable locally advanced NSCLC (see Table A, Appendix IV, for 
a summary of the major trials). In these trials, an average of 60-66 Gy of conventionally- fractionated 
radiation (1.8-2.0 Gy/day) was delivered to sites of clinically involved cancer, including the primary 
tumor, hilum, mediastinal, and supra-clavicular regions. Despite this, rates of local failure at the site of 
the primary tumor ranged from 25-40%. Local progression is well- established to be a major driving 
force of mortality in lung cancer patients(1-3). These high rates of local failure argue for better 
control of the primary tumor, which could decrease morbidity and mortality due to local disease 
progression, as well as reduce survival of remaining clonogens and development of metastatic disease 
from any residual primary tumor. 
 
While local failure remains high after standard CRT, regional nodal failures are low in both early stage 
and locally advanced NSCLC (4-6). In a large group of Stage I-III patients treated with involved field 
irradiation (IFI) at Memorial Sloan-Kettering Cancer Center, local failure occurred much more 
commonly than regional recurrence at 49% and 6%, respectively.(7) Classically, locally advanced 
NSCLC patients were treated with elective or prophylactic nodal irradiation (PNI). PNI treats 
uninvolved nodal basins (i.e. ipsilateral hilum, mediastinum, +/- supraclavicular region) in an attempt 
to eliminate subclinical microscopic disease. Modern practice has shifted towards omitting PNI to spare 
patients the added toxicities associated with comprehensive nodal radiation. Involved field irradiation 
(IFI) directs radiation only to areas involved with tumor on imaging, or confirmed via biopsy 
(mediastinal/endoscopic staging). Modern studies suggest that the rates of nodal failure are low 
when using IFI. Multiple studies have shown regional failure to be 10% or lower in patients treated 
with involved field radiation (i.e. no elective nodal RT) with standard doses. (2, 7, 8) It appears that 
local failure, not regional nodal recurrence, accounts for the majority of thoracic recurrences for both 
early stage and locally advanced stage NSCLC patients treated with standard CRT. This argues 


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that additional control should be focused on the primary tumor, not the regional lymphatics.  
 
2.2 Potential Toxicity from Dose-Escalation 
The results of RTOG 0617 were recently presented at the ASCO Annual Meeting 2013. This trial 
compared standard 60 Gy in 30 fractions concurrent with weekly carboplatin+paclitaxel 
chemotherapy to a dose-escalated schedule of 74 Gy in 37 fractions with the same chemotherapy, 
followed by consolidation carboplatin+paclitaxel chemotherapy. The results showed, disappointedly, 
that after a median follow-up of 18 months, higher dose was associated with inferior median survival 
of 19.5 months versus 28.7 months (HR 1.56, p<0.001). More deaths that considered to be treatment-
related occurred in the high-dose arm (10 versus 2). In addition, local failure was unexpectedly higher 
in the high-dose arm at 34.3% (versus 25.1%). In multivariate analysis, higher radiation dose and 
higher cardiac radiation exposure  were associated with inferior survival. Given that the high-dose arm 
included radiation not only to the primary tumor but also the involved nodes in the hilum and 
mediastinum, one possible explanation is that the high mediastinal/cardiac dose resulted in these 
excess deaths. 
 
2.3 Stereotactic Body Radiation Therapy 
Stereotactic body radiation therapy (SBRT) is a novel technique that permits highly conformal 
radiation therapy which facilitates high doses of radiation to tumors, while minimizing dose to 
normal tissues. SBRT is a type of hypofractionated radiation, which is defined as radiation 
delivered in larger doses and less than once a day compared to conventional fractionation. 
SBRT has shown excellent control rates in treating tumors of the lungs, liver, and other sites. With 
3-year local control rates commonly 90-95% following SBRT in early-stage (T1-2N0M0) NSCLC 
(4, 5, 9), it is attractive to hypothesize that SBRT may be one potential way to improve on the high 
local failures rates in locally advanced NSCLC. As a single treatment modality, SBRT in early 
stage NSCLC is associated with minimal toxicity. Rates of pneumonitis are reported to be 11% 
or less from large series of patients treated with SBRT (10-12). Furthermore, long-term changes 
in pulmonary function appear to be sub-clinically evident, with only minimal reductions in pulmonary 
function such as FEV-1 and DLCO (12-15). Recently, investigators reported on the safety of a 
SBRT boost dose for Stage III NSCLC with residual disease (16). SBRT boost doses were given 
approximately several weeks after completion of conventional chemoradiation (~60 Gy in 30-33 
fractions). With SBRT boost doses ranging from19.5-20 Gy in 2-3 fractions for both central and 
peripherally-located primary tumors, rates of radiation pneumonitis were low, with grade 3 and 4 
rates of 8.6% and 2.9%, respectively. Local control appeared to be improved compared to historical 
controls, but was only 83%, which perhaps was due to several weeks of treatment break 
following completion of CRT, which could have allowed for repopulation of tumor clonogens. 
Importantly, they found that the addition of SBRT to standard chemoradiation was safe: their 
findings confirm the safety of this approach and obviate the need for another phase I trial based on 
the doses we propose in this trial (which are similar to theirs).  Furthermore, a recent study published 
in 2015 by Woody et al., shows the relative safety and efficacy of treating larger tumors with radiation 
(Woody et al., Int J Radiat Oncol Biol Phys, volume 92(2), pp 325-31).  In this study with primary 
tumors ranging from 5.1 cm to 10 cm in size, SBRT showed high local control rates with low rates of 
grade 3 or higher toxicity.  
 
 


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2.4 Radiobiologic High Dose Modeling 
Mathematical models have been created to permit comparison of tumor control across various 
radiation schedules and fraction sizes. The most prevalent model applied to conventionally- 
fractionated radiation is the linear quadratic (LQ) equation, which allows for comparison across 
treatment schedules by converting dose and fractionation into a term referred to as the “biological 
effective dose (BED)”. Different tissues are assigned “α/β ratios”, which essentially is a reflection of a 
tissue’s sensitivity to changes in fraction size. With regard to tumor cells, a high α/β ratio confers 
“high sensitivity” to radiation, while a lower α/β predicts “low sensitivity” to radiation. Based on both 
laboratory and clinical trial data, the LQ model only appears to predict BED accurately for fraction 
sizes less than 3.25 Gy.(17) SBRT doses, however, fall well outside of this range. The LQ model, 
therefore, may not accurately predict the BED for extremely hypofractionated radiotherapy.(17-20) 
Several models have attempted to more 
accurately predict the response of tumors to 
hypofractionated radiotherapy relative to the LQ model. The universal survival curve (USC) (21), 
modified linear quadratic model (formerly the MLQ model, now termed the LQL model) (20), and the 
generalized linear quadratic (gLQ) model(17) all have been shown to radiobiologically model high dose 
per fraction (HFRT) better than the LQ model, with varying success at retaining accuracy in the low 
dose per fraction (CFRT) region (17, 18, 20). The gLQ model (developed at the Ohio State University) 
has been shown to radiobiologically model high dose per fraction better than the LQ model, and 
can accurately model tumor cell survival both at the low and high dose fraction range (17). 
 
In early stage NSCLC, commonly used SBRT treatment fractionations for peripherally located tumors 
include 54 Gy in 3 fractions and 48-50 Gy in 4 fractions. For more centrally-located lesions (those 
lying within 2 cm of the trachea, carina, main stem or lobar bronchi), excessive toxicity was associated 
with these standard regimens (22). Thus, standard dosing for centrally- located lesions is 50-60 Gy in 
5-10 fractions. 
 
Using the gLQ model, we have determined that the effective α/β ratio for lung cancer (from fitting 
the model to the published lung cancer cell survival data in the literature) is ~5.45 Gy, using cell 
lines, or 4.3 Gy using our own clinical data of approximately 85 patients treated with SBRT for early-
stage NSCLC at the Ohio State University. In this modeling, we have also accounted for a potential 
tumor doubling time of 7 days, and that the onset of time of accelerated repopulation starts at 14 days 
based on published data in NSCLC. Thus, we have calculated the SBRT boost doses which when 
added to 60 Gy in 2 Gy per fraction (conventional chemoradiation dose), will bring the total biological 
effective doses to that of 54 Gy in 3 fractions (for peripheral primary tumors) and 60 Gy in 5 fractions 
(for central primary tumors) for tumor control (Table B, Appendix IV) that would provide much more 
effective local control than traditional doses. The differences in dose between centrally-located and 
peripherally-located primary tumors is necessary due to previous findings from Timmerman et al.: 
centrally-located tumors need to receive a more protracted radiation schedule with lower radiation 
dose per day, due to toxicity observed with three fraction regimens (22). Using this modeling, we 
calculated that 17.3 Gy (2 fractions) and 13.95 Gy (2 fractions) is necessary for peripheral and 
central tumors respectively using a cell-line derived α/β ratio of 5.45 Gy (Table B). If we use the clinical 
data and an α/β ratio of 4.3 Gy, then the calculated doses are 13 Gy (2 fractions) and 11.5 Gy (2 
fractions) for peripheral and central tumors respectively (Table B). In order to translate this clinically, 
and understanding that there are limitations related to radiobiologic modeling, we have integrated these 
data and have determined that the optimal SBRT boost doses to the primary tumor only, will consist 
of an additional 8 Gy for 2 fractions for peripherally-located tumors (total 16 Gy), and 6 Gy for 2 
fractions (total 12 Gy) for centrally-located tumors. In terms of safety, 9-10 Gy x 2 fractions for a 
boost has been shown to be associated with acceptable acute and late toxicity (i.e. pneumonitis) as 
mentioned above in a trial exploring SBRT boost doses several weeks after completion of standard 


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conventionally fractionated chemoradiation(16). 
 
2.5 Magnetic Resonance Imaging Biomarkers 
Tumor oxygenation and microvasculature are well investigated components of the tumor 
microenvironment. Tumor hypoxia and impaired vascularity are associated with radiotherapy and 
chemotherapy resistance, high invasiveness, increased metastatic potential and poor prognosis (23). 
There is substantial literature that hypofractionated radiation or SBRT has dramatic effects on 
tumor vasculature in the acute post-radiation period. From a review of about 25 pre-clinical 
publications, moderately-high doses of radiation (i.e. 5-10 Gy), causes increases in tumor blood 
flow initially, which return to pre-irradiation levels 3 days later (24). In addition, in this same report, 
studies have shown that low or moderate radiation doses can increase tumor oxygenation and 
oxygen tension, therefore decreasing hypoxia, which could result in improved efficacy of 
chemotherapy and radiation, since hypoxia is known to promote therapeutic resistance. However, this 
effect has not been well-studied in human patients. Furthermore, this phenomenon has potential 
therapeutic implications.  We propose that treating a primary lung tumor with a single dose of 
stereotactic radiation during the SBRT boost, will result in increased tumor blood flow to the tumor, 
which could allow better accessibility and efficacy of standard radiation and chemotherapy. Thus, 
we will incorporate functional MRI methods (DCE/PWI, BOLD, and DWI) immediately before and 
after the first dose of SBRT (i.e. within 1 week before and 24 hours after SBRT) to evaluate and 
quantitate the changes in the tumor microenvironment. MRI DCE/PWI (dynamic contrast enhanced, 
perfusion weighted imaging) provides information on tumor vascularity, vessel permeability and blood 
volume with time dependent delivery of IV contrast agent. DCE/PWI parameters also correlate with 
tumor oxygenation (25). MRI BOLD (blood oxygenation level dependent) is based on T2* contrast 
induced by deoxyhemoglobin which is paramagnetic, whereas oxyhemoglobin is not. Several studies 
have shown relationship between BOLD signal response and tumor oxygenation. BOLD will be 
performed during delivery of room air and oxygen via face mask (26). DWI (diffusion weighted 
imaging) is based on the random or Brownian motion of water molecules in relation to their thermal 
energy. Tumor cell death is supposed to lead to unrestricted extracellular water motion and increase 
in the apparent diffusion coefficient (ADC) derived from DWI (27). Such imaging correlative studies 
will be informative in documenting tumor perfusional changes after SBRT and may provide additional 
information on optimal dosing of chemotherapy. Functional MRI methods are also expected to provide 
prognostic information. 
 
3.0 STUDY DESIGN 
3.1 GENERAL DESIGN 
Open-label, single-arm, Phase II study to evaluate the efficacy and safety of SBRT hypofractionated 
radiation boost doses in patients with Stage II-III unresectable (or medically- inoperable) locally-
advanced non-small cell lung cancer. Given that a recently reported phase I trial has  shown minimal 
toxicity using similar  doses  as  a boost for  residual disease after conventional chemoradiation for 
this group of patients, we believe a phase I trial is not necessary (16). 
 
Patients will be registered on trial after meeting eligibility criteria, blood-work, baseline MRI imaging 
(optional study), and CT simulation during Weeks -2 to 0.   During Week 1, the patient will receive 2 
SBRT boost doses at least 20 hours apart (with MR imaging performed within 24 hours after SBRT 
boost dose 1, prior to SBRT boost dose 2 if patient elects to have MRI). Following this, patients will be 
treated with conventionally fractionated chemoradiation for Weeks 2-7 (60 Gy in 30 daily fractions, 
5 days/week, with chemotherapy).  
 
The decision to perform the SBRT boost before the start of conventional CRT instead of 
immediately after CRT was: 1) due to the ease of performing 1 simulation for SBRT and 
conventional CRT; 2) to be able to accurately calculate and meet dosimetric constraints by 


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simultaneous planning of SBRT and conventional radiation plans; 3) moderate doses of radiation may 
transiently increase tumor perfusion thereby reducing hypoxia and allowing for improved subsequent 
chemotherapy delivery and ultimately, chemoradiation response; 4) to minimize interaction with 
chemotherapy (since the normal tissue side effects of the addition of high-dose radiation concurrent 
with radiosensitizing chemo are largely unknown); and 5) allow for more objective analysis of the 
effects of SBRT on tumor perfusion for the correlative MRI studies. 
 
3.2 PRIMARY STUDY ENDPOINTS 
Primary tumor control (of the primary tumor) at 12 months after all chemo/RT. Local failure is the 
combination of the primary tumor and involved lobe failure, with local control being the absence of 
local failure. Local failure rate is measured from the time of treatment completion until the first 
documented date of local failure. Local failure will be assessed by CT chest imaging during follow-
up as detailed in the Evaluation section. See assessment of primary tumor and local failure in Section 
9.2.  Confirmation of local failure will be required by one of the study P.I.s. 
 
3.3 SECONDARY STUDY ENDPOINTS 
-Safety is measured by the frequency of all adverse events, with special attention to grade 3-5 
esophagitis, pneumonitis, and cardiac adverse events as defined by the NCI Common Terminology 
Criteria for Adverse Events CTCAE v5.0. 
 
-Tolerability will be measured by the number of patients who discontinue treatment. 
 
-Clinical endpoints such as regional control, distant control, progression-free survival, and overall 
survival will be determined by progression or failure (occurrence of local, regional, and distant 
progression) or death, as measured from the time of treatment completion, and calculated at 12 and 
24 months of follow-up, with medians also estimated. 
 
-Objective response rate as measured by RECIST criteria. 
 
-Correlative MR imaging as measured by correlating pre-SBRT baseline perfusion, diffusion, hypoxia 
measurements with clinical endpoints, and measuring changes in tumor perfusion, diffusion, and 
hypoxia measurements after SBRT. 
 
3.4 IMAGING CORRELATIVE ENDPOINTS 
For imaging correlative endpoints, there will be multiple measurements made. For DCE-MRI, we will 
measure semi-quantitative (e.g. peak enhancement) and pharmacokinetic (e.g. washout rate 
constant kel) parameters derived from the analysis of the DCE (dynamic contrast enhancement) 
curve. For DWI, we will measure differences in mean apparent diffusion coefficient (ADC) between 
baseline and post-SABR images. Lastly, for BOLD-MRI, we will measure differences in BOLD (blood 
oxygenation level dependent) contrast between baseline and post-SABR images.      


