A Pilot Study of Response-Driven Adaptive Radiation Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer
Phase: NA
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2015.035 
     
 
 
 
 
 
 
 
A Pilot Study of Response-Driven Adaptive 
Radiation Therapy for Patients With Locally 
Advanced Non-Small Cell Lung Cancer 
    NCT02492867 
 

1 
 
 
A Pilot Study of Response-Driven Adaptive Radiation Therapy for 
Patients with Locally Advanced Non-Small Cell Lung Cancer 
 
 
 
Principal Investigator:  
Shruti Jolly, M.D. 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
University of Michigan 
 
 
Co-Investigators: 
 
James A. Hayman, M.D. 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
University of Michigan 
 
James Balter, Ph.D. 
Department of Radiation Oncology  
University of Michigan 
 
Gregory Kalemkerian, M.D. 
Department of Internal Medicine, Hematology/Oncology 
University of Michigan 
 
 
 
 
 
Theodore S. Lawrence, M.D., Ph.D. 
Department of Radiation Oncology 
University of Michigan 
 
Martha M. Matuszak, Ph.D. 
Department of Radiation Oncology 
University of Michigan 
 
Randall K. Ten Haken, Ph.D. 
Department of Radiation Oncology 
University of Michigan 
 
Muneesh Tewari, M.D., Ph.D. 
Department of Internal Medicine, Hematology/Oncology 
University of Michigan 
 
Aamer Chughtai, M.D. 
Department of Radiology 
University of Michigan 
 
Jason Hearn, M.D. 
Department of Radiation Oncology 
University of Michigan 
 
Caitlin Schonewolf, M.D. 
Department of Radiation Oncology 
University of Michigan 
 
Primary Statistician: 
 
Matthew Schipper, Ph.D. 
Department of Radiation Oncology 
University of Michigan 
 
Study Drug: 
 
 
None 
Version: 
 
 
05/22/2022 

2 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS…………………………………………………………………………………...……… 3 
STUDY SCHEMA………………………………………………………………………………….………... 6 
STUDY SYNOPSIS…………………………………………………………………………………..……... 7 
1.0 
BACKGROUND AND RATIONALE………………………………………….…………………… 8 
1.1 
Disease Background……………………………………………….……………..….…........ 8 
1.2 
PET Guided Adaptive Radiotherapy to Improve Long-Term Tumor Control…...………. 8 
1.3 
V/Q SPECT, PET, and Biomarkers to Decrease Lung and Esophageal Toxicity..........10 
1.4 
Combination of Chemotherapy and/or Immunotherapy in NSCLC…………………… 13 
1.5 
Rationale…………………………………………………………….…………...…………… 14 
2.0 
STUDY OBJECTIVES…………………………………………….………………………………...15 
3.0 
PATIENT ELIGIBILITY………………..…………………………………….………………..…….16 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES……….…………………….17 
5.0 
TREATMENT PLAN………………………………………………………….…………………......17 
5.1 
Treatment Dosage and Administration……………………………….……………..……..17 
5.2 
Delays/Dose Modifications during consolidation chemotherapy..................................24 
6.0 
DRUG INFORMATION…………………………………………………………….……….......…..27 
7.0 
TOXICITIES TO BE MONITORED AND REPORTED ………………………..………..……….29 
8.0 
CORRELATIVE TRANSLATIONAL STUDY.…………………………….………..….………….30 
9.0 
STUDY PROCEDURES AND CALENDAR….…………………………………..…………….…31 
10.0 STATISTICAL CONSIDERATIONS…………………………………………….….……………...34 
11.0 REPORTING ADVERSE EVENTS ………………………………..…………….……………......35 

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12.0 DATA AND SAFETY MONITORING…………………………………………………..…………..37 
13.0 DATA MANAGEMENT…………………………………………………………………..…………..37 
14.0 QUALITY ASSURANCE AND AUDITS…………………………………………………..……….38 
15.0 CLINICAL MONITORING PROCEDURES…………………………………………………..……38 
 
16.0   REFERENCES…………………………………………………………………………………….…40 
 
 
17.0   APPENDICES………………………………………………………………………………………..47 
 
ABBREVIATIONS 
 
ABC 
Active Breathing Control 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
CBC 
Complete Blood Count 
COPD 
Chronic obstructive pulmonary disease  
CR 
Complete response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
CTV 
Clinical Target Volume 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMR 
Data and Safety Monitoring Report 
EQD2 
Biologically isoeffective dose at 2 Gy fractions 
FDG  
18-Fluorodeoxyglucose  
FISH 
Fluorescence in situ Hybridization 
FUNBIPM 
Lung Functional Imaging and a Functional BioPhysical Model 
GTV 
Gross Tumor Volume 
H&P 
History & Physical Exam 
IGRT 
Image Guided Radiation Therapy 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
LPFS 
Local Progression-free Survival 
LRPFS 
Local Regional Progression-free Survival 
MTV 
              Metabolic tumor volume 
NSCLC 
Non-small Cell Lung Cancer  

4 
 
NTCP 
Normal Tissue Complication Probability 
OS 
Overall Survival 
p.o. 
per os/by mouth/orally 
PART 
Personalized Adaptive Radiotherapy 
PD 
Progressive Disease 
PET 
Positron Emission Tomography  
PFS 
Progression-free Survival 
PI 
Principal Investigator 
PR 
Partial Response 
PTV 
Planning Target Volume 
RIE 
Radiation induced esophagitis 
RILT 
Radiation Induced Lung Toxicity 
RITT 
Radiation Induced Thoracic Toxicity 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPECT 
Single-photon Emission Computed Tomography  
SPGT 
Serum Glutamic Pyruvic Transaminase 
TKI 
Tyrosine-kinase Inhibitor 
3D-CRT 
Three dimensional conformal radiation therapy 
TS 
Thymidylate Synthase 
UMCCC 
University of Michigan Comprehensive Cancer Center 
WBC 
White Blood Cell 
 
 

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 STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stage II-III 
NSCLC 
Response based 
adaptive radiation 
therapy to the 
same toxicity level 
of standard clinical 
practice 
Tumor: 
• PET to guide tumor adaptive plan to improve local tumor 
control 
Normal Tissue: 
• SPECT to optimize dose distribution in lung (functional 
avoidance) 
• PET to spare the inflamed esophagus to decrease RIE 
• Refine NTCP model with cytokine data to individualize dose  
prescription to 15% RILT and 30% RIE 
Adaptive RT + weekly carboplatin + paclitaxel 
          Consolidation chemo  
   Follow-up 
Pre-Tx evaluation 
• SPECT 
• PET-CT 
• Cytokine analysis 
During-Tx evaluation 
(40-50 Gy EQD2) 
• SPECT 
• PET-CT 
• Cytokine analysis 
Carboplatin + paclitaxel 
(q 21d x 3c) 
Or Immunotherapy 
(Durvalumab)                 
(q 14 d x 26c) 
CTCAE 4.0 and imaging 
assessment q 3 mo 
• Refinement of NTCP 
model 
RT plan 1 
• Conformal 
avoidance (21 
fractions) 
RT plan 2 
• Response-based 
adaptation  (9 
fractions) 

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STUDY SYNOPSIS 
Title 
Response-driven Adaptive Treatment in Patients with Non-Small Cell 
Lung Cancer  
Phase 
Pilot 
Methodology 
A pilot study  
Study Duration 
7 years 
Study Center 
University of Michigan, Ann Arbor Veterans Affairs Health System 
Objectives 
To improve local tumor control while maintaining the same rate of 
treatment toxicity by adapting therapy to the uninvolved lung and 
esophagus while continuing to adapt therapy to the tumor for patients with 
Stage II/III NSCLC cancer.  
Number of Subjects 
55 evaluable patients  (up to 70 patients may need to be enrolled in order 
to obtain 55 evaluable patients) 
Inclusion Criteria 
NSCLC, unresectable/inoperable  stage II-III 
Exclusion Criteria 
Any component of small cell lung carcinoma, prior radiotherapy to the 
thorax or not candidate for systemic chemotherapy  
Study Regimen 
FDG-PET-CT and SPECT guided radiation at the start of treatment. After 
administration of approximately 60% of the treatment,  dose will be 
intensified to the residual FDG avid tumor identified on the during-RT 
scans, and V/Q SPECT-CT scanning during-treatment will be used to 
avoid functionally recovered lung, and FDG-PET to minimize radiation 
sensitive esophagus. 
Duration of Administration 
6 weeks of radiation with concurrent chemotherapy  
Reference Therapy 
Patient enrolled in UMCC 2006.040 standard radiotherapy (60Gy in 30 
fractions in 6 weeks)+concurrent chemotherapy  
Statistical Methodology 
This is a pilot study with a primary aim to obtain preliminary estimates of 
toxicity and doses achievable with the proposed adaptive treatment 
strategy.  The proportion of patients experiencing G2+ lung toxicity or G2+ 
esophagitis will be reported with 90% confidence intervals.  The doses 
given to the tumor will be compared to what would have been given to 
these patients if they had been treated on UMCC 2007-123. In addition, 
local control will be summarized with Kaplan-Meier methods.  An 
additional secondary aim was regarding imaging uncertainty.   
 
 
 
 
 
 
 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background: Overview of Lung Cancer 
Lung cancer is the leading cause of cancer death in the United States and worldwide. In 
2012, there were 226,160 new cases and 160,340 deaths related to lung cancer in the 
United States (1). Approximately, 80-85% of lung cancers are NSCLC, and 40% of these 
are locally advanced (stage II/III) at diagnosis (2). The current standard of care for these 
patients is “one size fits all” RT with concurrent chemotherapy and recently data shows 
benefit of adjuvant immunotherapy when appropriate in uniform regimens (94).  Even after 
concurrent chemoradiation, however, the five year overall survival was still about 15%; 
almost one half of the patients failed locally (3). The addition of consolidative 
immunotherapy extends overall survival from 14 to 23 months, suggesting further 
intensification of therapy is necessary. At the same time, intensification of both 
radiotherapy and concurrent chemotherapy may result in excessive toxicity or incomplete 
treatment. Therefore, it is critical to tailor the treatment to each individual’s sensitivity in 
combination with functional imaging guided response-driven treatment and biomarker 
guided individualized dose prescription, thus taking into consideration both the tumor and 
toxicity profile.  
1.2 
PET Guided Adaptive Radiotherapy to Improve Long-term Tumor Control 
 
1.2.1  Effective Local Radiation Improves Long-term Tumor Control 
 
Local tumor failure remains a major problem after radiation-based non-surgical treatment. 
Approximately one half of patients with locally advanced NSCLC failed locally (4). The 
earliest positive dose-response relationship was demonstrated by RTOG 73-01, in which 
376 patients were randomized to 40 Gy split-course radiations, a continuous-fractionation 
40 Gy, 50 Gy or 60 Gy. The intrathoracic failure rates at 3 years were 44%, 52%, 42% and 
33% respectively (5, 6). Although that study did not show improved overall survival with 
higher dose therapy, secondary analysis from RTOG trials led to the conclusion that local 
tumor control is significantly correlated with improved survival (6). In an extensive literature 
review, Vijayakumar, et al. estimated that a dose of 80 Gy was required for 90% local 
control in lung cancer (7). Using 3D CT-based conformal techniques, several prospective 
studies have escalated radiation doses much higher than 60–70 Gy (8-20). Higher doses 
appear to be associated with better local tumor control and survival in medically inoperable 
or unresectable NSCLC (11, 16, 21). For patients with stage I-III disease, multivariate 
analysis of our UMCC 9402 demonstrated the radiation dose to be the only significant factor 
for local tumor control and overall survival in the dose range of 63-103 Gy (16). An increase 
of 1 Gy was associated with a > 1% improvement in the 5-year tumor control, and a 3% 
decrease in risk of death. An RTOG secondary analysis of 11 RTOG trials (9/11 treated 
with concurrent chemoradiation) in 1,356 patients receiving standard 60-69.6 Gy  therapy 
reported that a 1 Gy increase in biologically equivalent dose (BED) was associated with a 
4% risk reduction in local failure and a 3% risk reduction of death in patients with stage III 
NSCLC treated with combined chemoradiation (22) (23). This study took treatment duration 
into consideration, reporting 2-year and 5-year survival rates of 38% and 15%, with 2-year 
and 5-year local-regional failure rates of 46% and 52%, respectively. For higher dose 
ranges, we have demonstrated that radiation dose is a significant factor in patients with 
larger tumors of early stage NSCLC (24). In patients receiving >70 Gy with concurrent 
chemoradiation, we recently reported positive dose-survival relationship in the range of 60-
100 Gy with concurrent and adjuvant carboplatin and paclitaxel  (25). The median rate of 
local-regional and progression-free survival (95%CI) was 10.7 (Range: 8.4-13.0) months 
and non-reached (14.1 to date), (p=0.001) for physical doses <70 and >70 Gy, respectively. 
The median survival was 15.5 (Range: 6.5-24.4) and 41.9 (Range: 18.3-65.5) months 
(p=0.003), for physical doses < and >=70 Gy, respectively. One Gy of dose escalation was 
associated with a 3% reduction in the risk of death. All this evidence suggests that high-
dose radiation has the potential to improve local-regional control and overall 
survival in patients treated with fractionated therapy with concurrent chemotherapy. 
 

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However, it is challenging to deliver high dose RT in the majority of patients with 
locally advanced NSCLC without exceeding doses to OARS and causing significant 
side effects. After our clinical trials described above for patients treated with radiation 
alone or sequential chemoradiation, we designed a study for Stage III patients 
(UMCC2003073) treated with concurrent  chemoradiation followed by adjuvant 
chemotherapy.  We found that, using our standard complication limits, 60% of our patients 
could not be safely treated beyond 66 Gy.  More importantly, RTOG 617, a phase III 
randomized trial was conducted to compare the survival outcome between 60 and 74 Gy 
arms without consideration of treatment tolerance in each patient. The first interim results 
reported significantly worse survival at 1 year in the high-dose arm. Thus, our pilot study 
and RTOG 0617 suggest that high dose uniform dose prescription to the entire tumor 
is limited by the radiation toxicities (4, 8).  Therefore, new strategies are required. 
 
We hypothesized that we could develop safer and more effective therapy by adapting 
treatment to the individual patient’s response.  With respect to the tumor, we hypothesized, 
that we could improve outcome by redistributing dose to the more aggressive regions of 
the tumor, assessed using mid-treatment FDG-PET scanning.  With respect to uninvolved 
organs, we need methods of estimating tolerable radiation doses for the individual patient 
rather than the population average. Such a strategy requires assessing both global and 
regional normal lung function and the technology to deliver dose in a manner that minimizes 
damage to functional lung and esophagus.  The background supporting this approach is 
laid out in the following sections. 
 
1.2.2 FDG-PET to Adapt Radiotherapy  
FDG-PET, a Medicare approved tumor functional PET, is widely available in daily oncology 
practice for diagnosis, staging, radiation treatment planning, and monitoring treatment 
response. The literature on FDG-PET/CT has been focused on scans performed at 
approximately 3 months after completion of RT. Limited studies have demonstrated that an 
early (1-2 months) post-treatment FDG-PET/CT scan is a prognostic factor for survival and 
is more predictive than CT response, stage, or pretreatment performance status (26). 
Furthermore, evaluation of post-treatment images is significantly complicated by the 
presence of variably hypermetabolic inflammatory post treatment changes. Images done 
during the course of chemoradiation have shown markedly less inflammatory changes, 
suggesting that during-treatment FDG-PET/CT may allow a less confounded evaluation of 
response to therapy (27). We and others have demonstrated that FDG-PET can be 
performed earlier during the course of therapy to predict post-treatment outcome. The 
change in FDG uptake early during the course of chemotherapy was found to be predictive 
of progression-free and overall survival (28-32). Researchers from the Netherlands 
reported a large intra-individual heterogeneity in the evolution of FDG uptake during the 
early course of RT (33). They reported a non-significant increase in the first week (p=0.05) 
and a small but statistically significant decrease in the second week (p=0.02) during RT. 
We have demonstrated a greater and more significant reduction of peak FDG activity at 
40-50 Gy (4-5 weeks during the course of fractionated RT) (27). The regions of peak tumor 
FDG activity during-RT correlated with those seen 3 months post-RT (R2 = 0.7; p < .001). 
Investigatorsfrom Stanford University (RSNA 2008) and Princess Margaret Hospital 
(ASTRO 2008) also studied the role of FDG-PET/CT during RT and reported a 
heterogeneous reduction of FDG uptake at about 4 weeks during RT. The Stanford group 
also reported a correlation of FDG uptake during RT with progression-free survival. Indeed, 
the role of PET/CT in therapeutic monitoring and prediction of outcome is expanding rapidly 
because of its ability to provide earlier and more robust identification of non or poor 
responders than is provided by conventional CT. Therefore, during-RT FDG-PET/CT 
potentially can provide important benefits to individual patients by intensifing dose 
to more resistent tumor, allowing early changes to alternative, more efficacious 
treatment or by avoiding the unnecessary toxicity related to ineffective therapy.  
 
We have conducted a series of prospective studies to examine this issue at the 
University of Michigan. The key findings include the following: 1) FDG uptake and tumor 
volume were significantly reduced after 40-50 Gy of fractionated RT (27); 2) Adapting the 

9 
 
planned target volume to this decreased tumor size with a fixed composite NTCP of 15% 
allows escalation of the total dose by 30-102 Gy (mean: 58 Gy) or a reduction in NTCP if 
the dose remained unchanged (34); 3) PET MTV can be defined reproducibly (35); 4) 
Reduction in the MTV was greater than the reduction of the CT-GTV during RT (35); 5) 
Using the MTV during RT, tumor dose can be escalated above 74 Gy while keeping lung 
NTCP unchanged in a majority of patients with stage III NSCLC (36).  Based on these 
findings, we have conducted a prospective clinical trial of PART using the during-RT FDG-
PET in 42 patients. Preliminary results demonstrated that during-RT PET adaptive RT 
produced significantly better local control and overall survival at 1 and 2 years than 
standard RT in patients with stage III NSCLC treated with concurrent and adjuvant 
carboplatin and paclitaxel. This methodody has been adopted in RTOG 1106, which is 
currently recruiting patients. The proposed study will use this promising 
methodology to intensify dose to the more resistent active tumor to improve local 
control.  
 
1.3 
V/Q SPECT, PET, and Biomarkers to Decrease Lung and Esophageal Toxicity 
 
1.3.1 V/Q SPECT to Guide Adaptive Radiotherapy to Decrease Lung Toxicity 
V/Q SPECT allows simultaneous imaging of regional blood flow and ventilation for the 
whole lung.  Lung blood flow is typically imaged using macroaggregates of albumin. Both 
radioactive gases and particulate aerosols labeled with radioactivity have been used for 
imaging of regional ventilation.  V/Q SPECT has a potential to guide RT planning to 
minimize radiation dose to functional lung.  Largely due to limited technology, most earlier 
studies focused on Q-SPECT at baseline to guide radiation planning for functional region 
avoidance (37-44).  However, ventilation is another important component of lung function. 
V/Q SPECT provides more information than Q-SPECT alone in the assessment of local 
pulmonary function at baseline for patients with NSCLC and tumor shrinkage during the 
course of RT (27) (45). V/Q SPECT can be used to assess the spatial distribution of lung 
blood flow and ventilation at baseline and during the course of RT. By co-registering with 
conventional CT images, SPECT images can provide functional information which can be 
used to refine RT planning.  A number of dosimetric planning studies suggested a potential 
to reduce pulmonary toxicity by use of SPECT with IMRT for functional lung avoidance (38-
40, 43). IMRT may produce better PTV90/fV20 ratio and reduce fMLD values compared to 
3-DCRT in patients with stage III disease due to a reduction in fV20 for fixed PTV coverage.  
By comparing IMRT treatment plans generated with and without SPECT guidance for 5 
patients, investigators from Duke University found that the Q-SPECT-guided plan 
produced a more favorable DFH compared with the non-SPECT guided plan. Additionally, 
the fV20 and fV30 values were reduced for all patients by an average of 13.6% ± 5.2% and 
10.5% ± 5.8%, respectively (40).  
 
Modern radiotherapy technology may allow for improved target volume coverage and 
better selective avoidance of normal tissues. IMRT for NSCLC may lead to a 6–15% 
absolute decrease of V20 compared to 3-DCRT. The current standard for evaluating the 
normal tissue sparing effect of modern RT techniques considers the whole lung as a 
uniform organ. However, patients with NSCLC have frequent respiratory comorbidity 
particularly in the form of COPD resulting in heterogeneous function within different lung 
regions, and the presence of the tumor itself may affect local vascular supply and 
ventilation. Indeed, the majority of patients with lung cancer have some functional defect 
at baseline. From imaging analysis of over 50 consecutive patients, the V/Q defects were 
matched, reverse mismatched (V- defect greater than Q-defect), and mismatched (Q-
defect greater than V-defect) in 61%, 31% and 8% patients, respectively. The tumor is the 
leading cause of the defects in ipsilateral lung in 73% patients. The defect scores of 
ipsilateral lung were greater in patients with central primary tumors than those with 
peripheral primaries for both V- (2.3±1.1 vs. 1.5±0.8, p=0.017) and Q-SPECT (2.2±0.8 vs. 
1.4±0.6, p=0.000). The patients with COPD had greater defect scores in contralateral lung 
for both V- (1.5±0.7 vs. 1.0±0.8, p=0.006) and Q- SPECT (1.4±0.6 vs. 1.0±0.4, p=0.010). 
On assessing the potential value of SPECT on RT planning, 39% of patients could have 
their RT application type changed from SPECT of Q-scan alone to V/Q-scan. Combining 
using co-registered V/Q SPECT and CT images, we can also classify the lung functional 

10 
 
defects to: Type A defect as a defect from tumor occupation; Type B1 defect as a complete 
function defect due to COPD or other unrecoverable diseases; Type B2 as reduced lung 
function due to COPD or other unrecoverable diseases; Type B3 as temporarily 
dysfunctional lung due to tumor and other potentially reversible conditions; Type C as 
normal functional lung. Specific avoidance of functioning lung (i.e. type C, B3 and B2) 
defined by a V/Q SPECT scan may decrease dose to functioning regions and thus 
decrease functional damage of the lung.  
 
During the course of radiation therapy, lung function changes globally and locally. Our 
previous study demonstrated a significant improvement in breathing assessed by dyspnea 
grade during-RT, and remarkable improvements in regional V/Q function by the time a 
mean dose 45 Gy was delivered. Regional V/Q improvements were mostly in the ipsilateral 
lung in patients with central tumors, which may be due to tumor volume reduction. 
Additionally, regional V or Q functional mapping changed most remarkably in B3 regions. 
An adaptive plan based on V/Q SPECT during-RT may better spare the functioning lung. 
Significant V/Q SPECT changes during-RT suggest the value of obtaining a V/Q SPECT 
to re-optimize the treatment plan, especially in patients with central tumors. V/Q functional 
mapping based on our recently proposed classification on pre-RT V/Q SPECT may guide 
the potential applications of SPECT on RT planning based on the regional function level, 
etiology and potential for recovery (45).  SPECT may provide an opportunity for RT plan 
optimization as follows: Type A tumor occupying lung treated to the maximum safe dose; 
Type B1 regions, with unrecoverable non-functioning “bad” lung, can be given high dose 
RT without causing a change in the global lung function; B2 regions, with unrecoverable 
low functioning lung, may be given a high dose without causing remarkable change in the 
global lung function; Type B3 should be spared whenever possible and may be given high 
dose RT if it remains nonfunctioning on the during-RT SPECT; The RT dose to type C 
regions should be minimized to decrease functionally or clinically significant complications.  
By further studying the functional mapping on the V/Q scan during-RT, the current study to 
some degree validated our previous functional classification. Type B3 regions, potentially 
recoverable, were observed in 71.4% (43/56) of patients on pre-RT SPECT. The V/ Q 
function recovered in 51.2% (22/43) of these regions, accounting for 39.3% (22/56) patients. 
This group of patients may benefit from V/Q SPECT acquired during-RT for RT plan re-
optimization for sparing of functional lung. An adaptive plan based on during-treatment 
SPECT may further optimize PART to avoid high dose radiation to the well-
functioning regions, and would thus decrease RILT. 
 
In summary, we proposed the combination of pre- and during V/Q-SPECT to improve the 
sparing of healthy lung. V/Q SPECT adds lung ventilation mapping on top of the Q-SPECT, 
providing more information (including the mechanism for lung function defects and their 
potential for recovery). During-RT V/Q SPECT allows adaptive-RT because lung function 
changes globally and locally during-RT, largely due to RT induced tumor volume reduction 
improving the vascular supply and ventilation(46). The combination of pre- and during 
V/Q SPECT can classify the lung into different functional regions, and a strategy to 
give differential priority to the regions has been developed to minimize lung damage.   
 
1.3.2 PET-CT to Guide Adaptive Radiotherapy to Decrease Esophageal Toxicity 
In addition to RILT, esophagitis is a common side effect of thoracic radiation therapy and 
a source of considerable morbidity (47).  Patients often complain of dysphagia and/or 
odynophagia in the late course of fractioned radiotherapy that can cause significant 
complications from dehydration and weight loss leading to interruption of radiation therapy 
and in rare instances, can result in esophageal perforation or obstruction and death (48, 
49). Clinical and dosimetric studies have shown that the dose and volume of esophagus 
irradiated, as well as the concurrent use of chemotherapy correlate with the severity of 
esophagitis (50-52), but the predictive value of these correlations is only modest (51-54). 
Our preliminary results (see below) show that the increase in FDG uptake in esophagus at 
40-45 Gy identifies the sensitive esophagus, improves the ability to estimate esophagitis 
over the predictions made by using maximum esophageal radiation dose alone. Thus, we 
propose to adapt treatment in patients with greater esophageal FDG avidity 

11 
 
midtreatment by decreasing the esophageal dose to keep esophagitis levels at no 
greater level than that produced by 60 Gy of standard therapy. 
 
1.3.3 Serum Biomarkers to Predict Lung Toxicity and Potentially Guide Adaptive 
Therapy 
While it seems essential to deliver an adequate dose of radiation with chemotherapy to 
shrink the tumor for disease control, it is important to note that patients often respond to 
treatment differently in terms of both tumor control and treatment-related toxicity. Strictly 
limiting lung NTCP to 15% does not predict which 15 of 100 patients will develop 
complications. Given that DVH parameters are associated with RILT in populations of 
patients but lack optimal predictive ability for individuals, we hypothesized that the addition 
of biologic parameters to the model will improve the prediction of post-treatment RILT for 
individual patients. 
 