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4.0 SUBJECT SELECTION AND WITHDRAWAL 
Patients must have baseline evaluations performed prior to the first dose of SBRT and must meet all 
inclusion and exclusion criteria. Results of all baseline evaluations will be reviewed by the treating 
physician prior to enrollment, to verify that all inclusion and exclusion criteria have been satisfied. 
In addition, the patient must be thoroughly informed about all aspects of the study, including the 
study visit schedule and required evaluations and all regulatory requirements for informed 
consent. The written informed consent must be obtained from the patient prior to screening 
procedures being performed. The following criteria apply to all patients enrolled onto the study 
unless otherwise specified. 
 
4.1 INCLUSION CRITERIA 
All prior treatment-related toxicities must be CTCAE (Version 5.0) ≤ grade 1 (except 
alopecia) at the time of enrollment. 
Adequate baseline organ function defined in the Table below, obtained within 30 days of study 
registration: 
 
System 
Laboratory Values 
Hematologic 
Absolute neutrophil count 
≥1.5 × 109/L 
Hemoglobin 
≥9 g/dL 
Platelets 
≥100 x109/L 
Hepatic 
Total bilirubin 
≤1.5 x ULN 
AST and ALT 
≤2.5 x ULN 
Renal 
Creatinine or 
<1.5 mg/dL 
Calculated creatinine clearancea or 
≥ 50 mL/min 
24-hour urine creatinine clearance 
≥ 50 mL/min 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; 
LLN = lower limit of normal; a= Calculated by the Cockcroft-Gault formula. 
 
 
1. > 18 years old 
2. Non-small cell lung cancer (NSCLC), histologically and/or cytologically proven 
3. Clinical AJCC stage IIA-IIIB NSCLC (T1-4N0-3M0). 
4. Patients must be considered unresectable or medically-inoperable. 
5. Patients must have primary tumor ≤ 10 cm as defined by CT largest axial dimension. 
6. Within 60 days of registration:  patients must have FDG-PET-CT scan (or CT 
chest/abdomen/pelvis with IV contrast), and MRI brain with IV contrast (preferred) or 
CT scan of the brain with contrast.  Non-contrast MRI scans of the 


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chest/abdomen/pelvis or brain are permitted for workup if patient has allergy to CT 
contrast or renal insufficiency. 
7. Within 30 days of registration: patients must have vital signs, history/physical 
examination, laboratory studies (CBCP with differential, chemistries including liver 
function tests, CrCl assessment; pregnancy test if needed within 14 days of 
registration). 
8. If a pleural effusion is present and visible on both CT scan AND chest Xray, the 
investigator should exclude malignant disease by pleurocentesis to confirm 
cytologically-negative pleural fluid. If fluid is exudative or cytologically positive for tumor 
cells, patient is excluded. 
• 
Patients with effusions that are minimal (i.e. not visible on chest x-ray) and that 
are too small to safely tap are eligible. 
9. Life expectancy of at least 12 weeks in the opinion of investigator. 
10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
within 30 days of registration. 
11. Patients must have a measurable primary tumor (undetectable NSCLC primary tumor is 
ineligible). 
12. Patients must be a minimum of 3 weeks from thoracotomy (if performed) and well-
healed before starting treatment. 
13. Ability to provide written informed consent obtained prior to participation in the study and 
any related procedures being performed. 
14. Women of child-bearing potential (WOCBP) must have a negative pregnancy test 
within 14 days of registration.  Urine HCG is an acceptable pregnancy assessment. 
15. Nursing women may participate only if nursing is discontinued, due to the possibility of 
harm to nursing infants from the treatment regimen. 
16. Women/men of reproductive potential must be counselled on contraception/ 
abstinence while receiving the study treatment. 
17. Patient is suitable to receive standard chemotherapy with radiation during Weeks 2-7 
(e.g. cisplatin+ etoposide or carboplatin+paclitaxel). 
 
4.2  EXCLUSION CRITERIA 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Patients with contralateral hilar involvement (greater than 1.5 cm on short axis or positive 
on PET scan, or biopsy-proven). 
 
2. Documented or pathologically-proven metastatic disease. 
 
3. Presence of nodules considered neoplastic in the same lobe or other ipsilateral lobe as 
the primary tumor (stage T3-4), unless the nodule can be encompassed in the 
stereotactic boost (GTVboost) without exceeding a total GTVboost size of 10 cm as 
defined by the sum of the largest CT axial dimensions of each nodule. 
 
4. Presence of nodules considered neoplastic in contralateral lobes (M1a). 
 
5. Patients with history of pneumonectomy. 


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6. Prior cytotoxic chemotherapy or molecularly-targeted agents (e.g. erlotinib, 
crizotinib) as anticancer therapy, unless > 2 years prior. 
 
7. Any concurrent malignancy other than non-melanoma skin cancer, non-invasive 
bladder cancer, or carcinoma in situ of the cervix. Patients with a previous malignancy 
without evidence of disease for ≥ 3 years will be allowed to enter the trial. 
 
8. History of active connective tissue disease (scleroderma) or idiopathic pulmonary fibrosis. 
 
9. History of previous radiation therapy which would result in overlapping radiation fields. 
 
10. Uncontrolled neuropathy grade 2 or greater, regardless of cause. 
 
11. Subjects who are breast-feeding and plan to continue breast-feeding during therapy, or 
have a positive pregnancy test will be excluded from the study. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should inform 
her treating physician immediately. 
 
12. If patient elects to have two research MRIs, medical contraindication to MR imaging (e.g. 
pacemakers, metallic implants, aneurysm clips, known contrast allergy to Gadolinium 
contrast, pregnancy, nursing mothers, weight greater than 350 pounds) or severe 
anxiety/claustrophobia related to MR imaging despite medications to relieve 
anxiety/claustrophobia  
 
13. Any serious and/or unstable pre-existing medical disorder (aside from malignancy 
exception above), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the Investigator. This could include severe, active co-morbidities such as: 
 
- 
unstable angina and/or congestive heart failure requiring hospitalization within 
the last 6 months 
 
- 
transmural myocardial infarction within the last 6 months 
 
- 
Acquired immune deficiency syndrome (AIDS) based upon the current 
CDC definition; note, however, that HIV testing is not required for entry 
into this protocol.  The need to exclude patients with AIDS from this 
protocol is necessary because the treatments involved in this protocol 
may be significantly immunosuppressive 
 
- 
Chronic obstructive pulmonary disease exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy within 30 
days of registration 
 
- 
Hepatic insufficiency resulting in jaundice and/or coagulation defects 
 
4.3 GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH 
This study includes both genders and minority patients. Pediatric patients are excluded. 
 


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4.4 SUBJECT RECRUITMENT AND SCREENING 
Patients who are 18 year of age or older with non-metastatic locally advanced non-small cell lung 
cancer are eligible for the study. Patients can be recruited from PI or co-investigators’ clinical 
practices. Potential study subject should be notified to PI and study designated research 
nurse/research associate. Appropriate laboratory or diagnostic testing necessary to meet any 
noted inclusion or exclusion criteria will be ordered through the recruiting physician. The treating 
physician will screen and determine the final eligibility of the subject for enrollment. 
 
4.5 EARLY WITHDRAWAL OF SUBJECTS 
 
4.5.1When and How to Withdraw Subjects 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 
1. Intercurrent illness 
2. Occurrence of an unacceptable adverse event 
3. A treatment delay in radiation therapy >1 weeks 
4. Patient request 
5. Protocol violations 
6. Non-compliance 
7. Administrative reasons 
8. Failure to return for follow-up 
9. General  or  specific  changes  in  the  patient’s  condition  unacceptable  for  
further treatment in the judgment of the investigator 
10. Progressive disease  
 
The primary reason for a patient’s withdrawal from the study is to be recorded in the source 
documents. 
 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
According to FDA regulations, when a subject withdraws from the study, the data collected on the 
subject to the point of withdrawal remains part of the study database and may not be removed. A 
subject who is withdrawing needs to state whether he/she wishes to provide continued follow-up 
and further data collection subsequent to withdrawal from the study.  If a subject withdraws from the 
study, but agrees to continued follow-up of associated clinical outcome information, the subject will 
continue follow up visit and evaluation per the protocol. 
 
If a subject withdraws from the study and does not consent to continued follow-up of associated 
clinical outcome information, study data related to the subject collected prior to the subject’s 
withdrawal from the study will be included in the study analysis. 
 
Patient with progressive disease will be followed for survival, non-protocol related treatment, and 
adverse events.  AEs for patient with progressive disease should be recorded until patient starts a new 
treatment for progressive disease or hospice care (whichever comes first).  The follow-up assessment 
may be done over the phone by the study nurse/CRC.  
 
5.0 STUDY PROCEDURES 


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5.1 TREATMENT OVERVIEW 
 
The study will consist of the following schedule: 
 
• 
Patients will be registered and obtain baseline laboratory studies (CBCP, 
chemistries, liver function tests). If no pulmonary function tests (including FEV-1 and 
DLCO) within last 90 days, patient will be sent to obtain these. Within 3 weeks of 
planned start (Weeks-3 to 0), patients will undergo a CT simulation. 
 
• 
Treatment will then proceed with two SBRT boost doses (directed at the primary 
tumor only) in Week 1 (Days 1-5). For peripheral tumors, 8 Gy x 2 fractions will be 
administered, while for central tumors, 6 Gy x 2 fractions will be administered. 
SBRT boost doses must be a minimum of 20 hours apart.  If research MRIs are being 
performed, the 1st research MRI must occur prior to SBRT boost dose 1, and the 2nd 
research MRI must occur within 24 hrs of SBRT boost dose 1, and prior to SBRT boost 
dose 2.  Ideally, these treatments would begin towards the end of Week 1 (Wednesday-
Friday), if standard chemoradiation will be started the following week (Week 2). 
 
• 
This will be followed by standard fractionated radiation with chemotherapy in Week 2. 
Chemoradiation will occur during Weeks 2-7, with 60 Gy in 30 fractions concurrent with 
cisplatin (50 mg/m2 IV, days 8, 15, 36, 43) and etoposide (50 mg/m2 IV, days 8-12, 36- 
40), or carboplatin (AUC=2 mg/min/mL IV weekly) and paclitaxel (50 mg/m2 IV weekly)   
 
• 
If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of 
carboplatin (AUC=6 mg/min/mL IV on day 1, 22) and paclitaxel (200 mg/m2 IV on day 
1, 22) consolidation chemotherapy are required, to be administered starting 4-6 weeks 
after concurrent chemoradiation has ended. Each cycle is 21 days long. At the 
discretion of the medical oncologist, consolidation chemotherapy can be omitted if 
patient plans to receive durvalumab immunotherapy. If cisplatin and etoposide is 
administered concurrently with radiotherapy, consolidation chemotherapy is not 
allowed.  
 
 
 
 


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5.2 SCREENING 
Within 7 days of starting treatment, patient will have the first research blood draw. 
 
Within 14 days of registration, patient will have optional research MRI, and women of 
childbearing potential will have a pregnancy test. 
 
Within 21 days of registration, patient will have CT simulation. 
 
Within 30 days of starting treatment, patients will have CT chest with contrast unless there is an 
issue with insurance coverage, or patient has an allergy to CT contrast or renal insufficiency.  
Patient will also have baseline hematologic studies including complete blood count, blood 
chemistries, hepatic and renal function tests.  
 
Within 60 days of registration, patients will have PET/CT scan (or CT chest/abdomen/pelvis with 
contrast), and MRI brain with intravenous contrast (or CT of the brain with IV contrast). 
 
Within 90 days of registration, patient must have pulmonary function tests including FEV-1 
and DLCO. 
 
 
5.3 RADIATION THERAPY 
Note:  The experimental Week 1 treatments (hypofractionated boost) need to occur at the James 
Cancer Hospital.  However, standard chemoradiation treatments (Weeks 2-7) and consolidation 
chemotherapy (for patients receiving carboplatin and paclitaxel) can be performed locally if 
performed by a James Cancer Network physician (e.g. Foster J. Boyd Regional Cancer Center, 
Wilmington, OH).   
 
 
5.3.1 CT Simulation and Target Delineation 
During CT simulation for the Week 1 treatment, patients will undergo a 4D-CT simulation with 
or without abdominal compression and stereotactic immobilization (e.g. Vac-Lock bag), along with 
a free-breathing or breath hold CT scan for treatment planning. If 4D-CT scan cannot be performed, 
a series of exhale and inhale scans can be performed to assess motion.  
 
For the Week 2-7 treatments, a separate CT scan can be performed without abdominal compression 
on a standard wingboard/arm shuttle, which will be used for radiation planning for the conventional 
chemoradiation portion of the treatment. This scan can also be performed with a 4D-CT scan, or series 
of exhale & inhale scans to assess motion.  Administration of IV contrast will be left to the discretion of 
the treating physician. 
 
CT simulation images for the stereotactic planning should be 2.5 mm or less in slice thickness. 
 
Alternatively, if all radiation treatments will be performed at the James, a single CT simulation can be 
performed for both the stereotactic boost treatment and conventionally fractionated treatments, but 
must include a 4D-CT (or exhale/inhale series) and a free-breathing scan at the minimum, and either 
abdominal compression or respiratory gating. 
 
After CT simulation, images will be transferred to the treatment planning system for radiation 
planning. Radiation planning for both SBRT and conventional treatments will be performed 
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delineated in the protocol. Therefore, for patients treated at James Cancer Network affiliate sites by 
a James radiation oncologist, the Weeks 2-7 radiation DICOM plan must be sent to the James 
Cancer Hospital, Department of Radiation Oncology, for evaluation.   
 
Patients can be treated with or without respiratory-gating, including breath-hold technique. Contouring 
normal structures: 
• 
Heart/pericardium:  superior aspect is the inferior aspect of the aortic arch. 
• 
Esophagus:  contour from one slice below the inferior aspect of the cricoid cartilage  
to the gastroesophageal junction 
• 
Spinal cord:  contour at least 5 cm above and below superior and inferior extent of PTVs 
• 
Brachial plexus: contour for cases with apical tumors or supraclavicular nodal disease 
as necessary depending on location of PTVs, using the RTOG brachial plexus 
contouring atlas from C5-T2. 
• 
Whole Lung:  not to include GTVs. 
• 
Skin:  outer 0.5 cm of the body surface. 
• 
Ipsilateral proximal bronchial tree (for SBRT planning scan only): The proximal bronchial 
tree will include the most inferior 2 cm of distal trachea and the proximal airways. The 
following airways will be included according to standard anatomic relationships: the 
distal 2 cm of trachea, the carina, the right and left mainstem bronchi, the right and 
left upper lobe bronchi, the intermedius bronchus, the right middle lobe bronchus,  the 
lingular bronchus, and the right and left lower lobe bronchi. Contouring of the lobar 
bronchi will end immediately at the site of a segmental bifurcation. If there are parts 
of the proximal bronchial tree that are within GTV, they should be contoured separately, 
as “ipsilateral proximal bronchial tree GTV”, not as part of the “ipsilateral proximal 
bronchial tree”. 
• 
Great vessels (for SBRT planning scan only): for right sided tumors, contour the 
vena cava.  For left sided tumors, contour the aorta.  Contour at least 5 cm above 
and below superior and inferior extent of PTVs. 
 
Target Delineation for SBRT Plan 
Using the treatment planning scan, the physician will designate the boost gross tumor volume 
[GTVboost] by delineating the primary tumor. The primary tumor will generally be drawn using CT 
pulmonary windows; however, soft tissue windows with contrast may be used to avoid 
inclusion of adjacent vessels, atelectasis, or mediastinal or chest wall structures within the GTV. 
This target will not be enlarged whatsoever for prophylactic treatment (including no “margin” for 
presumed microscopic extension); rather, include only abnormal CT signal consistent with gross 
tumor (i.e., the GTV and the clinical target volume [CTV] are identical). Then, an internal target 
volume (ITV) boost [ITVboost] will be constructed to account for motion using the 4D-CT, unless the 
patient is being treated with breath-hold technique, in which case there will be no ITV.  Finally, 
ITVboost will be expanded by a minimum of 0.5 axially and craniocaudally (at the discretion of the 
radiation oncologist) to make the final PTVboost for planning. 
 
Target Delineation for Conventionally-Fractionated Radiation Plan 
 
Please note: elective nodal irradiation is not permitted, except in the case of the ipsilateral 
hilum. The decision to include the ipsilateral hilum will be left to the discretion of the radiation 
oncologist. 
 
Gross tumor volume (GTV) for all clinically involved disease will be designated by the treating 
physician on the CT planning dataset.  Internal target volumes (ITVs) will be generated from the 


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GTVs to account for motion noted on the 4D-scans (or exhale/inhale scans).   
 
Next, CTVs will be made from the ITVs (or GTVs if no ITVs) by expanding all ITVs/GTVs by 0.5-1.0 
cm in both axial and craniocaudal dimension, as determined by the treating physician. CTVs will 
be edited by the physician to exclude uninvolved organs (bone, air, muscle, etc) as necessary. 
 
Finally, CTVs will be expanded by a minimum of 0.5-1.0 cm axially and craniocaudally (at the 
discretion of the radiation oncologist) to make the final PTVs for planning. Each individual PTVs will 
be summed together to create a total PTV (PTV60). 
 
 
5.3.2 Radiation Treatment Planning and Treatment Delivery 
 
***NOTES: SBRT boost and conventionally- fractionated radiation plans should be created at the 
same time in order to evaluate sum dose between the 2 radiation plans.  It is recommended that the 
conventionally-fractionated plan (60 Gy in 30 fractions) be planned first using the objectives outlined 
below, followed by planning of the SBRT boost.  It is REQUIRED to have both plans signed and 
evaluated by a study PI prior to having the patient start treatment. 
 
Radiation Planning for SBRT 
 
Density corrections will be employed for planning. 6-18 MV photons will be used for planning. The 
PET-CT can be used to help delineate the primary tumor but should not be used solely for defining 
the GTVboost. 
 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for each 
case to deliver highly conformal prescription dose distributions. Non-opposing, non- coplanar beams 
are preferable. Typically, ≥ 10 beams of radiation will be used with roughly equal weighting. 
Generally, more beams are used for larger lesion sizes. When static beams are used, a minimum 
of seven non-opposing beams should typically be used. For arc rotation techniques, a minimum of 
340 degrees (cumulative for all beams) should be utilized. 
 
Field aperture size and shape should typically correspond nearly identically to the projection of the 
PTV along a beam’s eye view (i.e., no additional “margin” for dose buildup at the edges of the 
blocks or MLC jaws beyond the PTV). The only exception will be when observing the minimum 
field dimension of 3.5 cm when treating small lesions. As such, prescription lines covering the 
PTV will typically be the 60-90% line (rather than 95-100%); however, higher isodoses (hotspots) 
must be manipulated to occur within the target and not in adjacent normal tissue. 
 
The isocenter in stereotactic coordinates will be determined directly from the tumor in the case of 
volumetric imaging and translated to the treatment record. 
 
Intensity Modulated Radiation Therapy and Volumetric Modulated Arc Therapy 
Intensity Modulated Radiation Therapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) 
technologies are allowed. 
 
Prescription Isodose Surface Coverage: The dose per fraction is to be prescribed to the prescription 
line at the edge of the PTVboost. The prescription isodose surface will be chosen such that the 
goal will be to have 95% of the target volume (PTVboost) be conformally covered by the 
prescription isodose surface and 99% of the target volume (PTVboost) receiving a minimum of 


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90% of the prescription dose. 
 
The dose for peripheral tumors will be 8 Gy x 2 fractions (or a total of 16 Gy). The dose for 
central tumors will be 6 Gy x 2 fractions (or a total of 12 Gy), delivered at least 20 hours 
apart. 
 
Central tumors are defined as those tumors within or touching the zone of the proximal bronchial 
tree, defined as a volume 2 cm in all directions around the proximal bronchial tree (carina, right 
and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe 
bronchus, lingular bronchus right and left lower lobe bronchi). [See figure below from RTOG 
stereotactic radiation lung protocols] Tumors that are immediately adjacent to mediastinal or 
pericardial pleura are also considered central tumors. 
 
With central tumors, efforts should be made with beam angles to minimize dose to heart and 
mediastinum (e.g. esophagus). 
 
 
 
 
High Dose Spillage: 
a. Location: Any dose > 105% of the prescription dose should occur primarily within the 
PTVboost itself and not within the normal tissues outside the PTV. Therefore, the 
cumulative volume of all normal tissue outside the PTVboost receiving a dose > 
105% of prescription dose should ideally be no more than 15% of the PTVboost volume 
b. Volume: Conformality of PTVboost coverage will be judged such that the ratio of the 
volume of the prescription isodose volume of the PTVboost is ideally < 1.2 (see Table 
below). These criteria will not be required to be met in treating very small tumors (< 2.5 
cm axial GTV dimension or < 1.5 cm craniocaudal GTV dimension) in which the required 
minimum field size of 3.5 cm results in the inability to meet a conformality ratio of 1.2. 
 
 
Low Dose Spillage: The falloff gradient beyond the PTVboost extending into normal tissue 
structures must be rapid in all directions and should ideally meet the following criteria: 


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a. Location: The maximum total dose over all fractions in Gray (Gy) to any point 2 cm or 
greater away from the PTVboost in any direction should be no greater than D2cm where 
D2cm is given by the table below. 
b. Volume: The ratio of the volume of 50% of the prescription dose isodose to the volume of 
the PTV should be no greater than R50% where R50% is given. See Table below 
(derived from RTOG 0813 protocol). 
 
 
 
 
Planning for Conventionally Fractionated Radiation 
As for the SBRT planning, density corrections will be employed for planning. 6-18 MV photons will 
be used for planning. The PET-CT can be used to help delineate the primary tumor but should 
not be used solely for defining the GTVs. 
 
 
A multi-field three-dimensional conformal or IMRT plan is recommended, and VMAT is allowed.  
Respiratory-gating techniques are also allowed. 
 
All efforts will be made to ensure that with normalization of the treatment plan, 95% of the PTV60 
will be covered with the prescription dose ideally. The maximum dose within the PTV60 should ideally 
not exceed a value that is 110% of the prescribed dose. 
 
 
The final plan normalization is based upon the Plan Sum coverage of the PTV60 and PTVboost.  
Normalization values may need to be altered to maintain 95% PTV60 receiving >95% of the 
prescription dose (60 Gy), while respecting OAR (summed dose) constraints.  Additional 
recommendations include keeping hot spots in the plan sum within the PTV boost. 
 
 
5.3.3 Normal Tissue Constraints 
 


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For SBRT boost doses (6 Gy or 8 Gy per day x 2 fractions), the following objectives and 
their associated priorities for planning are listed: 
Spinal cord (PRIORITY 1): 
• 
5.5 Gy max point dose per fraction (0.03 cc) REQUIRED 
• 
<0.25 cc receives 4.5 Gy per fraction (ideal) 
• 
<0.5 cc receives 2.5 Gy per fraction (ideal) 
 
Ipsilateral Brachial Plexus (PRIORITY 1) 
• 
7.5 Gy max point dose per fraction (0.03 cc) REQUIRED 
• 
<3 cc receives 5.5 Gy per fraction (ideal) 
 
Esophagus (PRIORITY 2) 
• 
Max 105% of PTVboost prescription (0.03 cc) 
• 
<5 cc receives 5 Gy per fraction 
 
Heart/Pericardium (PRIORITY 2) 
• 
Max 105% of PTVboost prescription (0.03 cc) 
• 
<15 cc receives 5 Gy per fraction 
 
Trachea and ipsilateral bronchus (non-adjacent wall) (PRIORITY 3) 
• 
Max 105% of PTVboost prescription (0.03 cc) 
• 
<4 cc receives 3.5 Gy per fraction 
 
Great vessels (non-adjacent wall) (PRIORITY 4) 
• 
Max 105% of PTVboost prescription (0.03 cc) 
• 
<10 cc receives 9 Gy per fraction 
 
Skin (PRIORITY 4) 
• 
Max 6 Gy per fraction (0.03 cc) 
• 
<0.25 cc receives 4.5 Gy per fraction 
• 
<0.5 cc receives 2.5 Gy per fraction 
 
Chest Wall (2 cm rind) (PRIORITY 4) 
• 
30 cc < 6 Gy per fraction 
 
Stomach (PRIORITY 4) 
• 
Max 7 Gy per fraction (0.03 cc) 
 
The spinal cord maximum dose is an absolute limit and treatment delivery that exceeds this limit will 
constitute a major protocol violation.  However, some organs at risk (OAR) (e.g. esophagus, trachea, 
bronchi, and heart) may be situated adjacent to the treated GTV/PTV.  As such, there is no specified 
limit as tumor that are immediately adjacent to that organ will not be able to be treated to any of the 
prescription doses without irradiating a small volume of that organ to the prescribed dose.  In such a 
case, the planning needs to be done so that there is no hot spot within that organ, even if that organ 
is part of the GTV/PTV (i.e., that no part of any OAR receives more than 105% of the prescribed 
dose).  In addition, the volume of the OAR in question needs to be minimized both in length and in 
width (circumference), with efforts made to reduce the dose to the contralateral wall of the organ. 
 
For non-spinal cord OAR with known sensitivity to high doses of radiation (including the esophagus, 


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trachea/bronchus, and stomach) included within a PTVboost or immediately adjacent to PTVboost, it 
is reasonable to underdose the PTVboost to achieve the goals of the sum plan.  Additionally, every 
effort should be made to cover the GTV with the prescription dose while ensuring rapid falloff to the 
OAR.  Coverage of a section of PTVboost including or immediately adjacent to the OAR may be as 
low as 70% of the prescription dose ONLY in this situation. 
 
For Conventionally Fractionated Radiation Plans (2 Gy per day in 30 fractions, total 60 
Gy), the following objectives and their associated priorities for planning are listed: 
 
Spinal cord (PRIORITY 1): 
• 
45 Gy max point dose (0.03 cc) 
 
Ipsilateral Brachial Plexus (PRIORITY 1) 
• 
65 Gy max point dose (0.03 cc) 
 
Esophagus (PRIORITY 2) 
• 
Mean dose ≤ 34 Gy 
• 
V50 < 33% 
• 
V60 < 17% (ideal, but strive for V60 <30%) 
 
Heart (PRIORITY 2) 
• 
Mean heart dose ≤ 35 Gy 
• 
V30 ≤ 50% 
• 
V45 ≤ 35% 
 
Total Lung – all PTVs (PRIORITY 2) 
• 
Mean lung dose ≤ 20 Gy 
• 
No more than 25% is to exceed 30 Gy 
• 
No more than 35% is to exceed 20 Gy 
• 
No more than 50% is to exceed 10 Gy 
• 
No more than 65% is to exceed 5 Gy 
 
For Sum Plan between SBRT boost and conventionally fractionated radiation: 
***NOTE THAT THESE ARE STRICT REQUIREMENTS AND ARE NOT TO BE EXCEEDED 
UNLESS DEEMED ACCEPTABLE BY ONE OF THE STUDY P.I.s (in which case a note 
needs to be made in the chart explaining that this was deemed acceptable by one of the 
study P.I.s) 
Spinal cord (PRIORITY 1): 
• 
45 Gy max point dose (0.03 cc) 
 
Ipsilateral Brachial Plexus (PRIORITY 1) 
• 
65 Gy max point dose (0.03 cc) 
 
Total Lungs – all PTVs (including PTVboost) (PRIORITY 2) 
• 
Mean Lung Dose (MLD) should be ideally ≤18 Gy (max ≤ 20 Gy) 
• 
V20 ≤ 30% ideally (max ≤ 35%) 
 
Esophagus (PRIORITY 2) 


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• 
Mean dose ≤ 34 Gy 
• 
Max dose ≤ 65 Gy (0.03 cc) 
 
Heart (PRIORITY 3) 
• 
Mean heart dose ≤ 35 Gy 
• 
V30 ≤50% (ideal; acceptable ≤ 55%) 
• 
V45 ≤35% (ideal; acceptable ≤ 40%) 
• 
Maximum not to exceed 70 Gy 
 
 
*** If any of these values are exceeded, please contact study P.I.s for recommendations. One 
option is to decrease coverage to the PTVboost in order to meet Sum Plan objectives as stated 
above (i.e. coverage of a section of PTVboost including or immediately adjacent to the OAR may be 
as low as 70% of the prescription dose ONLY in this situation).  However, if the sum plan is deemed 
unacceptable by one of the study P.I.s, the patient will be removed from the clinical trial and treated 
with standard chemoradiation (with no SBRT boost). 
 
*** All plans are required to be reviewed by one of the study P.I.s prior to initiation of treatment. 
 
 
5.3.4 Treatment Delivery and IGRT 
Patients will receive 2 fractions of SBRT radiation, with a minimum of 20 hours between 
treatments, and which must occur during Week 1. 
 
SBRT may be delivered via VMAT, IMRT, conformal arc, or conventional stereotactic radiation, and 
may use Varian RPM gating if the patient will be treated with respiratory-gated or breath-hold methods. 
 
Daily image-guided radiation therapy (IGRT) will include a daily cone-beam CT for 
each PTVboost fraction. 
 
For the conventionally-fractionated treatment plan starting on Week 2, the daily prescribed dose is 2 
Gy per day with treatment given five days per week. All radiation fields shall be treated once per day. 
 
Recommended image-guided radiation therapy (IGRT) methods include orthogonal pair imaging, 
port film verification, and/or cone beam CT. The type and frequency of IGRT will be determined 
by the investigator but should include a minimum of one CBCT per week for matching. Portal 
verification of all fields should be performed prior to the delivery of the first fraction for patients 
treated with 3D conformal radiotherapy. 
 
 
5.3.5 Treatment Modification/Interruption/Toxicity: 
No treatment interruptions are planned. Treatment may be interrupted for acute toxicity. 
Chemotherapy will be held if RT is held. No modifications in total dose will be made for 
interruptions in therapy. Toxicities will be graded according to the NCI CTCE v.5.0. If grade 3 
dysphagia or esophagitis occurs, it is at the discretion of treating physician whether to interrupt 
treatment.  If interruption is warranted, every effort should be made to limit the treatment break to 3 
days or less.  If grade 4 dysphagia or esophagitis occurs, all treatments including chemotherapy 
and radiation therapy should be put on hold until patient is stable enough to continue with the 
treatment. If radiation is interrupted for grade 4 dysphagia or esophagitis, hold radiation until grade 
2 or less and do not restart chemotherapy even if radiation is restarted.  Radiotherapy also will be 


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held for grade 4 skin reaction until it is stable enough to continue. Chest Radiation Therapy may 
cause: 1) esophagitis, 2) fatigue (tiredness), 3) skin reaction within the radiation fields, 4) loss of 
chest hair, 5) decrease in white blood cells and platelets with increased risk of infection and/or 
bleeding, 6) lung fibrosis, 7) delayed wound healing or non-healing (fistulae), 8) chest pain, and 9) 
muscle spasm. 
 
 
5.4. CHEMOTHERAPY 
Note:  The experimental Week 1 treatments (hypofractionated boost) need to occur at the James 
Cancer Hospital.  However, standard chemoradiation treatments (Weeks 2-7) and consolidation 
chemotherapy (for patients receiving carboplatin and paclitaxel) can be performed locally if 
performed by a James Cancer Network physician (e.g. Foster J. Boyd Regional Cancer Center, 
Wilmington, OH).   
 
5.4.1. Concurrent Chemotherapy Schedule: 
Chemotherapy and radiation therapy will begin within 24 hours of each other with chemotherapy 
delivered first if possible/feasible.  However, alternate scheduling is allowed.  A single platinum-
based doublet chemotherapy regimen is to be administered during radiotherapy. The choice of the 
chemotherapy regimen is at the discretion of the treating physician.   One of the following 
recognized standard, protocol-allowed regimens must be given with radiation therapy:  
 
• 
Paclitaxel (50 mg/m2) intravenous over 1 hour followed by Carboplatin AUC = 2 mg/min/mL 
intravenous weekly (every 7 days) during radiotherapy.  Standard premedications with 
steroids, famotidine, diphenhydramine, and antiemetics must be administered per 
individual institutional guidelines.  
 