Recent insights into the pathogenesis of radiation-induced normal tissue injury have 
revealed the involvement of a number of pro-inflammatory and pro-fibrogenic cytokines, 
including TGF-ß1, IL-1ß, IL-6, IL-8, and TNF-α (55). TGF-ß1, a fibrogenic and radiation-
inducible cytokine, has been known to play a key role in this process. Data from animal 
models demonstrate significantly elevated TGF-ß1 mRNA and protein expression within 
type II pneumocytes and fibroblasts in radiation-sensitive mice after thorax radiation (56-
59), which subsequently contributed to an increased TGF-ß1 level in the circulation. TGF-
ß1 modulation normally precedes histologically discernible fibrosis.  In rats, the expression 
of TGF-ß1 mRNA and protein in lung peaks within 3 to 6 weeks and coincided with an initial 
influx of inflammatory cells in bronchoalveolar lavage, while pulmonary fibrosis was not 
apparent until 8-10 weeks after thoracic radiation (59). In humans, the Duke group reported 
that plasma TGF-ß1 levels at the end of radiation are correlated with the later onset of 
symptomatic lung toxicity in patients treated with definitive radiation therapy (57, 60, 61). 
Unfortunately, end-RT TGF-ß1 correlations have not been consistently reproduced by 
others (62). We have demonstrated that TGF-ß1 elevation in the middle of treatment (2-4 
weeks during-treatment) relative to pre-treatment is highly correlated with late-onset 
grade >2 RILT in NSCLC patients (63). This correlation is more important than end-
treatment markers, as it provides us an opportunity to adjust treatment accordingly. This 
finding was recently validated by an independent prospective study (64). IL-8 
overexpression was associated with impaired migration of neutrophils which may inhibit 
the inflammation effect. Hart et al from Duke reported that a lower pretreatment plasma 
level of IL-8 was an independent risk factor for the development of RILT (65). We have 
also recently demonstrated that a high level of baseline IL-8 is associated with decreased 
risk of clinically significant RILT. However, the sensitivity to change and predictive power 
from any single cytokine alone are limited.  We have recently reported that combining TGF-
ß1 and IL8 with MLD can provide more accurate prediction of RILT than MLD alone (65). 
Thus, we plan to continue to collect data on serum biomarkers to further refine our 
biophysical model with the ultimate goal of individualizing radiation dose prescription 
to isotoxicity of lung estimated by not only MLD, but also a cytokine signature. 
 
1.3.3.1 Circulating Extracellular RNA, DNA, and Urinary RNA/DNA as Additional Biomarker 
Approaches for Prediction of Lung Toxicity and Potentially Guiding Adaptive Therapy 
 
Clinically useful blood-based biomarkers based upon circulating cell-free nucleic acids 
are also under development. For example, circulating tumor DNA is emerging as an 
exciting new area and has been shown as a promising noninvasive biomarker for early 
detection, prognosis, and treatment follow-up for various cancers. Likewise, circulating 
cell-free RNA, including microRNA, is being actively developed as a biomarker approach 
for multiple oncology applications. New technologies are being developed to increase the 
sensitivity and specificity of cfNA detection in the blood. Hence, we plan to analyze cell-
free nucleic acids in plasma and serum specimens that will be collected to identify 
biomarkers for prediction or early detection of toxicity, which could be used to adapt 
therapy. 
 

12 
 
Recent studies have demonstrated that nucleic acid and other analytes in urine may 
serve as markers for systemic (i.e. non-urinary tract) disease status. This includes 
microRNA, cell-free (cf) trans-renal DNA fragments, potentially other diverse species of 
RNA, and other biomarker types. Hence, we also plan to study urine cfDNA and 
extracellular RNA as a source of potential biomarkers. 
 
1.3.3.2 Circulating and Infiltrating Immune Cell Infiltrates as Additional Biomarker 
Approaches for Prediction of Lung Toxicity and Potentially Guiding Adaptive 
Therapy 
 
The number and function of circulating hematopoietic populations can provide insight into 
the functional state of the immune system. The ratio of T cell reinvigoration to tumor burden 
has been hypothesized to serve as a biomarker for response to immune checkpoint 
blockade in metastatic melanoma patients (94). Tumor infiltration of T cells has been 
hypothesized to alter radiotherapy toxicity and efficacy (95). Peripheral blood functional 
immunophenotyping will be performed by flow cytometry. Multiparametric flow cytometry 
analysis will include enumeration and functional evaluation of antigen presenting cell 
subsets, innate lymphoid cell subsets, myeloid derived suppressor cells, and T cell subsets 
(including NKT cells, CD8+ effector cells, and CD4+ helper cells). Cytokine secretion, 
proliferation, immunoinhibitory ligand expression, and transcription factor profile will be 
quantified by flow cytometry in T cell subsets in hopes of developing new clinically useful 
biomarkers..  
 
Certain features of anti-tumoral immunity may be best assessed through examination of 
tumor tissue. It has been suggested that the Immunoscore (multiparametric 
immunohistochemistry and automated imaging for of CD3+ T cells density, CD8+ cytotoxic 
T cells density, and CD45RO+ memory T cells presence) in tumor tissue may have 
improved prognostic potential as compared to TMN systems in colorectal cancer (96).   
Further, preliminary studies have begun examining the hypothesis that the pre-treatment 
immune infiltrate or mid-treatment alteration in immune infiltrate induced by chemoradiation 
impact the tumor microenvironment and PDL1 expression (97).  We plan to perform 
quantitative multiparametric immune immunohistochemical tumor evaluation on patients at 
UM with diagnostic core needle biopsies in hopes of developing clinically useful biomarkers 
to predict treatment or toxicity (98). 
 
 
 
 
 
1.3.4  Summary of Normal Tissue Adapation Strategy 
In summary, patients receiving the same doses of RT often have very different levels of 
toxicity or toxicity patterns, largely due to their biologically different intrinsic sensitivity to 
radiation damage (66).  We propose to use functional imaging (V/Q SPECT) and dosimetric 
parameters (mean lung dose) to guide RT planning at baseline for RILT estimation.  We 
will continue to collect data on serum biomarkers to refine our biophysical model such that 
we can ultimately adapt treatment in patients with a cytokine signature predictive of RILT 
by decreasing lung dose to keep RILT levels at no greater level than that produced by 60 
Gy of standard therapy. Additionally, we will use during RT PET scan to identify sensitive 
esophagus (for sparing) for radiation plan optimization.  By identifying high risk patients 
and adjusting OAR dose limits to the threshold of tolerance, we anticipate a 
significant reduction in the incidence of toxicity from UMCC2007123 without 
compromised tumor control by applying the model to optimize radiation planning.  
 
1.4  
Combination of Chemotherapy and/or Immunotherapy in NSCLC  
The standard of care for patients with stage III unresectable NSCLC is combined 
chemoradiotherapy. The results with RT alone for stage III tumors that are deemed 
unresectable or marginally resectable are poor, with five-year survival rates of 5%–7% (6, 
67, 68). Radiation therapy alone is only used to treat patients who cannot tolerate 
chemotherapy. The addition of neoadjuvant chemotherapy resulted in a 2–4 month 
extension in median survival and 8%–20% improvement in 2–3-year overall survival (69, 

13 
 
70) in at least three randomized trials: CALGB 9433 (67), RTOG8808/ECOG4588 (68), and 
a French study (71). The French study also reported a significant reduction in distant 
recurrence rate. 
 
1.4.1 Sequential vs. Concurrent Chemoradiotherapy Several prospective randomized 
trials examining the treatment of  patients with stage III unresectable NSCLC have 
demonstrated superior results with concurrent chemoradiotherapy compared to sequential 
chemoradiotherapy, with a 2–3 month extension in median survival and 7%–10% 
improvement in 3–5-year survival, albeit with increased toxicity (72-74). In patients with 
locally advanced NSCLC who are medically fit, concurrent chemoradiotherapy is 
considered as a standard therapy.   
 
1.4.2 Adjuvant or Induction Chemotherapy and Immunotherapy with Concurrent 
Chemoradiotherapy Although there is general agreement on the principle of using 
combined modality therapy with a concurrent regimen for stage III unresectable NSCLC, 
there is controversy over the optimal approach and sequence in this population. A 
number of phase II and III trials have evaluated the use of either induction or 
consolidation chemotherapy (75-80). Researchers from the University of North Carolina 
reported a median survival of 24 months in patients treated with induction 
paclitaxel/carboplatin (CP) followed by concurrent chemoradiotherapy. However, CALGB 
39801, a phase III study comparing concurrent chemoradiotherapy alone to induction CP 
followed by concurrent chemoradiotherapy failed to show a significant survival difference 
between the two arms, with a median survival of 14.0 months in the induction arm versus 
11.4 months in the concurrent alone arm (P = .154) (81). A median survival of 26 months, 
the best survival result reported thus far for unresectable stage III NSCLC, was reported 
from a phase II trial (SWOG 9504) using docetaxel as consolidation chemotherapy (79). 
The median overall survival from the locally advanced multiple modality protocol (LAMP) 
was 13.0, 12.7, and 16.3 months with sequential chemoradiotherapy, concurrent 
chemoradiotherapy after induction CP, and concurrent chemoradiotherapy followed by 
consolidation CP, respectively (78). Although the LAMP was not powered to definitively 
address differences between arms, it suggested that concurrent chemoradiotherapy 
followed by consolidation chemotherapy resulted in the best median survival. Large 
phase III trials are still warranted to determine the optimal combination of chemotherapy 
and radiotherapy and a recent HOG study failed to show a benefit of adjuvant docetaxol 
(82). The PACIFIC trial recently showed that adjuvant administation of durvalumab (anti-
PDL1 antibody) in locally advanced NSCLC cancer patients who had not progressed 
during chemoradiation resulted in a 28% response rate, a improvement from 5.6 to 16.8 
months in progression free survival, and an improvement in median overall survival from 
14.6 months to 23.2 months (94).  Thus the current  practice in patients with good 
performance status is concurrent chemotherapy followed by consolidation immunotherapy 
and or chemotherapy in the United States (80). Therefore, this trial will use concurrent 
chemoradiation followed by adjuavant immunotherapy and or chemotherapy.  
 
1.5 
Rationale 
The standard therapy for patients with unresectable NSCLC is concurrent chemoradiation 
(83) with a fixed “uniform” of radiation in the dose range of 60-66 Gy. It was estimated that 
a dose of  100-180 Gy BED was associated with 90% of long-term tumor control (84).  
However, adequate target coverage also requires increased treatment of normal structures 
and thus increases radiation toxicities.  During-RT FDG-PET can potentially be used for 
prediction of treatment outcome, evaluation of response during treatment, and adaptation 
or alteration of the remaining treatment (27). Our preliminary results from the UMCC2007-
123 trial, which has reached its planned enrollment of 42 patients, demonstrated that 
adapting the planning target volume to the decreased tumor volume with a fixed composite 
NTCP of 17.2% allows for a substantial escalation of the total BED to the active tumor and 
with significantly improved overall survival (P=0.03) and local tumor control at 2 years 
(P<0.001) relative to standard RT in patients with stage III NSCLC treated with concurrent 

14 
 
and adjuvant carboplatin and paclitaxel. However the toxicity of radiation administered by 
UMCC2007-123 appears to be greater than that produced by standard therapy.  RILT, a 
key dose-limiting toxicity of treatment (55, 85-87), was about 5% higher than standard dose 
RT. RIE was about 10% higher than that of standard dose RT. To decrease lung damage,  
V/Q-SPECT images will be used to guide RT planning so that radiation is directed to the 
non-functional lung regions (38-40, 43) which may produce more favorable dose functional 
volume histograms compared to non-SPECT guided plans (40). Our preliminary results 
strongly suggest that avoiding V/Q SPECT-CT functional regions in pre- and during- RT 
can minimize dose to functional lung. For radiation esophagitis which is a source of 
considerable morbidity (47), we have demonstrated that the increase in FDG uptake in 
esophagus at 40-45 Gy identifies the sensitive esophagus, improves the ability to estimate 
esophagitis over the predictions made by using maximum esophageal radiation dose alone.  
We will thus adapt the treatment to avoid radiating the sensitive esophagus. Finally, we will 
use baseline IL-8 and TGF-ß1 in the middle of treatment (2-4 weeks during-treatment) to 
adjust treatment, as only these two cytokines have been independently validated by 2 
centers for their predictive values.  In summary, in this pilot study, we minimize treatment 
of functioning lung from the beginning of treatment using V/Q SPECT-CT scanning. After 
administration of approximately 60% of the treatment, we will not only intensify dose to the 
residual FDG avid tumor but also use V/Q SPECT-CT scanning during-treatment to avoid 
functionally recovered lung, and FDG-PET to minimize radiation sensitive esophagus. In 
addition, patients who are unusually sensitive to radiation will be identified at baseline (by 
measuing IL-8) and during treatment (by measuring TGF-ß1) so that the remainder of their 
treatment course can be modified and toxicity kept to acceptable levels.  We hypothesize 
that by adapting radiation therapy to the uninvolved lung and senstive esophagus, 
we can maintain the dose to the FDG-avid tumor that we achieved in UMCC2007-123 
while decreasing grade 2 and above RILT and RIE from the UMCC 2007-123 so that 
causing no greater overall toxicity than expected from standard therapy (60 Gy 
uniformly delivered to the tumor). 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1    Establish the feasibility of the proposed adaptive treatment strategy 
 
 
2.1.2 
To obtain preliminary estimates of the toxicity of and doses achievable by the 
proposed response-driven adaptive treatment strategy in patients with Stage II/III 
NSCLC. 
 