OR  
 
• 
Etoposide (50 mg/m2/d) intravenous on days 8-12 and days 36 to 40 and Cisplatin (50 
mg/m2/d) intravenous on days 8, 15, 36, and 43.  Standard premedications with steroids 
and antiemetics must be administered per individual institutional guidelines. Standard 
intravenous hydration must be administered in conjunction with cisplatin. 
 
Filgrastim and pegfilgrastim may not be used during concurrent chemoradiotherapy.  
Erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may not be used during 
concurrent chemoradiotherapy.  
 
Chemotherapy scheduling modifications of +/- 3 dyas are allowed due to weekends and holidays.  
 
5.4.2  Consolidation Chemotherapy Schedule: 
 
**Please note:  At the discretion of the medical oncologist, consolidation chemotherapy can 
be omitted if patient is planned to receive durvalumab. See section 5.5.1 for detailed 
information. 
 
The treating physician will administer 2 cycles of consolidation chemotherapy 4-6 weeks after 
concurrent chemoradiotherapy has ended, only if patients receive concurrent carboplatin and 
paclitaxel with radiotherapy. Each cycle length is 21 days. The consolidation chemotherapy regimen 
is carboplatin and paclitaxel.  


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• 
Paclitaxel (200 mg/m2) intravenous over 3 hours on day 1, and carboplatin at an area 
under the plasma concentration time curve (AUC) = 6 mg/min/mL intravenous on day 1.  A 
second cycle of paclitaxel and carboplatin will be administered on day 22.  
 
Standard premedications with steroids, famotidine, diphenhydramine, and antiemetics must be 
administered per individual institutional guidelines.  
 
Patients who receive concurrent cisplatin and etoposide with radiotherapy are not allowed to receive 
consolidation chemotherapy.  
 
Filgrastim, pegfilgrastim, or erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may be 
used during consolidation chemotherapy (Rizzo 2010). 
 
5.4.3  Cisplatin (CDDP) (Platinol®) (NSC-119875) 
Refer to package insert for detailed pharmacologic and safety information. 
 
Formulation  
Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric 
acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range will be 3.5 
to 4.5. Cisplatin injection also is available from the manufacturer in aqueous solution, each ml 
containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH. Cisplatin also is available 
in vials containing 50mL or 100mL of a 1mg/mL solution.  
 
Storage and Stability  
Reconstituted solution of cisplatin is stable for 20 hours when stored at 25°C and should be 
protected from light if not used within 6 hours. The vials and injection should not be refrigerated. 
Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 
minutes. Therefore, needles or intravenous sets containing aluminum parts that may come in 
contact with the drug must not be used for the preparation or administration of cisplatin.  
 
Adverse Events  
Human toxicity includes nausea, vomiting, anaphylaxis, neuropathies, ocular disturbances, renal 
toxicity (with an elevation of BUN and creatinine and impairment of endogenous creatinine clearance, 
as well as renal tubular damage, which appears to be transient), ototoxicity (with hearing loss that 
initially is in the high-frequency range, as well as tinnitus), and hyperuricemia. Much more severe and 
prolonged toxicity has been observed in patients with abnormal or obstructed urinary excretory tracts. 
Myelosuppression, often with delayed erythrosuppression, is expected 
 
Supply 
Commercially available. 
The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 
CFR 312.2(b) for IND exemption. 
 
5.4.4  Etoposide (VP-16) (Vepesid®) (NSC-141540) 
Refer to package insert for detailed pharmacologic and safety information. 
 
Storage and Stability  
Store the unopened vials under refrigeration 2º to 8º C (36º-46º F). Retain in original package to 
protect from light.  


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Adverse Events  
Hematologic: Myelosuppression is dose related and dose limiting with granulocyte nadirs occurring 7 
to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug 
administration. Bone marrow recovery is usually complete by day 20. Acute myeloid leukemia has 
been reported in rare instances.  
 
Gastrointestinal: Nausea and vomiting are the major gastrointestinal toxicities. Nausea and vomiting 
can usually be controlled with standard antiemetic therapy.  
 
Hypotension: Transient hypotension following rapid intravenous administration has been reported in 
1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic 
changes. No delayed hypotension has been noted.  
 
Allergic Reactions: Anaphylactic-like reactions characterized by chills, fever, tachycardia, 
bronchospasm, dyspnea and hypotension have been reported to occur in less than 1% of the 
patients treated with the oral capsules. These reactions have usually responded promptly to the 
cessation of the drug and to the administration of pressor agents, corticosteroids, antihistamines or 
volume expanders as appropriate. One fatal acute reaction associated with bronchospasm has been 
reported.  
 
Alopecia: Reversible alopecia, sometimes progressing to total baldness was observed in up to 66% 
of patients. 44 RTOG 1308; version date 10/24/13  
 
Other: The following adverse reactions have been infrequently reported: aftertaste, hypertension, 
rash, fever, pigmentation, pruritus, abdominal pain, constipation, dysphagia, transient cortical 
blindness, and a single report of radiation recall dermatitis. 
 
Supply 
Commercially available. 
The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 
CFR 312.2(b) for IND exemption. 
 
5.4.5   Carboplatin (NSC-241240) 
Refer to package insert for detailed pharmacologic and safety information. 
 
Formulation  
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 
mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol. 
Carboplatin also is available as a 10 mg/mL solution in 50, 150, and 450 mg vials.  
 
Preparation  
When available, prediluted vials of carboplatin should be utilized. Otherwise, the preparation of 
carboplatin should proceed as described below:  
 
Immediately before use, the contents of a carboplatin vial must be reconstituted with either sterile 
water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP.  
 
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore, 
needles or intravenous sets containing aluminum parts that may come in contact with the drug must 
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Storage and Stability  
Intact vials of carboplatin are stable for the period indicated on the package when stored at room 
temperature (15-30˚C or 59-86˚F) and protected from light. When prepared as described above, 
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The solution 
should be discarded after 8 hours since no antibacterial preservative is contained in the formulation. 
 
Adverse Events  
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, neutropenia, 
leucopenia, and anemia are common but typically resolve by day 28 when carboplatin is given as a 
single agent.  
 
Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of patients receiving the 
drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and 
hypotension. The reactions can be successfully managed with standard epinephrine, corticosteroid, 
and antihistamine therapy. Desensitization per the allergy team is allowed. 
 
Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin with 
mild paresthesia being the most common.  
 
Gastrointestinal: Nausea and vomiting are the most common gastrointestinal events; both usually 
resolve within 24 hours and respond to antiemetics. Other gastrointestinal events include diarrhea, 
weight loss, constipation, and gastrointestinal pain.  
 
Hepatic: Elevated alkaline phosphatase, total bilirubin, and SGOT have been reported.  
 
Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has been 
reported in 3% of the patients taking carboplatin. 
 
Supply 
Commercially available. 
The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title 21 
CFR 312.2(b) for IND exemption. 
 
5.4.6  Paclitaxel (Taxol®) (NSC 125973) 
 
Refer to package insert for detailed pharmacologic and safety information. 
 
Preparation  
Paclitaxel injection is a sterile solution concentrate, 6 mg/ml in 5, 16.7, and 50 ml vials (30, 100, and 
300 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. 
Paclitaxel will be diluted to a final concentration of 0.3 to 1.2 mg/ml in D5W, NS, or D5NS, in glass or 
polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer from polyvinyl 
chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which paclitaxel is 
solubilized. Each bag/bottle should be prepared immediately before administration. NOTE: 
Formation of a small number of fibers in solution (NOTE: acceptable limits established by the USP 
Particular Matter Test for LVPs) have been observed after preparation of paclitaxel. Therefore, in-
line filtration is necessary for administration of paclitaxel solutions. In-line filtration should be 
accomplished by incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 
microns (e.g.: Millex-GV Millipore Products) into the intravenous fluid pathway distal to the infusion 
pump. Although particulate formation does not indicate loss of drug potency, solutions exhibiting 


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excessive particulate matter formation should not be used.  
 
Storage and Stability  
Paclitaxel vials should be stored between 20-25°C (68°-77°F). When prepared as suggested (0.3 – 
1.2 mg/ml), the solution is stable for 27 hours.  
 
 
Adverse Effects  
Hematologic: Myelosuppression;  
 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain;  
 
Heart: Arrhythmias, heart block, hypertension;  
 
Neurological: Sensory and peripheral neuropathy;  
Allergy: Severe anaphylactic reactions;  
 
Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, induration, tenderness, 
rarely ulceration), hypotension, irritation to the injection site, mucositis 
 
 
5.4.7  Dose Modifications: 
 
Note:  Chemotherapy doses that are omitted due to the indicated toxicities below are not made up. 
 
5.4.7.1  Dose Modifications During Concurrent Chemoradiotherapy With Weekly Carboplatin and 
Paclitaxel  
 
Hematologic Toxicity  
Absolute neutrophil count (ANC) and platelet count (plt) must be obtained within 72 hours prior to 
each dose of carboplatin and paclitaxel, except for on day 8. 
 
If ANC < 1000 or plt < 75,000, omit weekly carboplatin and paclitaxel. Restart weekly carboplatin 
and paclitaxel at same dose if ANC > 1000 and plt > 75,000.  
 
Dysphagia/Radiation Esophagitis  
If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold weekly carboplatin 
and paclitaxel. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis and radiation 
is to be restarted, it is at the discretion of the treating physician whether or not to restart 
chemotherapy. If the decision is made to restart chemotherapy in this setting, consider reducing 
weekly carboplatin and paclitaxel dose by up to 50%. If radiation is interrupted for grade 4 dysphagia 
or radiation esophagitis, hold radiation until grade 2 or less and do not restart chemotherapy even if 
radiation is restarted. 
 
Neurologic Toxicity  
Paclitaxel doses will be modified for neurologic toxicity:  
• 
If grade 1 neurologic toxicity, no dose modification  
• 
If grade 2 neurologic toxicity, reduce dose to 75%.  
• 
If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to 
grade ≤ 2, then either reduce dose to 50% or discontinue chemotherapy, at the physician‘s 


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discretion.  
 
Renal Toxicity  
Carboplatin dose will be modified for renal toxicity. Serum creatinine must be obtained within 72 
hours prior to each dose of weekly carboplatin, except for day 8. Serum creatinine is required within 
10 days prior to day 8 carboplatin.  
• 
If renal toxicity occurs, the AUC will be re-calculated with a new serum creatinine, to account 
for the necessary dose adjustment. 
 
Neutropenic Fever [defined as temperature ≥ 38.3 C (101 F) and ANC < 500]  
• 
If neutropenic fever occurs and the patient subsequently meets criteria for further 
chemotherapy, the doses are reduced to 75%  
 
Other Toxicities Not Defined Above  
• 
If toxicities ≤ grade 2, then manage symptomatically, if possible, and retreat without dose 
reduction.  
• 
If toxicities ≥ grade 3 and attributed to the protocol treatment (possible, probably, or definite), 
drug should be withheld until patient is stable enough to continue with the treatment.  When 
medically appropriate to restart, consider reducing dose up to 50%. 
 
If carboplatin or paclitaxel doses are reduced, all future weekly doses are reduced. 
 
5.4.7.2  Dose Modifications During Concurrent Chemoradiotherapy With Cisplatin and Etoposide 
Hematologic Toxicity  
ANC and plt must be obtained within 72 hours prior to day 36 chemotherapy. 
  
For day 8 and day 36 cisplatin and etoposide:  
• 
If ANC ≥ 1250 and plt ≥ 100,000, give full dose  
• 
If ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1 week.  
• 
If after a 1 week delay ANC ≥ 1250 and plt ≥100,000, give full dose. If after a 1-week delay 
ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1 more week 
(total of a 2-week delay). If after a 2-week delay ANC ≥ 1250 and plt ≥ 100,000, reduce dose 
of chemotherapy by 25%. If after a 2-week delay ANC < 1250 or plt < 100,000, omit 
chemotherapy.  
 
For day 15 and day 43 cisplatin:  
ANC and plt must be obtained within 72 hours prior to day 15 and 43 chemotherapy. 
• 
If ANC ≥ 1000 and plt ≥ 75,000, give full dose  
• 
If ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in 1 week.  
• 
If after a 1-week delay ANC ≥ 1000 and plt ≥ 75,000, give full-dose cisplatin. If after a 1-week 
delay ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in 1 more 
week (total of a 2-week delay). If after a 2-week delay ANC ≥ 1000 and plt ≥ 75,000, reduce 
dose of cisplatin to 75%. If after a 2-week delay ANC < 1000 or plt < 75,000, omit the dose of 
cisplatin.  
 
Dysphagia/Radiation Esophagitis  
If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold cisplatin and 
etoposide. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis and radiation is to 
be restarted, it is at the discretion of treating physician whether or not to restart chemotherapy.  If the 
decision is made to restart chemotherapy in this setting, consider reducing cisplatin and etoposide 


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doses up to 50%. If radiation is interrupted for grade 4 dysphagia or radiation esophagitis, hold 
radiation until grade 2 or less and do not restart chemotherapy even if radiation is restarted.  
 
Neurologic Toxicity  
Cisplatin dose will be modified for neurologic toxicity:  
• 
If grade 1 neurologic toxicity, no dose modification  
• 
If grade 2 neurologic toxicity, reduce dose to 75%.  
• 
If grade > 2 neurologic toxicity, hold cisplatin until neurologic toxicity improves to grade ≤ 2, 
then either reduce dose to 50% or discontinue cisplatin, at the physician‘s discretion. 
 
Renal Toxicity  
Cisplatin dose will be modified for renal toxicity.  
Serum creatinine must be obtained within 72 hours prior to each dose of cisplatin, except for day 8. 
Serum creatinine is required within 10 days prior to day 8 cisplatin. 
• 
If serum creatinine ≤ 1.5 mg/dL, give full cisplatin dose.  
• 
If serum creatinine 1.5-2.0 mg/dL, calculate creatinine clearance. If calculated creatinine 
clearance is ≥ 50 ml/min give full cisplatin dose.  
• 
If serum creatinine 1.5-2.0 mg/dL and calculated creatinine clearance is < 50 ml/min, 
omit cisplatin dose and recheck serum creatinine at next scheduled cisplatin dose. If 
creatinine is < 2.0 and creatinine clearance has improved to ≥ 50 mL/min, reduce 
cisplatin dose to 75%.  
• 
If serum creatinine > 2.0 mg/dL, omit cisplatin dose, and recheck serum creatinine at 
next scheduled cisplatin dose. If creatinine is < 2.0 mg/dL and creatinine clearance ≥ 50 
mL/min, reduce dose to 50%; otherwise continue to omit cisplatin dose, recheck serum 
creatinine again at next scheduled cisplatin dose, and follow the same guidelines.  
 
Neutropenic Fever [defined as temperature ≥ 38.3 C (101 F) and ANC < 500]  
• 
If neutropenic fever occurs and the patient subsequently meets criteria for further 
chemotherapy, the doses are reduced by 25%.  
 
Other Toxicities Not Defined Above  
• 
If toxicities ≤ grade 2, then manage symptomatically, if possible, and retreat without dose 
reduction.  
• 
If toxicities ≥ grade 3 and attributed to the protocol treatment (possible, probable, or definite), 
drug should be withheld until patient is stable enough to continue with the treatment.  When 
medically appropriate to restart, consider reducing dose up to 50%.    
 
If cisplatin or etoposide doses are reduced, all future doses are reduced. 
 
5.4.7.3  Dose Modifications for Consolidation Chemotherapy With a Carboplatin and 
Paclitaxel Regimen 
Hematologic Toxicity  
ANC and plt must be obtained within 72 hours prior to each dose of carboplatin and paclitaxel. 
• 
If ANC ≥ 1500 and plt ≥100,000, give full dose  
• 
If ANC < 1500 or plt < 100,000, hold chemotherapy and repeat ANC and plt in 1 week. If 
ANC ≥ 1500 and plt ≥100,000, give full dose. If ANC < 1500 or plt < 100,000, hold 
chemotherapy again and repeat ANC and plt in 1 week (total of a 2-week delay). If ANC ≥ 
1500 and plt ≥ 100,000, give full dose; otherwise omit chemotherapy dose.  
 
 


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Neurologic Toxicity  
Carboplatin and paclitaxel doses will be modified for neurologic toxicity:  
• 
If grade 1 neurologic toxicity, no dose modification  
• 
If grade 2 neurologic toxicity, reduce dose to 75%.  
• 
If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to grade 
≤ 2, then either reduce dose to 50% or discontinue chemotherapy, at the physician‘s 
discretion.  
 
Renal Toxicity  
Carboplatin dose will be modified for renal toxicity.  
Serum creatinine must be obtained within 72 hours prior to each dose of carboplatin. 
• 
If renal toxicity occurs, the AUC will be re-calculated with a new serum creatinine, to account 
for the necessary dose adjustment. 
 
Neutropenic Fever [defined as temperature ≥ 38.3 C (101 F) and ANC < 500]  
If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy, the 
doses are reduced to 75%.  
 
Other Toxicities Not Defined Above  
• 
If toxicities ≤ grade 2, then manage symptomatically, if possible, and retreat without dose 
reduction.  
• 
If toxicities ≥ grade 3 and attributed to the protocol treatment (possible, probable, or definite), 
drug should be withheld until patient is stable enough to continue with the treatment.  When 
medically appropriate to restart, consider reducing dose up to 50%.    
 
If carboplatin or paclitaxel doses are reduced, all future doses are reduced. 
 
5.5 PERMITTED THERAPIES 
 
5.5.1  Immunotherapy: 
At the discretion of the medical oncologist, durvalumab can be administered to patients after 
completion of chemoradiation, since it is now FDA-approved after completion of chemoradiation, 
based on the results of the PACIFIC trial, which showed improved progression-free survival for 
patients receiving durvalumab for up to 12 months for patients who have not progressed after 
completion of platinum-based chemoradiation [Antonia SJ, et. al, N Engl J Med, 2017. 377(20): p. 
1919-1929].   
 
At the discretion of the medical oncologist, consolidation chemotherapy can be omitted if patient is 
planned to receive durvalumab, since patients on the PACIFIC trial did not receive consolidation 
chemotherapy.  
 
Durvalumab should ideally be started within 4 weeks of finishing chemoradiation or consolidation 
chemotherapy (if they receive consolidation chemotherapy). However, alternate scheduling is 
allowed.   
 
5.6 ON TREATMENT EVALUATIONS 
Patients will be examined every week by the treating physician during chemoradiotherapy to 
assess toxicity, with history and physical exam, vital signs, assessment of performance status. A 
complete blood count (CBCP) with differential will be obtained during chemoradiotherapy at the 


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discretion of the medical oncologist. Chemistries including liver function tests, sodium, 
potassium, chloride, blood urea nitrogen, creatinine, and glucose will be checked at the discretion 
of the medical oncologist. 
 
6.0 MR IMAGING 
For eligible patients, this trial includes correlative MRI studies to assess the effects of 
stereotactic body radiation therapy on tumor perfusion, diffusion, and oxygenation. There is 
literature that hypofractionated radiation or SBRT has significant effects on tumor vasculature in 
the acute post-radiation period. From a review of about 25 pre-clinical publications, moderately 
high doses of radiation (i.e. 5-10 Gy), causes increases in tumor blood flow initially, which return to 
pre-irradiation levels 3 days later (24). However, this effect has not been well-studied in human 
patients. Furthermore, this phenomenon has potential therapeutic implications, in particular when 
to dose chemotherapy. The goal of these correlative imaging studies is to determine what 
changes occur in the tumors after stereotactic body radiation therapy. If SBRT boost doses are 
found to reproducibly allow for increased tumor blood flow, this could inform when to dose 
chemotherapy in future trials. Thus, we will incorporate functional MRI methods (DCE/PWI, 
BOLD, and DWI) immediately before and after the first dose of SBRT (i.e. within 1 week before 
and within 24 hours after the first SBRT) to evaluate and quantitate the changes in the tumor 
microenvironment. MRI DCE/PWI (dynamic contrast enhanced, perfusion weighted imaging) 
provides information on tumor vascularity, vessel permeability and blood volume with time 
dependent delivery of IV contrast agent. DCE/PWI parameters also correlate with tumor 
oxygenation (25). BOLD-MRI (blood oxygenation level dependent) is based on T2* contrast 
induced by deoxyhemoglobin which is paramagnetic, whereas oxyhemoglobin is not. Several 
studies have shown relationship between BOLD signal response and tumor oxygenation. BOLD-
MRI will be performed during delivery of room air and oxygen via face mask (26). DWI (diffusion 
weighted imaging) is based on the random or Brownian motion of water molecules in relation to 
their thermal energy. Tumor cell death is supposed to lead to unrestricted extracellular water 
motion and increase in the apparent diffusion coefficient (ADC) derived from DWI (27). Such 
imaging correlative studies will be informative in documenting tumor perfusional changes after 
SBRT and may provide additional information on optimal dosing of chemotherapy.  Functional MRI 
methods are also expected to provide prognostic information. 
 
For imaging correlative endpoints, there will be multiple measurements made. For DCE-MRI, we will 
measure semi-quantitative (e.g. peak enhancement) and pharmacokinetic (e.g. washout rate 
constant kel) parameters derived from the analysis of the DCE (dynamic contrast enhancement) 
curve. For DWI, we will measure differences in mean apparent diffusion coefficient (ADC) 
between baseline and post-SABR images. Lastly, for BOLD-MRI, we will measure differences 
in BOLD (blood oxygenation level dependent) contrast between baseline and post-SABR images. 
MRI correlative imaging will be conducted at the Wright Center for Innovation in Biomedical 
Imaging. 
 
For eligible patients, each patient will receive a total of 2 MRIs, one within 2 weeks before the 
first SABR dose and the second within 24 hours after the first SABR dose. The MRI testing is 
mandatory for the first 10 patients on the study who do not have contra-indications to MRI as 
defined in the Exclusion Criteria. 
 
6.1 ANATOMICAL IMAGING 
Tumor will be located on breath-hold fast spin echo and fast multi-planar gradient-recalled echo 
anatomical images. The anatomical imaging protocol will include axial T1- and T2-weighted 
images for optimal tumor localization and delineation. 


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6.2  DWI (diffusion weighted magnetic resonance imaging) 
DWI will be acquired with an electrocardiographic (ECG) and respiratory-gated single-shot spine echo 
sequence using two b values (0 and 1000 sec/mm2). ADC maps will be generated from DWI 
images by using these two b values. 
 
6.3 BOLD-MRI (blood oxygenation level dependent magnetic resonance imaging) 
Respiratory-gated multi-echo gradient-echo technique will be used for BOLD imaging. Patients 
will wear a face mask for delivery of oxygen. T2*-weighted BOLD images will be obtained for a 
single sagittal slice through the center of the tumor. Three to four dynamics will be obtained 
when patients breathed room air, followed by another six to eight dynamics while breathing 
100% oxygen at 8 L/min via the face mask. 
 
6.4 DCE-MRI (dynamic contrast enhanced magnetic resonance imaging) 
T1-weighted 3D spoiled gradient echo (SPGR) sequence will be used for DCE-MRI acquisition with 
coverage of the entire tumor volume as determined on the anatomical images. The 3D SPGR 
sequence will be repeated for 10 minutes with a temporal resolution of 5-10 seconds/volume to 
allow a comprehensive analysis of contrast agent pharmacokinetics. Bolus injection of a 
commercially available low-molecular-weight MR contrast agent (0.1 mmol/kg) will be administered 
using an MR-compatible power injector with a flow rate of no faster than 5 ml/sec after the first 
5-10 volumes are acquired. 
 
6.5 SIDE EFFECTS AND RISKS OF MR IMAGING 
While scheduling the patient, it will be ascertained that the patient does not have an implant or 
device that may be contraindicated or requires special attention for the MR procedure (e.g., 
pregnancy, renal failure, metallic foreign body, ferromagnetic aneurysm clip, pacemaker, 
neurostimulation system, etc.). Preliminary screening helps to prevent scheduling patients that may 
be inappropriate candidates for MR examinations. Risks of MR imaging are potential bruising 
or contest extravasation at the contrast injection site. Management of contrast extravasation will 
include application of warm compresses, notification of the treating physician and follow-up with the 
patient by phone within the next day. Allergies to the MRI contrast occur rarely. The common side 
effects of the contrast agent include mild to moderate temporary headache (4.8%), nausea 
(2.7%), skin tingling (2.3%), metallic taste (1.3%), and dizziness (1%). Gadolinium-based contrast 
agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic 
fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage 
renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA 
scans. NSF/NFD is a debilitating and sometimes fatal disease. To eliminate the risk of renal toxicity 
from to the MRI contrast effects, only patients with a GFR of >30 will be included in the MRI study. 
 
7.0 RESEARCH BLOOD DRAWS 
7.1 Overview: Each patient enrolled on the trial will undergo 6 research blood draws for 
correlative research for circulating tumor DNA and miRNA biomarkers. 
 
7.2 Collection of Specimens: Blood draws will be collected in the Department of Radiation 
Oncology or Martha Morehouse. At each blood draw, venous whole blood (approximately 30 mL) 
will be drawn into three 10 mL lavender-top tubes containing EDTA (total of 3 tubes). Research 
blood draws will occur within 7 days prior to the first radiation treatment in Week 1, at the start of 
Weeks 2 and Week 5 (prior to chemotherapy administration on days 8 and 29), and at 1, 6, and 12 
months after all treatment is completed (including chemoradiation and consolidation chemotherapy).  
Note:  If patients are being treated during Weeks 2-7 or are being seen in follow-up after 
treatment at a James Cancer Network affiliate site, these specimens are not required to be 


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collected.  
 
7.3 Handling of Specimens: The tubes will be filled completely, and mixed by gentle inversion 8-
10 times. Tubes will be labeled with protocol number, de-identified subject number, date, time 
collected, and reference timepoint relative to protocol (e.g. Week 1 predose, Week 2 predose, Week 
5 predose, 1 month, 6 month, etc). Samples will be stored at room temperature or 4 degrees 
Celsius until pickup by the Clinical Trials Processing Lab (CTPL). Blood should be centrifuged at 
1,200g for 10 minutes at either room temperature or 4°C. Aliquot plasma into 8 equal cryovials and 
store at -70°C until pickup by the Williams laboratory until the end of November 2020, after which 
point all samples will be taken to the Clinical Trials Processing Lab (CTPL). 
 
7.4 Pickup and Storage of Specimens: Plasma samples will be brought to the Williams Laboratory 
by a member of Dr. Williams’ laboratory every 3 months or more frequently if requested by PI. 
Samples will go to the Williams lab until the end of November 2020, after which point all samples 
would then be housed with CTPL. Samples should be accompanied by a specimen inventory 
spreadsheet. Samples will be stored in a -70° C freezer until subsequent analysis.  Analysis for 
miRNA in plasma and circulating tumor DNA will be conducted in collaboration with (BRT 486). 
 
 
8.0 ADVERSE EVENTS, COMMON TOXICITY ASSESSMENT CRITERIA AND 
SUPPORTIVE CARE 
 
8.1 Adverse Events 
8.1.1 Adverse Events(AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related to 
study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
Adverse events will use the descriptions and grading scales found in the revised NCI Common 
Toxicity Criteria (CTC). This study will utilize the CTC version 5.0 for toxicity and Adverse Drug 
Experience reporting. A copy of the CTC version 5.0 can also be downloaded from the CTEP 
home page (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
 
All adverse events should be treated appropriately. Once an adverse event is detected, it should be 
followed until its resolution or stabilization of the event (to ≤ grade 2), whichever comes first. 
Assessment should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions required to treat it, and the 
outcome 
 
8.1.2 Serious Adverse Events (SAEs) 
 
Definition of an SAE: Any adverse experience occurring at any dose that results in any of 
the following outcomes: 
• Death; 
• A life-threatening adverse event; 


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• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 
• A persistent or significant disability/incapacity to conduct normal life functions 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE experience, when, based upon medical judgment, they may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the outcomes listed 
in the definition, 
 
Any pregnancy, including a male patient’s impregnation of his partner, occurring on study must be 
reported as a medically significant event. 
 
Any serious event should be reported to the DSMC within 48 hours of becoming aware of the 
event.  
 
Any unexpected late death (more than 30 days after the last treatment) attributed to the protocol 
treatment (possible, probable or definite) should be reported within 24 hours of discovery.   
 
 
8.1.3 SAE Reporting Requirements 
The investigator is required to submit all unexpected and serious adverse events to the OSU IRB 
within the institutional required timeframe. All AE/SAEs will be reported to the Data and Safety 
Monitoring Committee (DSMC) at the quarterly DSMC review meetings; however, the investigator 
determines corrective action is necessary, and “ad hoc” DSMC meeting will be called. 
 
Fatal adverse events related to treatment which are unexpected must be reported within 
10 days of the Investigators first awareness of the event to the OSU IRB and the DSMC. 
Fatalities not related to the study must be reported within the institutional required timeframe. 
 
The Ohio State University 
Office of Responsible Research Practices  
1960 Kenny Road 
Columbus, Ohio 43210 
Phone: 614-688-8457 
Fax:  614-688-0366 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality 
and data timeliness. Investigators will conduct continuous review of data and patient safety at 
their regular Disease Group meetings (at least monthly) and the discussion will be documented in 
the minutes. The PI of the trial will review toxicities and responses of the trial where applicable at 
these disease center meetings and determine if the risk/benefit ratio of the trial changes. 
Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the treatment from other sources; including published literature, scientific meetings, 
to determine if the trial should be terminated before completion. Serious adverse events and 
responses will be reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The 
PI will also submit a progress report (biannually for Phase II and quarterly for Phase I) that 
will be reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events 
(SAE) will also be reported to the IRB of record as per the policies of the IRB. 


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8.2 Interruption and discontinuation 
Treatment delays are occasionally encountered during radiation therapy due to logistic problems 
(e.g. machine break downs, patient transportation issues) or public holidays. If this occurs 
radiation therapy shall be completed as soon as possible, but with no more than one fraction 
per day, 5 fractions per week. 
For patients who are unable to tolerate the protocol-specified chemotherapy dosing schedule, 
dose adjustments are permitted in order to keep the patient on study chemotherapy. Toxicity will be 
assessed using CTCAEv4.0 as noted above. All interruption or changes to study chemotherapy 
administration must be recorded. 
 
In the absence of treatment delays due to toxicity, treatment continues per protocol until one of 
the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Patient develops progressive disease warranting change in treatment 
• 
Unacceptable toxicity 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
8.3 Management of Toxicity and Supportive Care 
 
8.3.1 Nausea/vomiting 
Prophylaxis and secondary treatment: Anti-emetics should be initiated at the onset of 
symptoms and continued as directed by the treating physician until resolution of symptoms to 
grade 0-1. Additional supportive care measures, e.g. oral or intravenous rehydration, etc., should 
be instituted as required by the patient’s clinical condition. Additional medical evaluation is 
recommended for those patients with continued nausea/vomiting > grade 2, lasting > 48 hours 
despite institution of optimal supportive care measures. Primary prophylaxis should be initiated 
once nausea or vomiting has occurred with the prior treatment. Admit to hospital and administer 
IV fluids and all supportive measures for symptoms unresponsive to medication and signs of 
dehydration. 
 
8.3.2 Hematopoietic Growth Factors 
 
WBC growth factors (G-CSF/GM-CSF) and erythropoietin will not be permitted during radiation.  
 