2.2 
Secondary Objectives  
2.2.1   To obtain preliminary estimates of local regional tumor control from an adaptive 
approach, which will aid in the design of a subsequent randomized phase II trial. 
 
2.2.2   To determine the residual uncertainties in V/Q SPECT scans related to the 
accuracy with which persistent tumor subvolumes and the spatial distribution of 
local function of uninvolved lung could be mapped to guide plan modification. 
 
2.2.3.  To determine the time to local regional progression and death in patients treated 
with this response-driven adaptive regimen. 
  
2.2.4.  To refine our biophysical NTCP model to individualize and adapt radiation dose 
prescription to minimize lung injury. 
 

15 
 
2.3 
Endpoints 
2.4.1 Primary Endpoints 
2.4.1.1 Grade 2 and above lung toxicities, as defined via NCI’s CTCAE version 4.0 in 
appendix); 
24.1.2. Grade 2 and above esophageal toxicities, as defined via NCI’s CTCAE version 4.0 
in appendix); 
2.4.1.3 Comparison of delivered dose to dose that would have been administered using 
the criteria described in UMCC2007-123. 
  
2.4.2 Secondary Endpoints 
2.4.2.1 Time to local progression, which will be defined as the time from start of treatment 
to time of local regional progression on PET.   
2.4.2.2 Overall survival time, which will be defined as the time from start of treatment to 
death.  Patients alive at their last follow-up will be censored at the date of last 
follow-up.  
2.4.2.3 Other tumor control measures: tumor response (based RECIST criteria). 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
3.1.1 
Patients must have FDG-avid and pathologically proven Stage IIA-IIIB non-small 
cell lung cancer (NSCLC) (according to AJCC staging, 8th edition).  
3.1.2 
Patients must be considered unresectable or inoperable 
3.1.3 
Patients must be 18 years of age or older. 
3.1.4 
Patients must have Karnofsky performance score ≥ 70.  
3.1.5 
Patients must have adequate organ and marrow function as defined below: 
WBC 
≥3,000/mm3 
absolute neutrophil count 
≥1,500/mm3 
platelets 
≥100,000/mm3 
total bilirubin 
≤3.0 mg/dl 
AST (SGOT) and ALT (SGPT) 
≤4 X institutional upper limit of normal 
Creatinine 
≤2.0 mg/dl 
 
3.1.6 
Patient must be willing to use effective contraception if female with reproductive 
capability for 3 months post last dose of study treatment. 
3.1.7 
Patients must be informed of the investigational nature of this study and given 
written informed consent in accordance with institutional and federal guidelines 
3.2 
Exclusion Criteria 
3.2.1 
Patients with any component of small cell lung carcinoma;  
3.2.2 
Patients with evidence of a malignant pleural or pericardial effusion; 
3.2.3 
Prior radiotherapy to the thorax such that composite radiation would significantly 
overdose critical structures, either per estimation of the treating radiation 
oncologist or defined by failure to meet normal tissue tolerance constraints; 
3.2.4 
Patients cannot tolerate concurrent chemotherapy  
3.2.5 
Pregnant women are excluded from this study because radiation has the potential 
for teratogenic or abortifacient effects; 
3.2.6 
Prisoners are excluded for this study. 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Patient registration for this trial will be centrally managed by the Clinical Trials Office of The 
University of Michigan Comprehensive Cancer Center as described below: 

16 
 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Clinical Trials Office. After patient eligibility has been determined, 
a copy of the completed Eligibility Worksheet together with all the pertinent de-identified source 
documents will be submitted by the requesting site to the Clinical Trials Office, either by fax or by 
email to CTSU-Oncology-Multisite@med.umich.edu.  Note: Expired studies need to be repeated if 
out of specified time frame. 
 
A Multi-Site Coordinator of the Clinical Trials Office, who acts as the registrar, will review the 
submitted documents and process the registration. Sites should inform the Multi-Site Coordinator 
of a potential registration by 5 p.m. on the day prior to registration.  Same day registrations cannot 
be guaranteed.   
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, a 
copy of the completed Eligibility Worksheet signed and dated by the registrar, will be sent back to 
the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
The completed, signed, and dated Eligibility Checklist will be retained in the patient’s study file. 
 
 
5.0  
TREATMENT PLAN   
 
 
5.1  
Treatment Dosage and Administration   
 
Protocol treatment must start within 14 business days of enrollment to the study. 
 
This project is a pilot therapeutic clinical trial that assesses the patient after approximately 
60% of the treatment has been delivered, and adapts the latter 40% of the treatment using 
the knowledge of (1) the mid treatment FDG-PET scan to deliver a high dose of radiation 
to the active regions of the tumor (as was done per UMCC2007123); (2) V/Q SPECT-CT 
scanning both at the beginning of therapy as well as mid treatment to adapt local dose to 
the lung; (3) the mid treatment FDG-PET scan to assess esophageal toxicity.  This first 
trial will establish the feasibility of incorporating V/Q SPECT-CT (to predict local lung 
function) and FDG-PET (to predict esophageal toxicity) while redistributing a high dose 
of radiation to the active regions of the tumor (determined by mid treatment FDG-PET, as 
was done per UMCC2007123). In addition, we will continue to collect data on plasma 
biomarkers (pre- and during-treatment) to further refine our biophysical NTCP model for 
lung injury.  The goal is to incorporate this model into the adaptive treatment schema by 
identifying patients who are unusually sensitive to radiation by changes in biofluid 
biomarkers (such as cytokine levels, circulating RNA/DNA, and/or urinary 
biomarkers) so that the remainder of the treatment course can be modified and 
toxicity can be kept to acceptable levels. Our overall goal is to deliver similar radiation 
doses to the FDG-PET avid tumor that we gave in UMCC2007-123 while causing no 
greater toxicity of lung and esophagus than standard therapy (60 Gy uniformly delivered to 
the tumor), i.e. ~15% grade 2 and above RILT (4, 78, 88), ~30% grade 2 and above RIE 
(4, 89).  
 
 
Response based 
adaptive radiation 
therapy to the 
same toxicity level 
f
i i
Tumor: 
• PET to guide tumor adaptive plan to improve local tumor control 

17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1.1 Radiation Therapy 
 
5.1.1a Radiation  Therapy Schema:   
 
Patients will receive treatment 5 days per week, in once daily fractions, for 30 treatments 
with dose per fraction individually adapted over the final 9 treatments to intensify dose to 
active tumor while limiting normal tissue toxicity to an estimated grade >2 pneumonitis rate 
of 15% and grade >2 esophagitis rate of 30%. The radiation dose will be delivered in 
daily fractions of ≥2.2 Gy, with the treatment duration limited to 30 fractions, and 
total radiation dose limited to 66-80.4 Gy physical dose.  
 
The first part of treatment (21 fractions:  46.2 Gy at 2.2 Gy per fraction) will be delivered to 
a target defined using pre-treatment CT and PET with the pretreatment V/Q SPECT-CT 
scan used to optimize the radiation dose distribution to minimize dose to functional lung 
(conformal avoidance RT).  This will be followed by an adaptive course of radiation (9 
fractions: 2.2 – 3.8 Gy per fraction) based on individual FDG-PET response (tumor and 
esophagus) as well as individual V/Q SPECT response (lung).  Patients will receive a total 
tumor dose up to 80.4 Gy, which will be constrained by dose limits of the thoracic organs-
at-risk (OARs).  Specifically, using population based NTCP models we will limit predicted 
grade 2 and above RILT to ≤15% and grade 2 and above esophagitis to ≤30%, the rates 
of the standard practice (4, 90). 
 
 
5.1.1a.1 Use of FDG-PET scans to intensify dose to active tumor:   
 
Patients will undergo a FDG-PET-CT at baseline and after delivery of 40-50 Gy EQD2 
(approximately 18 fractions). The first 21 fractions of radiation will be given based on a 
target defined at the start of radiation, and the remaining dose will be delivered to the target 
defined by FDG-PET acquired during the course of radiation. All patients receive a tumor 
dose up to a 15% NTCP for estimated RILT and the dose limits of other OARs per 
standard practice. All points in the dose distributions are corrected to their EQD2 using the 
linear quadratic model on a tissue by tissue basis.  The radiation dose is delivered in daily 
Stage II-III 
NSCLC 
Normal Tissue: 
• SPECT to optimize dose distribution in lung (functional 
avoidance) 
• PET to spare the inflamed esophagus to decrease RIE 
• Refine NTCP model with cytokine data to individualize dose  
prescription to 15% RILT and 30% RIE 
Adaptive RT + weekly carboplatin + paclitaxel 
Consolidation chemo and/or immunotherapy    
Follow-up 
Pre-Tx evaluation 
• SPECT 
• PET-CT 
• Cytokine analysis 
During-Tx evaluation 
(40-50 Gy EQD2) 
• SPECT 
• PET-CT 
• Cytokine analysis 
Carboplatin + paclitaxel 
(q 21d x 3c) and/or 
Durvalumab ( q 14 days 
for 28 c) 
CTCAE 4.0 and imaging 
assessment q 3 mo 
• Refinement of NTCP 
model 
RT plan 1 
• Conformal 
avoidance (21 
fractions) 
RT plan 2 
• Response-based 
adaptation  (9 
fractions) 

18 
 
fractions of ≥2.2 Gy, with the treatment duration limited to 30 fractions, and the total 
radiation dose limited to 66-80.4 Gy physical dose; 64-102 EQD2 for lung toxicity 
assessment (alpha/beta = 2.5 Gy); 66-92 EQD2 for tumor control (alpha/beta = 10 Gy).  
 
5.1.1a.2 Use of V/Q SPECT-CT scans to spare functional lung:   
 
The pre-RT SPECT will be used during the optimization of the initial plan to minimize dose 
to functional lung. A priority based, lexicographic ordering strategy (38, 91)  will be used to 
prioritize sparing functional lung relative to other targets and OAR objectives.  The lung will 
be divided into five regions as summarized in Table 5.1.1a.2. The actual classification of 
each lung region will be determined by our nuclear medicine radiologists and radiation 
oncologists according to the functional intensity of V/Q SPECT-CT and its geometric 
location relative to the tumor in CT are also shown, as well as other clinical information. 
For treatment planning optimization, doses associated with regional based intensities 
(surrogate for function) within each region classification will be used to preferentially 
distribute dose in the lung tissue according the desire for avoidance given in Table 
5.1.1a.2. 
 
Table 5.1.1a.2.  SPECT-CT functional classification of lung functional regions  
      
 Region 
Lung  
function 
  Intensity in V/Q 
SPECT 
Usually  location relative  
to the tumor in CT 
RT Plan dose  
avoidance 
A 
Truly bad 
Very low 
On tumor 
No avoidance 
B1 
Truly bad 
Very low 
Proximal to tumor 
No avoidance 
B2 
Not so bad 
Low 
Proximal to tumor 
Low priority avoidance 
B3 
Recoverable 
Low or very low 
Distal to tumor 
Medium priority avoidance 
C 
Good 
High 
Not on tumor  
High priority avoidance 
 
The V/Q SPECT-CT scan during treatment will be used to update the classified lung 
regions as shown above table from the scan obtained pretreatment. The scan during 
treatment can improve the estimate of the functional lung regions by determining whether 
the B1 region defined by the pretreatment scan remains poor, or if the B3 region has 
recovered after 40- 50Gy of RT. If the B3 region in pretreatment scan does recover, it would 
be redefined as the C region in the adaptive plan.  Our experience in 75 cases showed that 
the above classification based on pre-treatment V/Q SPECT-CT is about 80% reproducible 
on the V/Q SPECT-CT during radiation. The new regions will be used in adaptive radiation 
optimization to minimize functional lung dose through the same strategy as the initial plan. 
 
5.1.1a.3 Use of FDG-PET to spare esophagus scans:  
 
The FDG-PET-CT scan during treatment will be used to optimize treatment planning to 
minimize radiation to FDG avid esophagus. Instead of using post-treatment PET to 
retrospectively correlate with radiation esophagitis (92), we will identify those patients with 
severe radiation-induced esophagitis on the during-RT PET scan to guide adaptive 
planning (93).  
 
 
5.1.1b. Radiation Volume Definitions   
 
Treatment volume for the first plan (initial 46.2 Gy given in 2.2 Gy/Fx in 21 
fractions): The initial gross tumor volume (GTV) is a composite volume  based on both 
the GTV from the pretreatment CT (CT) and the GTV from the pretreatment PET (PET1).  
• 
The CT-based GTV (GTV_CT1) includes the primary tumor mass and any hilar or 
mediastinal lymph nodes ≥ 1 cm on the simulation CT scan (breath hold technique 

19 
 
or 4D-CT [ITV]), plus any abnormal findings detected on bronchoscopy and/or 
mediastinoscopy, if applicable.  
• 
The PET-based GTV (GTV_PET1) of both primary tumor and nodal disease will be 
contoured using a threshold technique.  The mean PET intensity of a 1.5 cc volume 
in the aortic arch will be calculated and then multiplied by 1.5 to determine the 
minimum threshold for auto-contouring of the PET-based GTV.  Care will be taken 
to review the autocontoured GTV_PET volumes, as editing may be required to 
remove regions outside known gross tumor, such as the esophagus, which may 
demonstrate uptake, especially on the during treatment PET, secondary to 
esophagitis.  
• 
The final pretreatment GTV (GTV_CT1+PET1) will consist of a composite of the 
GTV_CT1 and the GTV_PET1. 
• 
The pretreatment clinical target volume (CTV_CT1+PET1) will consist of the 
composite GTV (GTV_CT1+PET1) with an approximate 0.5 cm margin for 
microscopic extension.  Radiographically uninvolved supraclavicular, paratracheal 
and subcarinal lymph nodes will NOT be intentionally included in the CTV.  
• 
The pretreatment planning target volume (PTV_CT1+PET1) will consist of the 
CTV_CT1+PET1 plus a minimum of a 0.5 cm margin for set-up error.  
 
Treatment volume for the second plan (during treatment):  During treatment target 
volumes will be defined based on a repeat PET-CT scan acquired after delivery of 40-50 
Gy EQD2 (approximately 18 fractions).   
• 
The during treatment GTV (GTV_PET2) will be defined using the same auto-
contouring using methodology as was used to define the pretreatment PET GTV 
(GTV_PET1).  
• 
GTV_PET2 will be directly expanded to a PTV (PTV_PET2) with a uniform 
expansion of at least 0.5 cm.  
 
 
 
 
 
Treatment volume structures and doses: 
 
* ITV (internal target volume for 4D-CT scans)  
† Constrained by dose limits of the thoracic organs-at-risk (OARs). 
Structure Name 
Description 
Preferred Dose covering 
95% volume 
Acceptable Variation‡ 
Plan 1 
GTV_CT1+PET1 
GTV*_CT1 + GTV_PET1 
n/a 
 
CTV_CT1+PET1 
GTV_CT1+PET1 + 0.5 cm 
n/a 
 
PTV_CT1+PET1 
CTV_CT1+PET1 + 0.5 cm (minimum) 
46.2 Gy or above 
41.6 - 46.2 Gy 
Final composite plan (plans 1 + 2) 
GTV_CT1+PET1 
GTV*_CT1 + GTV_PET1 
n/a 
 
CTV_CT1+PET1 
GTV_CT1+PET1 + 0.5 cm 
n/a 
 
PTV_CT1+PET1 
CTV_CT1+PET1 + 0.5 cm (minimum) 
56.0 Gy or above 
50.4 - 56.0 Gy 
PTV_PET2 
GTV_PET2 + 0.5 cm (minimum)   
Up to 80.4 Gy† 
5-10% less of desired dose 

20 
 
‡ The minimum dose within the PTV can fall below the 90% of the prescription dose but underdosing must be 
confined to areas of overlap with critical OARs. In those regions, the minimum dose to the PTV should be equal 
to the maximum allowed dose to the OAR. 
 
 
 
 
5.1.1c. Radiation Technique:  
 
Position/Immobilization/Simulation: Patients will be positioned and immobilized using 
standard techniques. Simulation CT scans of the chest will be performed using either 4D-
CT or breath-hold techniques (for tumors with respiratory motion > 1 cm and patient 
tolerance permits).   
 
Treatment Planning: All patients will undergo CT- and PET-based treatment planning for 
conformal radiation therapy. GTV definition, CTV margin, and PTV margin are as described 
above. The treatment technique and number of fields will be optimized individually. Dose 
volume histograms will provide objective criteria for prescription dose selection based on 
the potential for normal tissue damage. Suitable treatment plans will minimize thoracic 
normal tissue doses while also providing the highest prescription dose with acceptable 
target volume coverage.  
 
Target Volume Coverage: The expectation is conformal treatments, which minimize lung 
dose and meet all normal tissue constraints. As a guideline, a conformity index (ratio of the 
volume of the prescription isodose surface to the PTV) of < 1.5 is desirable. For treatment 
plans limited by the dose to normal lung (the standard case), the prescription isodose 
surface should encompass at least 95% of each PTV or the lowest dose limit of OARs, if 
any of them is lower than the prescription dose. It is desirable for the minimum PTV dose 
not to fall below 90% of the prescription dose and for the maximum PTV dose not to exceed 
110% of the prescription dose. For PTVs which overlap or come near other critical OARs, 
greater PTV dose heterogeneity is acceptable. The table above describes the target dose 
objectives. 
 
 
Organs at Risk Tolerances: All critical organs (listed below) will be contoured in the 
treatment planning system when they are in the radiation field. Lung, spinal cord, 
esophagus, heart, pericardium and brachial plexus contours should be based on the 
published 
atlas 
on 
organs 
at 
risk 
available 
on 
the 
RTOG 
web 
site: 
http://www.rtog.org/CoreLab/ContouringAtlases.aspx. If constraints cannot be met, the 
prescription dose may be decreased heterogeneously accordingly. Tradeoffs in target 
coverage and OAR dose limits may be made at the discretion of the treating physician on 
a case-by-case basis.  
 
Structure Description 
Metric 
Goal 
 Lungs minus 
(GTV_CT1+PET1) 
  Max Dose (Gy, 0.03 cc) 
  ≤ 110 % Rx 
Dose 
 
  Mean Dose (Gy) 
  ≤ 20 Gy 
 
  Vol > 20 Gy (%) 
  ≤ 35 % 
 
  Vol > 5 Gy (%) 
  ≤ 65 % 
 Heart/ Pericardium 
  Max Dose (Gy, 0.03 cc) 
  ≤ 70 Gy 
 
  Mean Dose (Gy) 
  ≤ 30 Gy 
 
  Vol > 30 Gy (%) 
  ≤ 50 % 

21 
 
 
  Vol > 40 Gy (%) 
  ≤ 35 % 
 Esophagus 
  Max Dose (Gy, 0.03 cc) 
  ≤ 74  Gy 
 
  Mean Dose (Gy) 
  ≤ 34 Gy 
 Spinal Cord + 3 mm 
  Max Dose (Gy, 0.03 cc) 
  ≤ 50 Gy 
 Brachial Plexus 
  Max Dose (Gy, 0.03 cc) 
  ≤ 63 Gy 
 
 
Radiation Dose Calculations: Dose calculations will be performed using modern dose 
calculation 
algorithms 
(listed 
on 
the 
IROC 
Houston 
web 
site 
at 
http://irochouston.mdanderson.org) with inhomogeneity corrections that take into account 
the density differences within the irradiated volume. Non-validated dose calculation 
algorithms (i.e. simple pencil beam) will not be allowed for this study. For free-breathing 
treatment, dose calculations will be performed on an untagged or average scan generated 
from 4DCT data. For breathing controlled treatments, dose calculations will be performed 
on the CT taken at the breath hold state to be used for treatment. 
 
Treatment Equipment: Megavoltage equipment is required with effective photon energies 
of 6 MV (preferred) or higher. Inverse-planned, external beam techniques are preferred 
including intensity modulated radiation therapy and volumetric modulated radiation 
therapy. Daily image guidance is required, preferably with volumetric imaging. 
 
5.1.2 Chemotherapy Administration 
5.1.2.1 Concurrent chemotherapy:  
For patients with stage II or III disease and good performance status, chemotherapy will 
be administered weekly concurrent with radiation. Carboplatin (AUC 2, IV) and Paclitaxel 
(40-50 mg/m2, IV) will be started on week 1 of thoracic radiotherapy and will be continued 
weekly for six weeks. Patients may receive chemotherapy on any day of the week from 
Monday to Friday, but the day of administration should remain constant during the course 
of chemoradiotherapy. A one-day shift in the day of weekly chemotherapy infusion (or more 
at the discretion of the physician) will be allowed if necessary.   
 
Weekly Concurrent Chemotherapy Regimen 
 
Agent 
Dose 
Route 
Infusion Time 
Paclitaxel 
40-50 
mg/m2 
IV 
60 minutes 
Carboplatin 
AUC 2 
IV 
30 minutes 
 
Paclitaxel 40-50 mg/m2 IV will be given by one hour infusion. Paclitaxel is mixed in non-
PVC containers per the usual guidelines of the pharmacy.  
 
Carboplatin will be given at AUC 2 over 1/2 hour immediately after paclitaxel using the 
Calvert formula: calculated dose of carboplatin (mg) = target AUC x (GFR + 25) (GFR as 
per the Cockroft-Gault or Jelliffe formula). NOTE: Aluminum reacts with carboplatin 
causing precipitate formation and loss of potency; 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 carboplatin. 
 

22 
 
*Note:  Occasionally, the infusions may take longer than the stated time above.  If 
Paclitaxel is given within 90 minutes and Carboplatin is given within 60 minutes, these 
will not be considered deviations. 
 
Prior to receiving carboplatin and paclitaxel, all patients should receive standard pre-
medication.  One standard that is recommended is: 
 
• 
Dexamethasone 20 mg orally 12 and 6 hours before paclitaxel or 20 mg IV just prior 
to paclitaxel 
 • 
Diphenhydramine 50 mg IV (or equivalent) prior to paclitaxel 
 • 
Cimetidine 300 mg IV (or equivalent, ranitidine 50 mg or famotidine 20  mg) prior to 
paclitaxel 
 • 
Granisetron 2 mg orally (or equivalent) prior to chemotherapy 
 
5.1.2.2 Consolidation Chemotherapy Or Immunotherapy:  
 
Consolidation chemotherapy will start approximately 4-6 weeks after the completion of 
radiotherapy when esophagitis and chemo-induced neuropathy are grade 1 or less, and 
ANC > 1500 and platelet count > 100,000. The decision to receive cytotoxic 
chemotherapy or immunotherapy will be at the discretion of the medical oncologist. If 
cytotoxic chemotherapy is to be administered, Carboplatin (AUC 6, IV) and Paclitaxel 
(200 mg/m2, IV) will be given on day 1. This will be repeated every 21 days for a total up 
to 3 cycles. Administration of carboplatin and paclitaxel and standard pre-medications 
have been described in section 5.2.1. However, during consolidation chemotherapy, 
paclitaxel 200 mg/m2 will be administered over 3 hours. If immunotherapy is to be given 
(permitted for stage III patients only, that have not progressed following concurrent 
chemoradiation), durvalumab (10 mg/kg) will be given on day 1. This will be repeated 
every 14 days for a total of 26 cycles.  Patients will be monitored for infusion reactions 
and informed of risk for a delayed infusion reaction.  While these are current standard 
dosing regimens for both chemotherapy and immunotherapy, treating physician may use 
discretion to alter the treatment regimen as needed.   
 
 
 
Consolidation Chemotherapy Regimen 
 
Agent 
Dose 
Route 
Infusion 
Time 
Days for 
administration 
Paclitaxel 
200mg/m2 
          IV 
3 hours 
q 21 days × 3 cycles 
Carboplatin 
AUC 6 
IV 
½ hour 
q 21 days × 3 cycles 
Consolidative Immunotherapy Regimen 
Agent 
Dose 
Route 
Infusion 
Time 
Days for 
administration 
Durvalumab 
10 mg/kg 
 
IV 
 
1 hour 
q 14 days × 26 cycles 
5.1.3   Supportive Care Guidelines 
Nutritional support is recommended for all patients.  Supportive care with medications will 
be determined by participating physician, based on each individual situation. Suggested 
management for acute radiation pneumonitis includes bed rest, bronchodilators, and 
corticosteroids.  Oxygen and even assisted ventilation may be necessary for severe cases. 
Treatment of esophagitis varies with the severity of the patient’s symptoms. Diet 
adjustment and narcotic management may be sufficient for grade 2 esophagitis.  Nutritional 

23 
 
support via gastric tube or jejunostomy tube may be initiated upon development of grade 
3-4 esophagitis, per mutual preference of the physician and patient. 
 
5.1.4   Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue through 
completion of concurrent chemoradiotherapy and consolidation chemotherapy or until one 
of the following criteria applies: 
 
▪ 
Local-regional disease progression 
▪ 
Intercurrent illness that prevents further administration of treatment 
▪ 
Unacceptable adverse events(s) 
▪ 
Patient decides to withdraw from the study 
▪ 
General or specific changes in the patient's condition render the patient  
unacceptable for further treatment in the judgment of the investigator. 
If treatment is interrupted due to a non-dose-limiting adverse event or any reason other 
than toxicity, such as a holiday, bad weather, or a transportation problem, the duration of 
therapy will be extended accordingly.  If a patient misses a day of radiation and 
chemotherapy, then the weekly chemotherapy should be delivered the next day and the 
missed radiation fraction will be given after the completion of planned treatments.  
5.2        Delays/Dose Modifications during consolidation chemotherapy or immunotherapy. 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Dose of radiation and chemotherapy / immunotherapy will be modified independently. 
  
5.2.1 Radiation dose modifications 
Radiation treatment will be stopped if a patient develops severe lung toxicity at any point 
during the course of radiation therapy. It will be the decision of the treating physician if the 
patient should continue protocol treatment and the timing of restart treatment.  
 
Following the mid-treatment scans, a radiation treatment break of one day will be permitted 
in the event that additional time is needed for treatment planning and QA.   
 
5.2.2 Chemotherapy / Immunotherapy dose modifications: All toxicity will be graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 
3.0.  Dose modifications or delays in administration of chemotherapy and/or 
immunotherapy  may be based on results from local laboratories for concurrent 
chemotherapy.  For consolidative chemotherapy or immunotherapy, dose modifications 
should be made as per standard of care, or as per discretion of the treating medical 
oncologist. All dose modifications and alterations will be recorded in the patient’s medical 
chart.   A maximum of three dose reductions will be allowed per patient. 
 