8.3.3 Management of Pneumonitis and Other Respiratory Symptoms 
 
Pneumonitis has been observed in subjects receiving chemoradiation. To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, and evaluated with imaging and 
functional tests. For cough, dextromethorphan, benzonatate, or mild narcotic medications (e.g. 
codeine syrup) can be used. 
 
 
8.3.4 Management of Esophagitis 
 


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Esophagitis can be managed by the preference of the treating physician and may commonly 
include medications such as Magic Mouthwash (e.g. custom mix of Benadryl, Maalox, lidocaine), 
proton pump inhibitors, or narcotics for pain. 
 
8.4 Follow up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed until resolution or stabilization of the event (to ≤ grade 
2), whichever comes first. 
All patients will be followed for new adverse events and serious adverse events up to 30 days after 
the last study treatment. For toxicities that occur patients will be closely followed until resolution or 
stabilization of the event (to ≤ grade 2), whichever comes first. Any new adverse events or serious 
adverse events beyond 30 days after the study treatment that are possibly, probably, or definitely 
related to the study treatment should also be collected, and reported if necessary. 
 
9.0 FOLLOW-UP AND OUTCOME ASSESSMENT 
 
Outcome data will be collected during the study period, and beyond the study period for 5 years 
post-therapy.  Subjects who discontinue study therapy for any reason other than death, lost to 
follow-up, or withdrawal of consent will be followed through the completion of the study period.    
Patients can be followed in Radiation Oncology, Medical Oncology, or Thoracic Surgery at OSU or 
Foster J. Boyd Regional Cancer Center (Wilmington, OH). 
 
For patients who develop progression, data that will be collected will include survival, non-protocol 
related treatment, and adverse events (up to starting a new treatment for progressive disease or 
hospice care).   
 
9.1. Visit Schedule 
Follow-up will consist of regular clinic visits (including vital signs, history & physical examination, 
and/or laboratory studies including CBCP, comprehensive metabolic panel) at 1 month, every 3 
months up to 2 years, and every 6 months up to 5 years after end of all treatment (including 
consolidation chemotherapy). 
 
Laboratory studies including CBCP, comprehensive metabolic panel will be obtained at the 
discretion of the medical oncologist. 
 
 
CT chest with IV contrast or chest x-rays will be obtained at every follow-up visits.  
MRI scans are allowed should the patients have contraindications to CT scan. Contrast is 
recommended unless allergies to contrast or renal insufficiency. 
 
PET-CT will be performed if suspicion of tumor recurrence based on CT scan, as well as 
potential biopsy to document recurrence. Other imaging will occur at the discretion of the 
physician and if warranted for clinical symptoms. 
 
9.2. Efficacy Assessments 
Criteria for Evaluation and Endpoint Definitions 
(a) Definition of primary outcome/endpoint: The primary efficacy analysis will be based upon 
investigator assessment of primary tumor control at 12 months and on the intent-to-treat 


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principle. Primary tumor control is defined as the absence of primary tumor failure. Primary 
tumor failure is based on meeting both criteria: (1) local enlargement defined as at least a 
20% increase in the longest diameter of the gross tumor volume per CT scan and (2) evidence 
of tumor viability. Tumor viability could be affirmed by either demonstrating PET imaging with 
uptake of a similar intensity as the pretreatment staging PET, or by repeat biopsy-confirming 
carcinoma. Primary tumor failure includes marginal failures occurring within 1 cm of the 
planning target volume (1.5-2.0 cm from the gross tumor volume). Failure beyond the primary 
tumor but within the involved lobe is collected separately from disseminated failure within 
uninvolved lobes. Local failure is the combination of the primary tumor and involved lobe 
failure with local control being the absence of local failure. If sufficient evidence for radiologic 
progression is noted on serial imaging over 3-6 months despite a negative biopsy(s), then a 
failure can be declared by investigator. Please note: each primary tumor and/or local failure 
will be confirmed with one of the study P.I.s. 
 
(a) Definition of secondary outcomes/endpoints: Data from all subjects who received the 
treatment will be included in the safety analyses. The severity of toxicities will be graded 
according to the NCI CTCAE version 4.0 whenever possible. For toxicities, unacceptable 
adverse events [occurring within ≤ 30 days after treatment completion defined as possibly, 
probably, or definitely related to treatment] will include development of grade 3-5 toxicities for: 
• 
cardiac (cardiac arrhythmia [supraventricular, ventricular], left or right ventricular 
dysfunction, pericardial effusion, pericarditis, restrictive cardiomyopathy) 
• 
pulmonary/upper respiratory (atelectasis [grade 4-5 only], FEV-1 [provided grade 
• 
is worse than baseline], fistula, hypoxia [provided grade 3 is worse than baseline], 
obstruction/stenosis of airway, pleural effusion, pneumonitis, pulmonary fibrosis, vital 
capacity [provided grade 3 is worse than baseline]) 
• 
hemorrhage (pulmonary/upper respiratory) 
• 
neurologic (brachial plexopathy, laryngeal nerve dysfunction, myelitis, phrenic nerve 
dysfunction) 
• 
Also grade 4-5 gastrointestinal (dysphagia, esophagititis, and esophageal 
fistula/obstruction/perforation/stricture/stenosis/ulcer) and any grade 5 adverse event 
attributable to therapy will be considered unacceptable adverse events. 
 
Tolerability will be defined as the percent of patients who complete treatment without discontinuing 
treatment due to toxicity. 
 
Regional failure will be defined as failure in the intra-parenchymal/hilar (N1, or stations 10-14) and 
mediastinal (N2, or stations 1-9) lymph nodes, or supraclavicular/scalene (N3) lymph nodes. 
Distant failure will be defined as failure in an uninvolved/contralateral lobe or extrathoracic sites. 
 
Objective response rate (ORR) will be defined as the rate of complete response + partial response 
per RECIST 1.1 criteria (Appendix II), with complete response being disappearance of all target 
lesions, and partial response being at least a 30% decrease in the sum of the longest diameter of 
target lesions, taking as reference the baseline sum longest diameter. 
 
For imaging correlative endpoints, there will be multiple measurements made. For DCE-MRI, we will 
measure semi-quantitative (e.g. peak enhancement) and pharmacokinetic (e.g. washout rate 
constant kel) parameters derived from the analysis of the DCE (dynamic contrast enhancement) 
curve. For DWI, we will measure differences in mean apparent diffusion coefficient (ADC) between 
baseline and post-SABR images. Lastly, for BOLD-MRI, we will measure differences in BOLD 
(blood oxygenation level dependent) contrast between baseline and post-SABR images. 


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RECIST measurements to document primary tumor response in patients with regional and 
distant failure should be continued up until the point a patient starts a new treatment for 
progressive disease targeting the primary tumor, systemic therapy, or hospice. 
 
10. DURATION OF STUDY 
Patients are expected to be accrued over 36 months. Following the last accrual, 12 months will need 
to pass before reporting on 12 month primary tumor and local control can proceed. Follow-up 
will continue for all patients for at least 5 years, with evaluation of primary tumor and local control. 
 
The duration of the MRI correlative imaging study will extend from the pre-therapy phase (pre- 
SBRT MRI) to after the first SBRT boost dose (within 24 hours after initial SBRT boost dose). The 
duration of the imaging study will be limited to the first eligible and consenting 10 patients in this 
study. 
 
 
11. REGULATORY AND REPORTING REQUIREMENTS 
 
This study will utilize the CTCAE version 5.0 for toxicity and adverse event reporting. A copy of 
the CTCAE version 5.0 can be downloaded from the CTEP home page 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). All appropriate treatment areas should have 
access to a copy of the CTC version 5.0. 
 
12.0 STATISTICAL CONSIDERATIONS 
 
12.1 Sample Size Determination 
This study is designed to preliminarily assess the efficacy of SBRT with conventionally- 
fractionated chemoradiation in patients with unresectable or medically-inoperable non-small cell 
lung cancer (NSCLC). Our primary endpoint is the primary tumor control rate at 12 months (from 
date of treatment initiation). Due to long follow-up time, we will use a single stage design. A 
primary tumor control rate at 12 months of 70% or less was considered unacceptable, and a 
primary tumor control rate of at least 90% is desirable. A sample size of 28 provides at least 
80% power to detect a significant improvement of primary tumor control rate of 90% or greater 
based on a one-sided test at significance level of 5%. If, by the end of the study, we have equal or 
more than 24 patients with primary tumor control, then we will claim it is effective. Considering 
up to 15% attrition, such as ineligibility, or lost to follow-up, we will accrue a total of 34 patients. 
 
12.2 Feasibility 
We have an average of 4-6 patients per month with unresectable/medically inoperable locally 
advanced NSCLC per month at the Ohio State University. There are currently no competing 
investigator-initiated trials for this patient population. Assuming we accrue about 25% of these 
patients to this trial (1-2 patients per month), time for accrual is about 36 months. 
 
12.3 Data Analysis Plan 
 
12.3.1 Analytic plan for primary objective:  
Primary tumor control rate at 12 months, as well its 95% confidence interval, will be 
reported for all eligible subjects received treatment. In addition, the primary tumor and local 
control failure over time will be plotted using Kaplan-Meier survival analysis. Rate of primary 
tumor and local control at 2 years and 3 years will also be summarized. 


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12.3.2 Analytic plan for secondary objectives: 
Rates of all adverse agents, with special attention to grade 3-5 esophagitis, cardiac, and 
pneumonitis adverse events, and death during or within 30 days of discontinuation of protocol 
treatment will be calculated.  Rates of tolerability will be determined at the end of study. 
 
Regional and distant failure, PFS, and OS will be measured from date of treatment initiation to the 
event of interest or otherwise censored at last follow-up. Kaplan-Meier (K-M) analysis will be used to 
estimate PFS and OS. PFS will include any failure (local, regional, or distant) or death from any 
cause. 
 
For MRI correlative studies, all 3 metrics (perfusion/diffusion/oxygenation measurements) will be 
tested by comparing mean values pre- and post-SBRT using a paired t-test. Should there be 
concern for outliers, we will determine the median for each metric and compare medians using a 
corresponding non-parametric procedure. 
 
 
13.0 SUBJECT POPULATION(S) FOR ANALYSIS 
All patients are 18 years of age or older who have non-small cell lung cancer, Stage II-III, that is 
medically inoperable or unresectable.  Men and women are allowed on this study. 
 
 
14.0 STUDY CALENDAR 
 
See Appendix I. 
 
 
15.1 STUDY FINANCES 
 
15.2 Funding Source 
 
We have multiple sources of support, including philanthropic and internal funding 
mechanisms (Radiation Oncology, James Cancer Center). MRI correlative imaging will be 
performed at and may also be funded through the Wright Center for Innovation in Biomedical 
Imaging, Ohio State University (Director, Michael Knopp, MD, PhD). 
 
 
 


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Curran WJ, Jr., Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for 
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Rosenzweig KE, Sura S, Jackson A, et al. Involved-field radiation therapy for inoperable 
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Yuan S, Sun X, Li M, et al. A randomized study of involved-field irradiation versus elective 
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Takeda A, Sanuki N, Kunieda E, et al. Stereotactic body radiotherapy for primary lung cancer 
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calculated using a superposition algorithm. Int J Radiat Oncol Biol Phys 2009;73:442-448. 
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Baker R, Han G, Sarangkasiri S, et al. Clinical and dosimetric predictors of radiation 
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Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary 
function for safe and effective stereotactic body radiotherapy for early- stage non-small cell 
lung cancer? J Thorac Oncol 2012;7:542-551. 
13. 
Guckenberger M, Klement RJ, Kestin LL, et al. Lack of a dose-effect relationship for pulmonary 
function changes after stereotactic body radiation therapy for early-stage non-small cell lung 
cancer. Int J Radiat Oncol Biol Phys 2013;85:1074-1081. 
14. 
Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function 
Test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer 


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47 
 
in medically inoperable patients. J Thorac Oncol 2009;4:838- 844. 
15. 
Ohashi T, Takeda A, Shigematsu N, et al. Differences in pulmonary function before vs. 
1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors. Int J 
Radiat Oncol Biol Phys 2005;62:1003-1008. 
16. 
Feddock J, Arnold SM, Shelton BJ, et al. Stereotactic body radiation therapy can be used 
safely to boost residual disease in locally advanced non-small cell lung cancer: a prospective 
study. International journal of radiation oncology, biology, physics 2013;85:1325-1331. 
17. 
Wang JZ, Huang Z, Lo SS, et al. A generalized linear-quadratic model for radiosurgery, 
stereotactic body radiation therapy, and high-dose rate brachytherapy. Sci Transl Med 
2010;2:39ra48. 
18. 
Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is inappropriate to model 
high dose per fraction effects in radiosurgery. Semin Radiat Oncol 2008;18:240-243. 
19. 
Astrahan M. Some implications of linear-quadratic-linear radiation dose-response with regard 
to hypofractionation. Med Phys 2008;35:4161-4172. 
20. 
Guerrero M, Li XA. Extending the linear-quadratic model for large fraction doses pertinent to 
stereotactic radiotherapy. Phys Med Biol 2004;49:4825-4835. 
21. 
Park C, Papiez L, Zhang S, et al. Universal survival curve and single fraction equivalent 
dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol 
Phys 2008;70:847-852. 
22. 
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central 
tumors in a phase II study of stereotactic body radiation therapy for medically inoperable 
early-stage lung cancer. J Clin Oncol 2006;24:4833-4839. 
23. 
Graves EE, Maity A, Le QT. The tumor microenvironment in non-small-cell lung cancer. 
Seminars in radiation oncology 2010;20:156-163. 
24. 
Park HJ, Griffin RJ, Hui S, et al. Radiation-induced vascular damage in tumors: implications 
of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 
2012;177:311-327. 
25. 
Cooper RA, Carrington BM, Loncaster JA, et al. Tumour oxygenation levels correlate with 
dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the 
cervix. Radiother Oncol 2000;57:53-59. 
26. 
Jiang L, Weatherall PT, McColl RW, et al. Blood oxygenation level-dependent (BOLD)  
contrast  magnetic  resonance  imaging  (MRI)  for  prediction  of  breast 
cancer 
chemotherapy 
response: 
a pilot 
study. 
J Magn 
Reson
 
Imaging 
2013;37:1083-1092. 
27. 
Yabuuchi H, Hatakenaka M, Takayama K, et al. Non-small cell lung cancer: detection of 
early response to chemotherapy by using contrast-enhanced dynamic and diffusion-weighted 
MR imaging. Radiology 2011;261:598-604. 
28. 
Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential 
chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-
small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais 
de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 2005;23:5910-5917. 


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48 
 
29. 
Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential 
thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable 
stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692-2699. 
30. 
Zatloukal 
P, 
Petruzelka L, 
Zemanova M, 
et 
al. 
Concurrent versus sequential 
chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung 
cancer: a randomized study. Lung Cancer 2004;46:87-98 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17.1 ATTACHMENTS/APPENDICES 
Appendix I: Study Schedule 
 
Pre-Treatment 
During Treatment 
Follow-up 
< 30days 
of entry 
< 14days 
of entry 
Week 1 
Week 
2-7 
Week 
12 
Week 
15 
Mo 1 
Q3 mos for 
years 1-2 
Q6 mos for 
years 3-5 
Visit window (+/- days) 
 
 
3 
3 
7 
7 
14 
30 
30 
Informed consent 
X 
 
 
 
 
 
 
 
 
History and physical exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff & ANC, platelets1 
X 
 
 
X 
X 
X 
X 
 
 
CMP including LFTs1 
X 
 
 
X 
X 
X 
X 
 
 
CrCl assessment 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test (females 
of child-bearing potential) 
 
X 
 
 
 
 
 
 
 
CT simulation 
 
X (≤21 
days) 
 
 
 
 
 
 
 
MRI or CT brain with contrast 
X (≤60 
days) 
 
 
 
 
 
 
 
 
PET-CT scan of body (or CT 
chest/abdomen/pelvis with 
contrast) 
X (≤60 
days) 
 
 
 
 
 
 
 
 
CT chest with IV contrast  
X2  
 
 
 
 
 
 
 
 
Contrast-enhanced CT chest or 
MRI chest or PET-CT 
 
 
 
 
 
 
X 
X (Mos 6, 12, 
18, 24) 
X (Mos 36, 48, 
60) 
Chest X ray (PA and lateral) or 
CT chest with IV contrast 
 
 
 
 
 
 
 
X (Mos 3, 9 
15, 21) 
X (Mos 30, 42, 
54) 
Pulmonary function tests 
(including FEV- 1, DLCO) 
X (≤90 
days) 
 
 
 
 
 
 
X 
 
 
1 A complete blood count (CBCP) with differential and CMP including LFTs during the treatment and follow-up will be obtained at the discretion of 
the medical oncologist. 
2 CT chest with contrast unless there is an issue with insurance coverage, or patient has allergy to CT contrast or renal insufficiency. 