5.2.2.1 
Chemotherapy 
dosage 
modifications 
for 
toxicity 
during 
concurrent 
chemoradiotherapy.  
 
Hematologic Toxicity 
 
Peripheral 
Neuropathy 
 
Dysphagia 
Paclitaxel 
Dose 
Carboplatin 
Dose 

24 
 
ANC≥1000 
AND 
Platelet≥80K 
AND 
Grade 0-1 
AND 
Grade 0-1 
100% 
100% 
ANC≥1000 
AND 
Platelet≥80K 
AND 
Grade 2 
AND 
Grade 0-1 
50% 
100% 
ANC 500-999 
AND 
Platelet 50-79K 
OR 
Grade 2 
OR 
Grade 2 
50% 
50% 
ANC<500 
OR 
Platelet<50K 
OR 
Grade 3-4 
OR 
Grade 3-4 
Hold* 
Hold* 
Neutropenic 
fever 
OR 
Neutropenic 
fever 
OR 
Grade 3-4 
OR 
Grade 3-4 
Hold* 
Hold* 
*Resume chemotherapy when relevant toxicity becomes ≤ grade 1.  
 
 
5.2.2.3 Hematological Toxicity: The absolute neutrophil count must be  1500/mm3 and 
the platelet count must be  100,000/mm3 to receive chemotherapy on Day 1 of each cycle. 
 
Dose modifications must be made according to the criteria specified in the table below: 
 
Previous Cycle 
Next Cycle 
ANC nadir (/mm3) 
 
Platelet nadir (/mm3) 
Fever/Sepsis 
Carboplatin Dose 
Paclitaxel Dose 
≥ 500 
AND 
 50,000 
No 
No reduction 
No reduction 
< 500 
OR 
< 50,000 
No 
One dose level 
 One dose level 
< 1000 
AND 
Any 
Yes 
One dose level 
One dose level 
Note: Granulocyte colony-stimulating factor (G-CSF) may be used in case of hematological 
toxicity.  If G-CSF is used, it should be used in accordance with the American Society of 
Clinical Oncology (ASCO) guidelines. 
 
Treatment with carboplatin and paclitaxel may be delayed for up to 2 weeks until the ANC 
is  1500/mm3 and the platelet count is  100,000/mm3.  Patients should begin the next 
cycle as soon as possible after appropriate hematologic recovery. 
 
No dose reductions will be made for anemia.  Patients may be supported with packed red 
blood cell transfusions and/or erythropoietin. 
 
5.2.2.4 Hepatic Dysfunction 
The SGOT or SGPT and bilirubin values on Day 1 of each cycle should be used to 
determine the dose of paclitaxel on the next cycle. 
 
SGOT/SGPT (Day 1 of each cycle) 
 Bilirubin (Day 1 of each cycle) 
Paclitaxel Dose 
 4 × upper limit of normal 
AND 
≤ 3.0 mg/dl 
No change 
> 4 × upper limit of normal 
OR 
> 3.0 mg/dl 
Hold dose* 
*If paclitaxel is held due to hepatic toxicity, carboplatin should also be withheld and administered 
when the paclitaxel is resumed.  No dose reductions of carboplatin will be made for hepatic 
toxicity.  If recovery of hepatic toxicity exceeds 2 weeks, consolidation chemotherapy with 
paclitaxel and carboplatin should be discontinued. 
 
5.2.2.5 Neurologic Toxicity 

25 
 
Paclitaxel doses should be modified for neurologic toxicity based upon the worst grade 
experienced during the preceding cycle.  Dose modifications made for neurotoxicity are 
permanent reductions.   
 
Sensory Neuropathy (CTC Grade) 
Paclitaxel Dose 
Carboplatin Dose 
0-1 
No change 
No change 
2 
one dose level 
No change 
≥ 3 
Hold* 
No change 
*May restart with dose reduction of two dose levels when neuropathic toxicity improves to ≤ 
grade 1.   
 
5.2.2.6 Hypersensitivity Reactions: Patients who have had a mild to moderate 
hypersensitivity reaction to paclitaxel have been successfully re-challenged, but careful 
attention to prophylaxis and bedside monitoring of vital signs is recommended. 
Symptoms should be managed as follows: 
 
Grade 1 - Complete paclitaxel infusion.  Supervise at bedside.  No treatment required. 
 
Grade 2 - Stop paclitaxel infusion.  Give diphenhydramine 25 mg IV and dexamethasone 
10 mg IV. Resume paclitaxel infusion after recovery of symptoms at a low rate, 20 
ml/hour for 15 minutes, then 40 ml/hour for 15 minutes, then, if there are no further 
symptoms, resume the paclitaxel infusion at full dose rate until complete. If symptoms 
recur, stop paclitaxel infusion and after full recovery continue with carboplatin. 
 
Grade 3 or 4 - Stop paclitaxel infusion. Give diphenhydramine IV and dexamethasone IV, 
as above. Add epinephrine or bronchodilators if indicated. The patient should not be 
rechallenged with paclitaxel and will discontinue protocol treatment.   
 
5.2.2.7 Other Toxicity:  
For any drug-related Grade 3 or 4 toxicity not mentioned above except anemia, 
lymphopenia, or nausea, treatment with paclitaxel and carboplatin should be withheld for 
a maximum of 14 days until the toxicity improves to ≤ Grade 1. Treatment may then be 
resumed at a one dose level reduction.  For Grade 1 or 2 toxicities, no dose reduction 
should be made.   
 
 
 
 
 
 
 
6 
DRUG INFORMATION 
 
6.1   
Paclitaxel (Taxol)  
Description: Paclitaxel is a poorly soluble plant product from the western yew, Taxus 
brevifolia. Improved solubility requires a mixed solvent system with further dilutions of 
either 0.9% sodium chloride or 5% dextrose in water.  
Mechanism of Action: Paclitaxel affects microtubule formation during interphase and 
mitosis with a mechanism distinct from the vinca alkaloids. 
 
Human Toxicology: Hematologic toxicity includes myelosuppression.  Gastrointestinal 
toxicities include nausea and vomiting, diarrhea, stomatitis, mucositis, pharyngitis, typhlitis, 

26 
 
ischemic colitis, neutropenic enterocolitis, increased liver function tests (SGOT, SGPT, 
bilirubin, alkaline phosphatase) hepatic failure and hepatic necrosis.  Cardiac 
complications may include arrhythmias, heart block, ventricular tachycardia, myocardial 
infarction (MI), 
bradycardia, 
atrial arrhythmia, 
hypotension, hypertension, and 
lightheadedness.  Neurologic morbidity may manifest as sensory changes (taste), 
peripheral neuropathy, seizures, mood swings, hepatic encephalopathy, encephalopathy, 
sensation of flashing lights, blurred vision, and scintillating scotoma.  Anaphylactoid and 
urticarial reactions (acute), flushing, rash, and pruritus are also possible.   In addition, 
alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, induration, 
tenderness, rarely ulceration), and radiation recall reactions are described. 
 
 
Formulation: Paclitaxel is available in sterile solution concentrates in 5, 16.7, 25 and 50mL 
multi-dose vials in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated 
alcohol, USP, 50%. Paclitaxel will be diluted at the appropriate dose, in D5W, USP, in 5% 
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.  NOTE: Formation of a small number of fibers in solution (NOTE: 
acceptable limits established by the USP Particular Matter Test for LVP’s) 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 
(eg: Millex-GV Millipore Products) into the IV fluid pathway distal to the infusion pump. 
Although particulate formation does not indicate loss of drug potency, solutions exhibiting 
excessive particulate matter formation should not be used. 
 
Storage and Stability: Paclitaxel vials should be stored between 2°-25°C (36°-77°F). Vials 
will be labeled with shelf-life. All solutions of paclitaxel exhibit a slight haziness directly 
proportional to the concentration of drug and the time elapsed after preparation, although 
when prepared as described above, solutions of paclitaxel (0.3-1.2 mg/ml) are physically 
and chemically stable for 27 hours. 
 
Supplier: Commercially available and should be purchased by a third party. 
 
Premedications: Dexamethasone, diphenydramine (or equivalent) and an H2-receptor 
antagonist are recommended before paclitaxel administration. 
 
6.2    
Carboplatin (Paraplatin)  
 
Description: Carboplatin is supplied as a sterile lyophilized powder. 
 
Mechanism of action: Carboplatin inhibits DNA synthesis through intracellular platinum 
complexes to form intrastrand, interstrand and protein cross-linking through covalent 
binding of DNA molecules. Carboplatin is considered to be cell cycle phase-nonspecific, 
but recent studies have shown complex and variable effects on the cell cycle. 
 
Human Toxicology: Adverse effects include myelosuppression, nausea, vomiting, 
peripheral 
neuropathy, 
ototoxicity, 
hepatic 
toxicity, 
electrolyte 
imbalance, 
hypomagnesaemia, hypercalcemia and allergic reaction. 
 
Formulation: Carboplatin is supplied as a sterile lyophilized powder available in a single-
dose vial containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by 
intravenous infusion. Each vial contains equal parts by weight of carboplatin and mannitol.  
Immediately before use, the content of each vial must be reconstituted with either sterile 
water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP, 
according to the following schedule: 
 
Vial Size 
Diluent Volume 
50 mg 
5 ml 

27 
 
150 mg 
15 ml 
450 mg 
45 ml 
 
These dilutions all produce a carboplatin concentration of 10 mg/ml. 
 
Storage and Stability: Unopened vials of carboplatin are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light. When 
prepared as directed, carboplatin solutions are stable for eight hours at room temperature; 
since no antibacterial preservative is contained in the formulation, it is recommended that 
carboplatin solutions be discarded eight hours after dilution. 
 
Supplier: Commercially available and should be purchased by a third party 
 
Premedication: Antiemetics and hydration are recommended before carboplatin 
administration. 
 
6.3 Immunotherapy  / Durvalumab 
 
Supply and Storage:  Durvalumab Injection is a clear to opalescent, colorless to slightly 
yellow solution supplied in a carton containing one single-dose vial either as: 
• 
500 mg/10 mL (NDC 0310-4611-50) 
• 
120 mg/2.4 mL (NDC 0310-4500-12) 
 
Store in a refrigerator at 2oC to 8oC (36oF to 46oF) in original carton to protect from light.  
Do not freeze.  Do not shake.   
 
 
Mechanism of action: Durvalumab inhibits PDL1. This alters immune checkpoints to  
potentiate anti-tumoral immunity.  Expression of programmed cell death ligand-1 (PD-L1) 
can be induced by imflammatory signals (e.g., IFN-gamma) and can be expressed on both 
tumor cells and tumor-associated immune cells in the tumor microenvironment.  PD-L1 
blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1)  By 
binding to its receptors, PD-L1 reduced cytotoxic T-cell activity, proliferation, and cytokine 
production. 
Durvalumab is a human immunoglobulin G1 kapp (IgG1k) monoclonal antibody that binds 
to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1).  Blockade of PD-
L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, 
without inducing antibody dependent cell-mediated cytotoxicity (ADCC).  
PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and descreased 
tumor size in co-engrafted human tumor and immune cell xenograft mouse models.   
 
Human Toxicology: Adverse effects include autoimmune disease, including endocrine, 
neurologic, gastrointestinal, pulmonary, and dermatologic. 
 
Formulation: 
• 
Injection: 500 mg/10 mL (50 mg/mL) solution in a single dose vial. 
• 
Injection: 120 mg/2.4 mL (50 mg/mL) solution in a single dose vial.   
 
Storage and Stability: Per package insert. 
 
Supplier: Commerically Available and should be purchased by a third party.   
 
Premedication: No premedication is indicated for the administration of Cycle 1 of 
durvalumab. However, patients who experience an infusion-related reaction (IRR) with 
Cycle 1 of durvalumab may receive premedication with antihistamines or 
antipyretics/analgesics (e.g., acetaminophen) for subsequent infusions. Metamizole 
(dipyrone) is prohibited in treating durvalumab-associated IRRs because of its potential 
for causing agranulocytosis. 

28 
 
 
 
7 
TOXICITIES TO BE MONITORED AND REPORTED 
 
7.1 Radiation Induced Lung Toxicity  
 
Lung toxicity includes radiation pneumonitis and clinical fibrosis will be reported. Grade 2 and above 
are the study endpoint. .Grade 3 and above are considered to be severe. Diagnosis and grading of 
radiation pneumonitis and clinical fibrosis are listed on the table below.  
 
 
Table 7.1. Diagnosis and Grading System for Radiation Pneumonitis and Clinical Fibrosis 
 
 
Radiation Pneumonitis 
Clinical Fibrosis 
Grade 1 
Minimal or mild symptoms of dry cough 
AND/OR dyspnea on exertion; AND without 
evidence of tumor progression or other 
etiology; AND with radiographic evidence of 
acute pneumonitis  
Radiographic evidence of radiation fibrosis 
without or with minimal dyspnea 
Grade 2 
Persistent 
dry 
cough 
requiring 
narcotic 
antitussive agents or steroid; AND/OR dyspnea 
with minimal effort but not at rest; AND without 
evidence of tumor progression or other 
etiology; AND with radiographic evidence of 
acute pneumonitis, and requiring steroid for 
treatment  
Radiographic evidence of radiation fibrosis; 
AND dyspnea with minimal effort but not at rest, 
not interfering with activities of daily living  
Grade 3 
Severe cough, unresponsive to narcotic 
antitussive agent; AND/OR dyspnea at rest; 
AND with radiographic evidence of acute 
pneumonitis; 
AND 
requiring 
oxygen 
(intermittent or continuous)  for treatment 
Radiographic evidence of radiation fibrosis 
AND dyspnea at rest, interfering with activities 
of daily living; AND home oxygen indicated 
Grade 4 
Radiation 
pneumonitis 
causes 
respiratory 
insufficiency requiring assisted ventilation 
Radiation 
fibrosis 
causes 
respiratory 
insufficiency, requiring assisted ventilation 
Grade 5 
Radiation pneumonitis directly contributes to 
the cause of the death 
Radiation fibrosis directly contributes to the 
cause of the death 
 
7.2 
 Esophageal Toxicity 
 
 
Esophageal toxicity, including dysphagia and odynophagia, will be graded per CTCAE4.0, 
Severe acute esophageal toxicity is defined as persistent grade 3 or higher esophageal 
toxicity occurring within 3 months of the start of radiation therapy.  According to the RTOG 
acute radiation morbidity scoring criteria for esophagitis, grade 3 is defined as severe 
dysphagia or odynophagia with dehydration or weight loss > 15% from treatment baseline, 
requiring a feeding tube, IV fluids, or hyperalimentation. Grade 4 is defined as esophagitis 
causing life-threatening consequences, such as perforation, obstruction, or fistula 
formation. Grade 5 is severe esophagitis directly contributing to death. Persistent grade 3 
esophageal toxicity is defined as esophageal toxicity dependent on a feeding tube, IV 
fluids, or hyperalimentation longer than 6 weeks after the completion of radiation therapy. 
 
 
The incidence of severe acute esophageal toxicity is expected to be lower than 5%.  Since 
only pneumonitis is modeled by the NTCP function, doses to the lung will not be adjusted 
if excess severe esophageal toxicity occurs.  Instead, the normalization dose to the 
esophagus will be adjusted if at least 2 of the first 10 patients, or 4 of the first 20 patients, 
or 5 of the first 30 patients experience severe acute esophageal toxicity as described. 
 
7.3 
Other Toxicities 
 
 
Lung and esophageal toxicities will be graded using CTCAE v4.0. These will include, but 
not be limited to: cough, dyspnea, pneumonitis, radiation pneumonitis, radiographic or 
clinical pulmonary fibrosis and esophagitis. Lung and esophageal toxicities of grade > 2 

29 
 
will be collected in the database for analysis. Other toxicities will also be monitored and 
reported using the NCI CTCAE) v4.0.    
 
 
8.0      CORRELATIVE TRANSLATIONAL STUDY 
 
We will collect data to investigate the role of biomarkers for treatment outcome prediction.  
 
Blood and urine will be collected on the following schedule: 
 
• 
4 weeks prior to radiation therapy (RT) 
• 
Day 1 – 1 hour post radiation 
• 
Day 2 – prior to radiation 
• 
Day 5 – prior to radiation 
• 
Day 5 – 1 hour post radiation 
• 
Thereafter, blood and urine will be collected weekly during chemoradiation.   
Blood and urine will also be collected at ~1 month and at ~ 3 months post-RT,  and every 
~3 months through one year post treatment, then every ~6 months through four years post 
treatment, and at five years post treatment.   
• 
Subjects who do not provide some samples, miss time-points or decline any or all of the 
sample collections will not be reported as protocol deviations. 
 
 
The absolute concentration of circulating, cfNA tends to be very low which typically requires 
analyses of larger volumes of blood than for other approaches such as measurement of protein 
biomarkers or cytokines. In addition, for different analyte types, different collection tubes and 
preservatives are needed (eg, EDTA tubes for extracellular RNA and Streck tubes for circulating 
tumor DNA). We therefore propose to collect: 
 
1 x 10 mL of blood will be collected for serum isolation. 
2 x 10 mL of blood in EDTA (purple top) tubes will be collected to use for preservation and 
subsequent recovery of plasma and blood cells. Tubes will be stored and transported at room 
temperature. 
1 x 10 mL of Streck Cell-Free DNA BCT tube (brown top) will be collected for preservation and 
subsequent recovery of cfDNA from plasma. 
 
Platelet-poor plasma will be obtained for cytokine and proteomic assays; plasma and/or serum 
samples will be used for metabolomics, microRNA and other extracellular RNA profiles, circulating 
tumor DNA, cell death assays and other markers as indicated; buffy coat will be used for genomic 
and/or transcriptomic studies. Urine will be used for analysis of RNA, DNA, protein, and other 
biomarkers.  
 
RNA and DNA biomarkers, whether cell-free or cell-associated, will be analyzed using methods 
including quantitative PCR, digital PCR, and next-generation sequencing. Bioinformatic analyses 
may be used in these profiling studies. 
 
Plasma TGF-β1 will be measured by molecular specific Enzyme Linked Immune Sandwich Assay 
(ELISA). The levels of plasma cytokines will be measured by ready to use kits, such as LINCOplex 
(microsphere-based sandwich immunoassay) for the concentrations of 29 proinflammatory 
cytokines, including G-CSF, IL-1α, IL-1β, IL-1ra, IL-6, IL-8, IP-10, MCP-1, MIP-1, TGF-α, and TNF-
α. RILT will be diagnosed and graded based on CTCAE 4. The plasma proteomes will be compared 
using a multiplexed quantitative proteomics approach involving ExacTag labeling, RP-HPLC and 
LC-ESI-MS/MS.  
 
For genomic studies, we will focus our efforts on (but not limited to) gene specific SNPs of TGFβ1, 
tissue plasminogen activator (tPA) and angiotensin-converting enzyme (ACE), which are 
associated with radiation-induced thoracic toxicity such as RILT. Genetic variations within 
functional locus of these genes will be assessed for in each patient by using gene specific PCR 

30 
 
technology. Such SNP studies will be performed using polymerase chain reaction (PCR) and allele 
specific primers. Variance components models will be used to identify the differential protein 
expression between patients with and without toxicity. Bioinformatic methodology may be applied 
for data analysis.  
 
For cellular studies (from archival tissue as a block or slides), we will focus our efforts on (but not 
limited to) CD8 T cell effector number and function, which have been shown to correlate with 
radiation induced local control and toxicity. Flow cytometric analysis will be performed in patients 
with and without toxicity. Immunohistochemical evaluation of T cells will be performed in patients 
with and without toxicity. Bioinformatic methodology may be applied for data analysis.  
 
Since this is a prospective study, we anticipate advancement in experimental technology and 
preliminary results. Other techniques and tests also will be applied if they are found to be superior 
to the ones stated above. Blood markers (cytokine, proteomic, cell-free DNA/RNA, immune cell 
alterations, and genomics) during early course of treatment will be correlated to clinical outcome in 
tumor control and treatment related thoracic toxicity.  
 
If patients are also participating in UMCC 2015.006, or other protocols with a similar biospecimen 
collection schedule, only one set of specimens will be collected.  
 
 
9.0     
STUDY PROCEDURES AND CALENDAR 
 
9.1  
Pre Treatment Clinical Evaluation 
 
The following clinical evaluations should be done within the specified times prior to patient 
enrollment: 
  
9.1.1 Complete history and physical examination should be performed within 4 weeks;  
9.1.2 Weight and Karnofsky performance status should be evaluated within 4 weeks;  
9.1.3 CBC with differential, complete chemistry panel including alkaline phosphatase, 
creatinine, serum albumin, total bilirubin and AST/ALT should be done within 4 weeks;  
9.1.4 CT scan (if possible with IV contrast) of chest should be done within 6 weeks; 
9.1.5 MRI or CT of the brain with contrast should be done within 6 weeks; 
9.1.6 A total body FDG-PET scan is required within 2 weeks from CT simulation. PET scan 
performed outside hospital is allowed if it can be transferred to our treatment planning 
system and the image is quality assured.  A bone scan is optional, pending the decision 
of the treating physician;  
9.1.7 A V/Q SPECT scan is required within 2 weeks from CT simulation;       
9.1.8 Complete pulmonary function tests should be done within 6 weeks;  
9.1.9 Blood samples for biomarkers (such as IL-8 and TGF-ß1) should be drawn within 4 
weeks.  
9.1.10  Quality of life questionnaires will be collected within 4 weeks 
 
All the tests above, except biomarker measurements and questionnaires, are part of 
routine staging work-ups. 
 
 
9.2    
Pretreatment and during treatment studies  
 
Procedure 
Pretreatment 
Weekly During 
Chemotherapy / 
RT 
History and physical 
Within 4 wks 
X 
Weight and KPS 
Within 4 wks 
X 
Tumor measurement 
Based on treatment 
planning CT 
 

31 
 
Chest CT* 
Within 6 wks 
 
CBCP, differential 
Within 4 wks 
X 
Electrolytes, creatinine, liver 
function tests 
Within 4 wks 
As Clinically 
Indicated 
Complete pulmonary function 
tests 
Within 6 wks 
 
CT Simulation (re-planning) 
 
Xa 
Head CT or MRI  
Within 6 wks 
 
PET scan  
Within 2 wks, before or after, 
treatment planning CT 
Xa 
SPECT scan 
Within 2 wks, before or after, 
treatment planning CT 
Xa 
Blood drawing for biomarkers  
Within 4 wks 
Xb 
Urine collection for biomarkers 
 
Within 4 wks 
 
Xb 
 
Toxicity evaluation 
 
Within  4 wks 
 
X 
Quality of Life Questionnaires 
Within 4 wks 
Xc 
Tissue Evaluation 
At diagnostic biopsyd   
 
* High-resolution CT is preferred. Upper abdomen preferred but not required.  
a. PET-CT scan, SPECT-CT scan, and re-planning CT Simulation scan will be repeated 
after patient has received 40-50 Gy EQD2 of radiotherapy 
b. In addition to pre-treatment samples, blood and urine will be collected for biomarkers 
at the following time points:   
 
• Day 1 – 1 hour post-radiation 
• Day 2 – prior to radiation 
• Day 5 – prior to radiation 
• Day 5 – 1 hour post-radiation 
• Thereafter, blood and urine will be collected weekly during chemoradiation 
c.  Quality of life questionnaires will be done pre-treatment, mid-treatment (3rd week of 
treatment), and also the last week of treatment.  Since patients can be seen in a variety 
of clinics, missed QOLs will not be reported as a protocol deviation. 
d.  For UM patients only, tissue collected from diagnostic biopsy will be assessed for 
immunohistochemical analysis as described in section 8.0.   

32 
 
   9.3     Follow-up calendar 
 
 
Procedure 
Time since 
the end of 
RT 
1, 3 
months* 
6,9,12 
months* 
18,24,30,36 
months* 
Frequency of Follow-
up 
Q 3 months Q 6 months 
History and physical 
X 
X 
X 
 
Weight and KPS 
X 
X 
X 
 
Tumor measurement 
3 mo only 
X 
X 
 
Chest CT** 
Xa 
Xa 
X 
 
CBCP, differential 
X 
X 
X 
 
Electrolytes, creatinine, liver function 
tests 
X 
X 
X 
 
Pulmonary function tests 
Xb 
Xb 
 
 
Toxicity evaluation 
X 
X 
X 
 
Blood and urine collection for 
biomarkers c 
X 
X 
X 
 
Consolidation Chemotherapy or 
Immunotherapy 
Xd 
 
 
 
Quality of life questionnairese 
X 
X 
X 
 
*Timing of follow-up:  From 2 months to 15 months = (+/-) 3 week window.  For 18 
months to 36 months = (+/-) 1 month window. 
** High-resolution and IV contrast enhanced CT. 
a:   Chest CT will be done approximately 1 month after last chemotherapy 
consolidation cycle, or as per standard of care during consolidation immunotherapy.  
Upper abdomen preferred but not required.  At 6 months and later, chest CT will be 
done every 6 months.  
 
b:  Pulmonary function tests will be done at 3 and 12 months .   
 
 
 
c:  If a patient experiences severe toxicity (as defined in 9.1 and 9.2) and returns for 
clinical evaluation at a time not designated on study calendar, TGF ß1 and other 
molecules will be drawn.  
 
 
 
Blood and urine will be collected at each of the timepoints indicated in the table 
above.   
 
d:  Consolidation Chemotherapy per 5.1.2.2 or Immunotherapy per 5.1.3. 
 
e.  Questionnaires will be given to patients at follow-up visits 1 month, 3 months, 6 
months, 9 months, 12 months, 18 months, 24 months, 30 months, and 36 months. 
Since patients can be seen in a variety of clinics, missed QOLs will not be reported 
as a protocol deviation.   
 
 
Note:  PET scans, bronchoscopies, pulmonary function tests, and head CTs or MRIs 
may be done post-treatment as part of routine clinical care, to assist with disease or 
toxicity evaluation.  If these are done, the results may be used for research purposes. 
 
9.4   
Off Study Conditions 
 
9.4.1 Patients may be removed from study at any time by patient request or at the 
discretion of the investigator. 
 
 
 
9.4.2  Patients who exhibit tumor progression, metastatic disease, or move on to other 
treatment modalities, will discontinue all study calendar procedures.  Such patients will be 

33 
 
medically managed.  For the purposes of the research, they will continue to be followed 
for toxicity, further progression, and survival, by reviewing and collecting standard clinical 
information.  These patients may be treated with other agents.    
 