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(mos 6, 12, 
24) 
 
Pre-Treatment 
During Treatment 
Follow-up 
< 30days 
of entry 
< 14days 
of entry 
Week 1 
Week 
2-7 
Week 
12 
Week 
15 
Mo 1 
Q3 mos for 
years 1-2 
Q6 mos for 
years 3-5 
Research MRI studies 
(DCE/PWI, DWI, BOLD) – 
optional study 
 
X (pre- 
SBRT 
scan) 
X 
(≤24hrs 
of 1st 
SBRT) 
 
 
 
 
 
 
Research blood draws 
 
 
X (pre-
dose)3 
X 
(Day 8, 
29) 
 
 
X 
 
X (Mos 6, 12) 
 
SBRT (2 doses) 
 
 
X 
 
 
 
 
 
 
Radiation Therapy (30 
doses, 5 days/week)4 
 
 
 
 
 
 
 
 
 
Concurrent chemotherapy4 
 
 
 
X 
 
 
 
 
 
Consolidation chemotherapy 
(only for patients receiving 
concurrent carboplatin & 
paclitaxel)5 
 
 
 
 
X 
X 
 
 
 
AE assessment6 
 
 
X 
X 
X 
X 
X 
X7 
X7 
 
 
 
 
 
 
 
3 Week 1 research blood should be collected within 7 days prior to the 1st SBRT treatment. 
4 Concurrent chemotherapy and radiation should be done as soon as after the SBRT treatment, within 7 days after the 1st SBRT treatment unless 
there are contraindications determined by treating doctors. 
5 Consolidation chemotherapy: 2 cycles, each 21 days long, beginning at 4-6 weeks after chemoradiation. At discretion of medical oncologist.  
6 AE assessment during the treatment will be performed weekly, and generally coordinated with chemotherapy schedule.  
7 AEs will be followed until resolution or stabilization of the event (to ≤ grade 2), whichever comes first. 


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Appendix II: RECIST 1.1 Criteria 
 
Response Criteria: Evaluation of target lesions 
 
*Complete Response (CR): Disappearance of all target lesions. 
 
*Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
 
*Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions. 
 
*Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest. 
 
(LD= longest diameter) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix III: ECOG Performance Status Scale 
 
Grade Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- care. Totally 
confined to bed or chair. 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix IV: Supplementary Tables 
 
Table A. Local control in phase III randomized trials of concurrent chemoradiation for locally 
advanced NSCLC. 
 
Study 
N 
Med FU 
(mos) 
RT DOSE 
(Gy/fxs) 
BED 
Gy10 
LC 
(%) 
MS 
(mos) 
%OS 
(years) 
RTOG 9410(6) 
195 
120 
63/34 
74.7 
70 
17 
16 (5) 
GLOT 
NPC 95- 
10(28) 
100 
57.6 
66/33 
79.2 
76 
16.3 
61 (1) 
39 (2) 
25 (3) 
21 (4) 
WJLCG(29) 
156 
60 
58/28* 
67.2 
67 
16.5 
64.1 (1) 
34.6 (2) 
22.3 (3) 
16.9 (4) 
15.8 (5)   
CZECH(30) 
52 
39 
60/30 
72 
60 
16.6 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table B. Calculated SBRT boost doses necessary after conventional fractionation to bring total dose 
equivalency to that of SBRT regimens in early stage NSCLC. Comparisons between LQ and gLQ 
modeling. 
LQ= linear quadratic; gLQ= generalized linear quadratic 
Model 
Type 
α/β ratio 
BED (Gy) 
for 
54 Gy in 3 
fractions 
BED (Gy) 
for 
60 Gy in 5 
fractions 
BED for 
standard 
fractionation 
(60 Gy in 2 
Gy per 
fraction) 
SBRT Boost 
dose 
needed in 2 
fractions for 
biological 
equivalency 
to 54 Gy in 
3 fractions 
SBRT Boost 
dose needed 
in 2 fractions 
for biological 
equivalency 
to 60 Gy in 5 
fractions 
LQ 
10 Gy 
151.2 
132 
72 Gy 
31 Gy 
26 Gy 
gLQ 
(cell 
line) 
5.45 Gy 
89.37 
83.89 
60.51 Gy 
17.3 Gy 
13.95 Gy 
gLQ 
(clini 
cal) 
4.3 Gy 
79.78 
77.30 
59.42 Gy 
12.94 Gy 
11.52 Gy 
 
 
 
 


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Appendix V: Covid-19 Precautions 
 
Due to the emerging pandemic for SARS-CoV-2 virus, it has become necessary to enact social 
distancing and limit hospital and outpatient facility interactions and visits for vulnerable patient 
populations. Patients receiving active therapy to control their cancer are particularly vulnerable. 
 
This study involves patients receiving a radiation boost alongside conventionally-fractionated 
chemoradiation, and though it is vital that these patients continue to receive these therapies, it is 
also important that we mitigate the risk of virus transmission for patients, providers, and family 
members. In the coming weeks and months, as governments continue to manage the SARS-
CoV-2 virus pandemic, it is quite possible that travel between states and cities may be limited, 
or that cities may have curfews. This amendment seeks to mitigate risk and enable ongoing 
care as feasible.  
 
This appendix proposes the following changes for this investigator-initiated trial: 
 
Convert whenever possible all outpatient office visits to tele-medicine (video and phone) 
as necessary to continue monitoring, care, and treatment. Patients with concerning 
symptoms or labs from tele-medicine visits may be escalated to in-person evaluations as 
needed in the appropriate setting. This will serve to triage patients based on needs versus 
risk.  
 
Patients will continue to have necessary blood work and scans to monitor for toxicities and 
disease status. Basic study procedures such as blood draws, radiographic scans, and 
MRIs, can be done by patients’ local providers. These results will be reviewed by the Study 
Team centrally. 
 
Depending on circumstances, local healthcare providers in another city may be required 
to assess and evaluate patients, and the PI and/or the study team will communicate with 
these providers to facilitate care as it relates to study treatment.  
 
 
Time Frame: These changes are being made to minimize risk of COVID infection during the 
pandemic, as it continues to be an urgent and serious world health emergency. As research 
activities have resumed at OSUCC, we will consider the Appendix V changes to be permanent 
until the lifting of COVID restrictions or a vaccine is developed, which is not expected until at 
least 2021. Therefore these changes are valid until the time at which Covid-19 related 
restrictions are no longer deemed necessary by the State and/or University.  
 
 
 

ICF_001.pdf: 
CONSENT 
Biomedical/Cancer 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
Page 1 of 15 
The Ohio State University Consent to Participate in Research 
Study Title: 
A Phase II trial Combining Hypofractionated Radiation 
Boost with Conventionally-Fractionated 
Chemoradiation in Locally Advanced Non-Small Cell 
Lung Cancer Not Suitable for Surgery 
Principal 
Investigator(s): 
Eric Miller, MD, PhD 
Sponsor: 
The Ohio State University 
•
This is a consent form for research participation.  It contains important information
about this study and what to expect if you decide to participate.  Please consider the
information carefully. Feel free to discuss the study with your friends and family and
to ask questions before making your decision whether or not to participate.
•
Your participation is voluntary.  You may refuse to participate in this study.  If you
decide to take part in the study, you may leave the study at any time.  No matter what
decision you make, there will be no penalty to you and you will not lose any of your
usual benefits.  Your decision will not affect your future relationship with The Ohio
State University.  If you are a student or employee at Ohio State, your decision will
not affect your grades or employment status.
•
You may or may not benefit as a result of participating in this study.  Also, as
explained below, your participation may result in unintended or harmful effects for
you that may be minor or may be serious depending on the nature of the research.
•
You will be provided with any new information that develops during the study
that may affect your decision whether or not to continue to participate.  If you
decide to participate, you will be asked to sign this form and will receive a copy of the
form.  You are being asked to consider participating in this study for the reasons
explained below.
1. Why is this study being done?
You have been asked to participate in this study because you have been diagnosed with lung
cancer and have not received any chemotherapy.  We know that a combination of
chemotherapy and radiation therapy (chemoradiation) does have a benefit in treating your
cancer and is the standard way your cancer is treated. Cisplatin and etoposide and carboplatin
and paclitaxel are two chemotherapy drug combinations that have been approved for use by
the Food and Drug Administration (FDA) for your type of cancer. In this study we want to
add two higher doses of radiation (called boost doses) right before starting standard treatment


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 2 of 15 
 
 
of chemotherapy with cisplatin and etoposide or carboplatin and paclitaxel and radiation to 
see if we can improve the benefit of therapy on your cancer. 
 
Even with standard chemotherapy and radiation for your cancer, the risk of having the tumor 
come back where it started in the lung is about 1 in 3 patients with your type of cancer.  The 
two boost doses of radiation will be a type of radiation called stereotactic, or hypofractionated 
radiation, which is a newer way to deliver radiation much more precisely and accurately, 
allowing us to deliver higher doses of radiation more safely. This study tests whether a higher 
dose of stereotactic radiation delivered in two boost doses prior to starting standard 
chemoradiation therapy, will prevent the cancer coming back in the location it started. 
 
2.   How many people will take part in this study? 
 
Approximately 38 patients will take part in this trial. 
 
3.   What will happen if I take part in this study? 
 
Before you begin the study… 
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study. These exams, tests or procedures are part of regular cancer care and may or may not 
need to be repeated. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor. 
 
Some of the exams, tests, and procedures outlined in the study calendar may be completed via 
Telehealth visit (phone, video call, or email) if the investigator deems it appropriate. Ask your 
physician if you have questions about Teleheath or Telehealth visits. 
 
Within 14 days of entering the study: 
 
• Blood or urine pregnancy test (if necessary) 
• MRI of the chest - research scan to study the effects of radiation boost doses to the 
tumor 
o If you elects to get an optional MRI, you will undergo two research MRI scans 
(total) to be performed over 1 to 1.5 hours (each) at the Wright Center.  
 
The Wright Center of Innovation in Biomedical Imaging Concourse 
Building, Martha Morehouse Medical Plaza, 2050 Kenny Road 
Columbus, OH 43221  
 
The scans will be focused on a portion of the lung bearing the primary lung tumor, and will 
include several different sequences (perfusion-weighted, diffusion, and BOLD (Blood 
Oxygenation Level Dependent Imaging)) to measure tumor vessel blood flow, tumor cell 
density, and oxygenation. For the oxygenation (BOLD) portions of the study, you may be 
required to inhale oxygenated air through a nasal cannula or face mask temporarily.  


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 3 of 15 
 
 
 
Within 21 days of entering the study: 
• CT (computed tomography) simulation scan-  a scan we need to allow us to plan for 
the radiation you will be receiving 
 
Within 30 days of entering the study: 
 
• History and physical exam (including vital signs) 
• Blood Tests – complete blood counts, chemistries and liver function tests 
• CT scan of the chest 
 
 
Within 60 days of entering onto this study: 
 
• PET-CT scan (positron emission tomography)- to look for the tumor in the whole 
body (or CT chest/abdomen/pelvis)  
• MRI (magnetic resonance imaging) of the brain (or CT of the head), providing you are 
able to get an MRI. 
 
Within 90 days of entering onto this study: 
 
• Tests to determine the function of your lungs (spirometry/pulmonary function tests) 
 
 
Therapy consists of: 
 
Week 1 
• You will receive two boost doses of stereotactic radiation which will occur at a 
minimum of 20 hours apart. 
• Optional MRI of the chest about 24 hours after the first dose of radiation- research 
scan to study the effects of radiation boosts to the tumor 
o Performed at The Wright Center of Innovation in Biomedical Imaging similar 
to first research MRI 
• Physical exam (including vital signs) 
 
Weeks 2-7 
• You will receive standard chemotherapy with cisplatin and etoposide or carboplatin & 
paclitaxel and radiation for 6 weeks at the discretion of the medical oncologist.  Your 
study doctor will decide which combination you are best suited for.  You will receive 
chemotherapy treatment based on the standard treatment schedule of selected 
chemotherapy regimen. 
• Blood tests (total blood count and chemistries) will be completed prior to 
chemotherapy or at the discretion of your study doctor. 
• These treatments can be done at a James Cancer Network affiliate center. 


CONSENT 
Biomedical/Cancer 
 
 
 
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IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 4 of 15 
 
 
 
 
Consolidation Therapy 
• If you end up taking the carboplatin & paclitaxel chemotherapy combination you will 
be required to participate in 2 additional cycles of consolidation therapy.  
Consolidation therapy is typically done after initial treatment as a follow up attempt to 
ensure cancer cells are destroyed. Cycles are 21 days in length and are expected to 
begin 4-6 weeks after you end the initial treatment. 
• If you end up taking immunotherapy (e.g. durvalumab), you may not have 
consolidation chemotherapy at the discretion of the medical oncologist.    
• These treatments can be done at a James Cancer Network affiliate center. 
 
Follow up Visits 
 
 
After your treatment is complete, you will come back for a clinic visit and have all or some of 
the following tests/procedures at about 1 month post-treatment and every 3 months for 2 years 
at OSU or a James Cancer Network affiliate site: 
• History and Physical Exam (including vital signs) 
• Blood Tests – complete blood counts, chemistries and liver function tests (about 1 
tablespoon)  
• CT scan of the chest with intravenous contrast or Chest X-ray 
• Pulmonary Function Test 
. 
 
After 2 years of follow up, you will return to clinic every 6 months for an additional 3 
years and have the following tests/procedures: 
• History and Physical Exam 
• CT scan of the chest with intravenous contrast  
• Chest X-ray (or CT scan) 
 
If there is a reason not to do a CT scan due to allergies or poor kidney function, MRI can be 
done instead (providing you are able to get MRIs). 
 
If your cancer comes back before your follow-up period has ended, some tests/procedures 
may not be performed during the remainder of the follow-up period.  Talk to your study 
doctor about your requirements if your cancer comes back. 
 
Research Blood Samples 
 
In addition to the blood samples listed above, whole blood samples (30mL/each) will be 
collected to identify Tumor Biomarkers. These samples will be collected prior to your first 
radiation treatment, at the start of the first chemotherapy cycle, towards the end of 
chemoradiation, and at 1 month, 6 months, and 12 months after you complete treatment on 
this study.  If you are being treated or followed after treatment at a James Cancer Network 
affiliate site, these research blood samples are not required. 


CONSENT 
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IRB Protocol Number: 
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IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 5 of 15 
 
 
 
 
 
 
4.   How long will I be in the study? 
 
The chemotherapy and radiation therapy will last approximately 7 weeks.  Follow up will 
continue for approximately five years after study treatment has been completed.  
 
 
5. Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop. He or she will tell you how to stop safely. 
 
You may leave the study at any time.  If you decide to stop participating in the study, there 
will be no penalty to you, and you will not lose any benefits to which you are otherwise 
entitled.  Your decision will not affect your future relationship with The Ohio State 
University.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
treatment can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it 
is in your best interest; if you do not follow the study rules; or if the study is stopped. 
 
 
6.   What risks, side effects or discomforts can I expect from being in the study? 
 
You may have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effects. However, doctors don’t know all the side effects that 
may happen. Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking 
the drugs. In some cases, side effects can be serious, long lasting, or may never go away. 
There is also a risk of death. 
 
You should talk to our study doctor about any side effects that you have while taking part in 
the study. 
 
Risks from chemotherapy (Cisplatin) 
 
• Common (20-100 in 100 people): 
o Nausea, vomiting 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
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IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 6 of 15 
 
 
o Infection, especially when white blood cell count is low 
o Anemia which may cause tiredness, or may require blood transfusions 
o Bruising, bleeding 
o Kidney damage which may cause swelling, may require dialysis 
o Hearing loss including ringing in ears 
o Numbness, tingling, or pain of the arms and legs 
• Occasional (4-20 in 100 people, or less): 
o Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
o Confusion 
o Difficulty with balance 
• Rare (3 in 100 people, or less): 
o Cancer later in life caused by chemotherapy.  
o Seizures 
 
Risks from chemotherapy (Etoposide) 
 
• Common (20-100 in 100 people):  
o Hair loss 
o Chills 
o Sores in mouth which may cause difficulty swallowing 
o Diarrhea, loss of appetite, nausea, vomiting 
o Infection, especially when white blood cell count is low 
o Anemia which may require transfusion 
o Bruising, bleeding 
o Tiredness 
o Fever 
 
 
• Occasional (4-20 in 100 people, or less): 
o Heart failure or heart attack which may cause chest pain, shortness of breath, 
swelling of ankles, and tiredness 
o Severe skin rash with blisters and peeling which can involve inside of mouth 
and other parts of the body 
o Liver damage which may cause yellowing of eyes and skin, swelling 
 
• Rare (3 in 100 people, or less):  
o Cancer of bone marrow caused by chemotherapy 
o Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat  
 
 
Risks from chemotherapy (Carboplatin) 
 
Most likely effects:  


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
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IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 7 of 15 
 
 
• Diarrhea, nausea, vomiting, loss of appetite or constipation. These are expected to 
be mild and brief but may be severe or long-lasting.  
• Fatigue—expected to be mild but could be moderate or worse.  
• Decreased white blood cell count (white blood cells fight infection) - Decreased 
white blood count may lead to an increased risk of infection at the surgical site 
(wound infection) or infection in another part of the body such as pneumonia. 
• Lowering of the platelets (cells that stop bleeding), excessive bleeding that is hard 
to stop. 
• Lowering of the red blood cells (anemia)  
 
Less likely effects:  
• Fevers and chills  
• Infection if blood counts are low  
• Abdominal pain  
• Increase in liver tests-Damage to liver cells may result in abnormally high liver 
tests.  This may reflect a decrease in your liver's ability to function normally, 
including metabolize chemicals and compounds such as food and medicine taken 
orally or intravenously.  Routine tests will check liver tests and follow up any 
abnormal tests. 
• Hearing loss  
• Numbness or tingling in hands or feet  
• Changes in your electrolytes in your blood (sodium, potassium, magnesium or 
calcium)  
 
Unlikely effects:  
• 
Low blood pressure from an infection  
• 
Kidney damage  
• 
Allergic Reaction 
 
Risks from chemotherapy (Paclitaxel) 
  
 
Likely effects: 
• Low red blood cell count (anemia), which can lead to tiredness and shortness of 
breath and may require a blood transfusion. 
• Feeling weak or tired  
• Hair loss  
• Numbness, tingling, or burning in your hands or feet  
• Joint and muscle pain  
• Nausea and vomiting  
• Hypersensitivity reaction – trouble breathing; sudden swelling of your face, lips, 
tongue, throat, or trouble swallowing; hives or rash  
• Diarrhea  


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 8 of 15 
 
 
• Abdominal pain 
• Mouth or lip sores  
• Low white blood count, placing you at risk for infection 
• Infections – if you have a fever (temperature above 100.4ºF) or other sign of 
infection, tell your healthcare provider right away  
• Swelling of your hands, face, or feet  
• Bleeding events  
• Irritation at the injection site  
• Low blood pressure  
• Abnormal liver function tests 
• Rash, which may cause itching 
 
 
Less likely effects: 
• Low platelet count, which can increase the risk of bleeding or bruising 
• Nail changes 
 
Rare, but Serious: 
• Inflammation of the lung that can cause difficulty breathing 
• Abnormal heart rhythm 
• Blood clot in an extremity (leg, arm) or lung 
• Death 
 
Risks-from radiation therapy (both standard fractionation and high-dose radiation 
boost doses) include some or all of the following side effects:  
 
Chest Radiation Therapy may cause:  
• 
Sore throat. 
• 
Loss of appetite, nausea, weight loss, weakness. 
• 
Irritation of the large blood vessels that surround the heart (e.g. atherosclerotic 
changes or vasculitis).  Very rarely this can cause bleeding (coughing up blood). 
• 
Narrowing of the food pipe (esophageal strictures), which may require dilation. (Your 
throat will be numbed and a balloon or plastic device will be used for stretching your 
throat.)  
• 
Spinal cord damage and/or irritation may cause weakness, tingling or numbness of the 
lower body and legs.  This can lead to inability to move or control the lower half of the 
body (paralysis), but this is extremely rare. 
• 
Scar tissue or changes in heart that may cause heart attacks or heart failure.  
• 
Problems with your blood vessels (vascular complications). 
• 
Brachial plexus (a network of nerves in your neck) injury which may lead to loss of 
sensation or function of arm. 
• 
Radiation may cause a permanent unhealing skin ulcer. 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 9 of 15 
 
 
• 
Difficulty, pain, or a burning sensation on swallowing. This effect is from irritation of 
the food pipe (esophagus). The side effect usually begins after the second week of 
radiotherapy and usually goes away within one month of completion of radiotherapy.  
• 
Fatigue (tiredness). It is usually a temporary effect which resolves within several 
months after completion of treatment. 
• 
Skin reaction within the radiation fields. The skin may develop a sunburn-like 
appearance which may itch, feel dry, or burn. Although skin color and the sunburn- 
like reaction improve within 2-6 weeks after treatment, the skin may be permanently 
drier than other skin and may be tanner. Chest hair (if any) may not re-grow.  
• 
Decrease in white blood cells and platelets. A decrease in white blood cell production 
may predispose you to infection. A decrease in platelets may make you bleed or bruise 
easily.  
• 
Scarring of the lung (i.e. radiation fibrosis) may result in chronic shortness of breath 
and a cough. Chemotherapy may make the above side effects worse and may increase 
normal tissue damage.  
• 
Collapse of a portion of your lung may result in shortness of breath and cough.  This is 
due to irritation of the airways from radiation or from a tumor that is pushing the 
airways closed.  This is uncommon.   
• 
Chest wall discomfort if your tumor lies close to the outside of the lung where the 
chest wall is.  Radiation can irritate the chest wall requiring medications to relieve the 
pain until it resolves.  Much more rarely, radiation can cause a rib to weaken and 
break.  
• 
Inflammation of the lungs by radiation (i.e. radiation pneumonitis) which may result in 
low grade fevers, chest discomfort, cough, and shortness of breath and thus resemble a 
lung infection.  You may need to receive antibiotics and/or steroids to help relieve 
these symptoms.  Hospitalization due to this risk may occur.  In similar trials with 
similar patients where the radiation dose was escalated beyond the standard dose, the 
risks of symptomatic (requiring steroids) or severe radiation pneumonitis were 17-
25%.In addition, if pneumonitis becomes severe, it can be life-threatening.  In these 
trials, the risk of life-threatening symptoms or death from pneumonitis were very 
uncommon.  It is not clear how infection with COVID19 would alter these risks. 
• 
Collection of fluid around the lungs in the chest cavity (i.e. pleural effusion), which 
can cause shortness of breath and may require treatment.  This risk is less likely. 
• 
Difficulty breathing with low levels of oxygen in the blood (i.e. respiratory failure), 
which could be serious and life threatening and require you to have a tube inserted into 
your windpipe that is hooked up to a machine to help you breathe.  This risk is rare but 
serious. 
• 
Inflammation of the sac around the heart (i.e. radiation pericarditis) which may result 
in chest pain, irregular or rapid heartbeat, shortness of breath, low-grade fever, 
weakness, heart failure as well as fluid around the heart.  You may need to receive 
steroids or have fluid drained to help relieve these symptoms.  Hospitalization or 
surgery may be required to correct this symptom.  This risk is uncommon. 
• 
Chest pain 
• 
Muscle spasm 
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 10 of 15 
 
 
Other Risks 
 
You may feel discomfort from some of the procedures during this study. 
 
Interactions with Other Drugs: 
There are many drugs (prescription and over the counter medications) and dietary 
supplements (including what are sometimes called “complementary” or “alternative” 
medicines), which may interact with the experimental drugs. The doctor will review all of 
the medications and supplements you are currently taking before starting these experimental 
drugs. You should not take any new medications or dietary supplements without discussing 
it with your doctor first. 
 
 
Blood drawing risks:  
There may be bruising, bleeding, inflammation (redness and swelling) or, rarely infection, 
or nerve damage at the sites where blood samples are taken. There is a chance that you also 
may experience fainting.  Care will be provided to avoid these complications.  
 
CT scan/PET scan: 
You will get a small amount of radiation. Please discuss with your study doctor the amount 
of radiation for each scan if you have questions.  During the CT scans, and PET scan, you 
will get dye that will be injected into one of your veins.  There is a risk of allergic reaction 
to the dye and in rare cases kidney damage. This reaction may be mild (such as a skin rash 
or hives) to severe (such as breathing difficulties and shock).  There is also a risk that the 
injection of dyes may cause pain, swelling, bruising, irritation or redness at the site, 
infection at the site of the needle puncture, or feeling faint. Your study doctor will take 
steps to prevent this from happening, and may recommend medications that may help with 
these particular side effects.  
 
MRI Scan 
When having an MRI (magnetic resonance imaging) scan, you will lie still on a table that 
slides into a tunnel slightly wider than your body. People who feel uncomfortable in confined 
spaces (claustrophobia) may feel uncomfortable in the narrow cylinder. If you feel 
uncomfortable in confined spaces, please tell your study doctor. Your study doctor may give 
you a medication to make you feel more comfortable in a confined space. If severe 
anxiety/claustrophobia persists despite mediations to relieve these symptoms, an MRI will 
not be performed.  MRIs use powerful magnets to make images. Therefore, persons with 
certain metal implants, such as pacemakers, should not have an MRI. If you have an implant 
or any metal in your body, please check with your study doctor to find out whether or not 
you can have an MRI. For people without metal implants, there are no known health risks 
associated with exposure to the magnet.  
 
The risks associated with the MRI research portion of this study include:  
• 
Bleeding and /or infection at the site of the administration of the contrast into one 
of your veins  


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 11 of 15 
 
 
• 
Fainting during the injection  
• 
Anxiety associated with claustrophobia (i.e. fear of closed spaces) during the MR 
procedure [Please note: you may ask for a relaxation medicine before your MR 
scans],  
• 
Allergic reaction to the contrast agent, which occurs very rarely and/or decrease in 
kidney function.  
 
Note: If you have a pacemaker, implantable defibrillator, aneurysm clip, or if you are 
pregnant, nursing, weigh greater than 350 pounds, allergic to gadolinium contrast or have 
severe anxiety/claustrophobia related to MRIs despite medications to relieve your 
anxiety/claustrophobia, an MRI would not be safe for you, and thus you would not receive 
these scans during this study. 
 
Reproductive Risks:  
Females are required to use an effective method of contraception from the time of negative 
serum pregnancy test, throughout the study duration, and until 4 weeks after the last dose 
of chemotherapy.  Should a woman become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 6 months after 
completion of study drug administration. 
Infection complications 
The risks of complications from infections, including COVID-19, that may be contracted 
during and after study therapy is unknown. The study team will follow all of the standard 
infectious disease precautions for the medical procedures you will receive in this study, as 
well as any additional COVID-19 specific guidelines from the University.  
 
7.   What benefits can I expect from being in the study? 
 
If you agree to take part in this study, there may or may not be direct medical benefit to you. 
We hope the information learned from this study will benefit other patients with lung cancer 
in the future. 
 
8.   What other choices do I have if I do not take part in the study? 
 
You may choose not to participate without penalty or loss of benefits to which you are 
otherwise entitled. 
 
Your other choices may include: 
• 
Receiving treatment or care for your cancer without being in a study which would 
likely include the standard combination of chemotherapy and radiation therapy. 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 12 of 15 
 
 
• 
Taking part in another study. 
• 
Getting no treatment. 
 
Please talk to your regular doctor about these and other options. 
 
9.   Will my study-related information be kept confidential? 
 
Efforts will be made to keep your study-related information confidential.  However, there may 
be circumstances where this information must be released.  For example, personal information 
regarding your participation in this study may be disclosed if required by state law.   
 
Also, your records may be reviewed by the following groups (as applicable to the research): 
• 
Office for Human Research Protections or other federal, state, or international 
regulatory agencies; 
• 
The Ohio State University Institutional Review Board or Office of Responsible 
Research Practices; 
• 
Your insurance company (if charges are billed to insurance). 
 
If this study is related to your medical care, your study-related information may be placed in 
your permanent hospital, clinic, or physician’s office records. Authorized Ohio State 
University staff not involved in the study may be aware that you are participating in a 
research study and have access to your information.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search the website at any 
time.  
 
You may also be asked to sign a separate Health Insurance Portability and Accountability Act 
(HIPAA) research authorization form if the study involves the use of your protected health 
information. 
 
10. What are the costs of taking part in this study? 
 
The following tests/procedures will not be charged to you or your insurance company: 
 
• Optional MRI scans (two) before Week 1 and during Week 1 
• Whole blood for research 
 
Most of the tests/procedures required while on this study are considered routine care for your 
disease. This includes the two boosts of radiation, PET scans, CT and MRI scans, and lung 
function testing. You and/or your insurance will need to pay for some or all of the costs of 
these routine services. You will be responsible for any deductibles, co-insurance, and/or co-
payments required by your health plan/insurance company.  
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 13 of 15 
 
 
Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment. Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company about your insurance 
coverage and to find out if there are any limitations to your plan.  To find out more about 
costs, you can ask the study doctor or study staff.  If you have any questions about study 
expenses like medical bills and hospital bills, please speak with the study doctor.  
 
11. Will I be paid for taking part in this study? 
 
You will receive no payment for taking part in this study. 
 
12. What happens if I am injured because I took part in this study? 
 
If you suffer an injury from participating in this study, you should notify the researcher or 
study doctor immediately, who will determine if you should obtain medical treatment at The 
Ohio State University Medical Center.   
 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
Ohio State University does not have funds set aside for the payment of health care expenses 
for this study.  
 
13. What are my rights if I take part in this study? 
 
If you choose to participate in the study, you may discontinue participation at any time 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
legal rights you may have as a participant in this study. 
 
You will be provided with any new information that develops during the course of the 
research that may affect your decision whether or not to continue participation in the study. 
 
You may refuse to participate in this study without penalty or loss of benefits to which you 
are otherwise entitled. 
 
An Institutional Review Board responsible for human subject’s research at The Ohio State 
University reviewed this research project and found it to be acceptable, according to 
applicable state and federal regulations and University policies designed to protect the rights 
and welfare of participants in research. 
 
 
14. Who can answer my questions about the study? 
 
For questions, concerns, or complaints about the study you may contact Dr. Eric Miller at 
614-293-8415 (office) or 614-293-8000 (24 Hours). 
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 14 of 15 
 
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
the Office of Responsible Research Practices at 1-800-678-6251. 
 
If you are injured as a result of participating in this study or for questions about a study-
related injury, you may contact Dr. Eric Miller at 614-293-8415 (office) or 614-293-8000 
(24 Hours). 
 
I agree to participate in the following optional study: 
 
□ Two research MRIs 
 
 
 


CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0112 
IRB Approval date:  11/05/2022 
Version:  10/21/2022 
 
 
Page 15 of 15 
 
 
Signing the consent form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
 
 
 
 
 
Printed name of subject 
 
Signature of subject 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for subject 
(when applicable) 
 
Signature of person authorized to consent for subject  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
to the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time