 
10.0    STATISTICAL CONSIDERATIONS 
 
Overview/Design: 
This is a single arm pilot study of  adaptive radiation therapy in patients with stage II/III NSCLC.  A 
total of 55 evaluable patients will be enrolled (up to 70 patients may need to be enrolled in order to 
obtain 55 evaluable patients).  A patient will be considered evaluable if they complete treatment 
and a minimum of 6 months of follow up.  This will allow thorough analysis of treatment toxicity, 
which can be observed as late as six months after radiation treatment.  The adaptive elements to 
their treatment include  re-planning to redistribute dose through normal tissue based on SPECT 
scan and within tumor based on FDG PET.   
 
Objectives/Analysis: 
Primary aims:  
Establish the feasibility of the proposed adaptive treatment strategy 
 
To obtain preliminary estimates of the toxicity of and doses achievable by the proposed response-
driven adaptive treatment strategy in patients with Stage II/III NSCLC.  
The first primary aim is feasibility which is defined as the ability to successfully deliver the full 
treatment including all adaptations. In the simplest analyses, feasibility will simply be summarized 
as the proportion of patients for whom the intended treatment was feasible.  Feasibility is defined 
as the ability to successfully replan the patient based on the mid-treatment imaging. Whether or 
not this occurs will be recorded for each enrolled patient. The reasons for lack of feasibility for any 
patients will be investigated individually. 
Two types of toxicity are of primary interest, lung toxicity and esophageal toxicity.  The proportion 
of patients who experience these types of toxicity will be summarized by grade, and the proportion 
of patients who experience G2+ lung toxicity and the proportion of patients who experience G2+ 
esophageal toxicity will be calculated and reported with 90% confidence intervals.  In terms of 
achievable doses, the mean dose to the PET avid region will be summarized across patients and 
the proportion of patients able to receive doses of at least 70 and 75 Gy will be reported.  In addition, 
we will generate the treatment plan (and hence dose to PET avid region) each of these patients 
would have received had they been treated on UMCC 2007-123, which redistributed dose to the 
PET avid region but not through normal tissue.  These dose values will then be compared to the 
doses actually given to assess for any mean differences.     
 
Secondary aim 1: To obtain preliminary estimates of local control from an adaptive approach. 
 
Local control is defined as the absence of local/regional progression (as defined in section 2.3) and 
will be summarized as a time-to-event endpoint.  Patients without local progression will be censored 
at the last date they were assessed for local progression.  Local control will be summarized with 
the Kaplan-Meier method.  Our plan is follow this pilot trial with a randomized phase II trial where 
the primary aim would be to demonstrate improved local control in the adaptive arm (similar 
treatment to that on this protocol) relative to the control arm at the same overall level of toxicity.  
Data from this pilot trial will provide an estimate of the local control achievable with the proposed 
adaptive treatment strategy that will be important to have when designing and powering the phase 
II study.   
 
Secondary aim 2: To determine the residual uncertainties in V/Q SPECT scans related to the 
accuracy with which persistent tumor subvolumes and the spatial distribution of local function of 
uninvolved lung could be mapped to guide plan modification. 
 

34 
 
The mapping is done by (deformable) image registration using standard in-house software. For 
any given mapping method (e.g. from SPECT-CT space to the patient’s planning CT), there are a 
series of locations (either “voxels” of a given size or subregions) that contain functional  
information, and their use in the anatomic space of the patient (for treatment planning/delivery) 
requires a spatially-variant transform, with varying accuracy at different locations.  We will 
characterize the uncertainly in local mapping using a large number of expert-extracted landmark 
locations, visibly assessed on the reference (e.g. planning CT) and test (e.g. guiding CT for 
SPECT) images.  By manually measuring these locations, we have a reference library of known 
transformations (locations for both scans) for characterizing the uncertainty in any mapping 
method. These locations are not laid out on a uniform spatial grid, but they should be dense (on 
the order of 10^2 locations per case, with ~15 cases planned for lung and potentially as many for 
liver if needed as a secondary goal).  We will utilize two methods for characterizing the error or 
uncertainty in the V/Q SPECT scans. 
1) As a function of distance from the landmarks (e.g. interpolation). 
2) A function of local driving information, which depends on the nature of alignment (e.g. 
intensity-driven seeks out intensity gradients, FEM uses forces applied to specific surfaces). 
 
Justification of Design: 
 
The primary aims are to demonstrate feasibility and to obtain a preliminary estimate of the toxicity 
associated with the adaptive treatment strategy.  With 35 patients, the half-width of the 90% 
confidence interval will be at most 0.11 with greater than 80% probability when the true probability 
of toxicity is 15%.  A related goal is to ensure that the adaptive treatment strategy is not overly 
toxic.  If the true rate of Grade 2+ lung toxicity is 15%, then 35 patients gives 80% power to rule out 
toxicity rates of 30% or higher at a type 1 error rate of 10%.    
 
 
11.0      REPORTING ADVERSE EVENTS 
 
11.1 Adverse Event definitions   
 
11.1.1 An Adverse Event is any untoward medical event that occurs in a patient who has 
received an investigational treatment, and does not necessarily have a causal 
relationship with the investigational treatment. An AE can therefore be any unfavorable 
and unintended sign (including abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational treatment, whether or not related 
to the treatment. 
 
11.1.2 Pre-existing diseases or symptoms or abnormal laboratory values present upon 
recruitment are not considered an AE even when observed during the further course of 
the study. However, every worsening of a pre-existing condition is considered as an 
adverse event. 
 
11.1.3 All grade 3 and above AEs will be collected, in addition to all grade 1 and above 
lung/thoracic/treatment AEs.  The NCI CTCAE v4.0 will be utilized to grade AE’s for AE 
reporting. 
 
11.1.4 During the course of an adverse event, severity and/or causality and/or 
seriousness may change. For CRF documentation this adverse event represents one 
entity from onset to resolution and the worst of the observed categories shall be 
attributed. 
 
11.1.5 When event reoccurs after it disappeared, it should be handled as a new AE. 
However, AEs that occur intermittently can be recorded as one AE. 
 
11.1.6 A serious adverse event (SAE) shall be defined as an adverse advent which fulfills 
one or more of the following criteria: 
• Results in death 

35 
 
• Is immediately life threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent 1 of the outcomes listed above. 
 Any events or hospitalizations that are unequivocally due to progression of 
disease should not be reported as a SAE. The causality of SAEs (i.e., their 
relationship to study treatment) will be assessed by the investigators and will be 
labeled Definitely related to treatment, Probably related to treatment, Possibly 
related to treatment, Unlikely related to treatment or Not related to treatment. 
 
11.1.7 Only adverse events deemed serious and related will be reported to the IRB and 
the PI within 10 days of awareness of the event (see below SAE reporting 
procedures).  All other events will be noted in the patient’s medical record.  
  
11.1.8 Adverse events will no longer be reported if the patient has another lung-directed 
therapy or starts chemotherapy. 
 
11.1.9 The following types of hospitalizations do not constitute SAEs:  
• Hospitalization or Emergency room visits secondary to expected cancer  
morbidity: Admission for palliative care or pain management 
• Planned hospitalizations for surgical procedures, either related or unrelated to the 
patient’s cancer. 
 
 
11.2 Serious Adverse Event Reporting  
 
All serious adverse events (SAEs) and unanticipated problems (UPs) related to the study therapy, 
will be reported to the Principal Investigator and also to the Coordinating Center.  SAEs and UPs 
must be reported to the Coordinating Center within 10 days of first awareness of the event.  Events 
should be reported using the CTO SAE form as available in the study database (Velos)   A copy of 
the CTO SAE form should be sent to the Coordinating Center via fax or email to CTSU-Oncology-
Multisite@med.umich.edu within 10 days of the site’s knowledge of the event.  
 
Contact information for Principal Investigator SAE Reporting: 
Name: Shruti Jolly, MD 
Telephone: 734-936-7810  
Fax: 734-763-7370 
Email: snrutij@med.umich.edu 
 
 
Follow-up information must also be reported within 10 days of receipt of the information by the 
investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to the participating 
sites within 5 days of review of the information by the Coordinating Center’s Principal Investigator 
(or designee in the event of extended absence).  
 
 
 
12.0      DATA AND SAFETY MONITORING 
 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan.  This committee is responsible 
for monitoring the safety and data integrity of the trial.  

36 
 
 
Each participating site is required to have its own Data and Safety Monitoring Committee (DSMC) 
for the study.  The study specific Data and Safety Monitoring Committee (DSMC), consisting of 
the protocol investigators, data manager or designee and other members of the study team 
involved with the conduct of the trial, will meet quarterly or more frequently depending on the 
activity of the protocol. The discussion will include matters related to the safety of study 
participants (SAE/UaP reporting), validity and integrity of the data, enrollment rate relative to 
expectations, characteristics of participants, retention of participants, adherence to the protocol 
(potential or real protocol deviations) and data completeness. 
 
These meetings are to be documented by the site data manager or study coordinator using the 
Protocol Specific Data and Safety Monitoring Report (DSMR), signed by the site principal 
investigator.  Each site is required to submit the completed DSMR to the Multi-Site Coordinator at 
the University of Michigan Clinical Trials Office on a quarterly basis together with other pertinent 
documents. 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form 
and requires the signatures of both the sites data manager or study coordinator and the site 
principal investigator. These reports are to be sent to the University of Michigan Clinical Trials 
Office within 7 calendar days of awareness of the event and on a quarterly basis with the Protocol 
Specific Data and Safety Monitoring Report. 
 
For the specimen collections for biomarker analysis, we anticipate that patients may not be able 
to provide all requested specimens at every planned collection. This may result in missing 
specimens, however we will not consider this a protocol deviation. 
 
The Clinical Trials Office is responsible for collating all the Data and Safety Monitoring Reports 
from all the participating sites, and providing the information to the Data Safety Monitoring Board. 
 
 
13.0      DATA MANAGMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-
based Velos data management system of the University of Michigan. Online access will be 
provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior 
to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The 
investigator or study coordinator will be responsible for providing resolutions to the data queries, 
as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
 
The data submission schedule is as follows:  
• 
At the time of registration   
o 
Subject entry into Velos 
▪ 
Subject Status 
▪ 
Demographics 
• 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition.  Information 
on Serious Adverse Events must be entered within the reporting timeframe specified in 
Section 11.2 of the protocol.  
  
Long term data will be collected periodically either by chart review or by contacting the patients. 
 
All study information should be recorded in an appropriate source document (e.g. clinic chart).  
 
 
14.0      QUALITY ASSURANCE AND AUDITS 
The Data Safety Monitoring Board can request  a ‘for cause’ audit of the trial if the board identifies 
a need for a more rigorous evaluation of study-related issues. A “for cause” audit would be 

37 
 
conducted by the Quality Assurance Review Committee (QARC) of the University of Michigan 
Comprehensive Cancer Center. 
 
A regulatory authority may also wish to conduct an inspection of the study, during its conduct or 
even after its completion. If an inspection has been requested by a regulatory authority, the site 
investigator must immediately inform the Clinical Trials Office that such a request has been made. 
 
 
15.0      CLINICAL MONITORING PROCEDURES 
Clinical studies coordinated by The University of Michigan Comprehensive Cancer Center 
(UMCCC) must be conducted in accordance with the ethical principles that are consistent with 
Good Clinical Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the UMCCC. 
Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and his study 
staff should make every effort in attending the site initiation meeting. Study–related questions or 
issues identified during the site initiation meeting will be followed-up by the appropriate UMCCC 
personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ 
visit should occur after the first subject enrolled completes chemotherapy/RT.  The study site 
should send the de-identified source documents to the Coordinating Center for monitoring.  
‘Centralized’ monitoring may be requested by the Coordinating Center if an amendment requires 
changes to the protocol procedures. The site will send in pertinent de-identified source 
documents, as defined by the Coordinating Center  for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first.  The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring 
visit will be done at least once a year, or once during the course of the study if the study duration 
is less than 12 months. The purpose of these visits is to verify: 
 
➢ Adherence to the protocol 
➢ Completeness and accuracy of study data and samples collected 
➢ Proper storage, dispensing and inventory of study medication 
➢ Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given 
by the site investigator to the Coordinating Center representative conducting the monitoring visit 
to verify consistency of data collected on the CRFs with the original source data.  While most 
patient cases will be selected from patients accrued since the previous monitoring visit, any 
patient case has the potential for review.  At least one or more unannounced cases will be 
reviewed, if the total accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated to the site and are expected to be resolved by the site in 
a timely manner.  For review of study-related documents at the Coordinating Center, the site will 
be required to ship or fax documents to be reviewed.   
 

38 
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of a study 
to ensure fulfillment of study obligations during the conduct of the study, and that the site Investigator is 
aware of his/her ongoing responsibilities. In general, a site close-out is conducted during a site visit; 
however, site close-out can occur without a site visit.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.0 
REFERENCES: 
 
1. 
Siegel R, Desantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship 
statistics, 2012. CA Cancer J Clin. 2012;62(4):220-41. Epub 2012/06/16. doi: 10.3322/caac.21149. 
PubMed PMID: 22700443. 
2. 
Tyldesley S, Boyd C, Schulze K, Walker H, Mackillop WJ. Estimating the need for radiotherapy for 
lung cancer: an evidence-based, epidemiologic approach. Int J Radiat Oncol Biol Phys. 2001;49(4):973-85. 
Epub 2001/03/10. doi: S0360-3016(00)01401-2 [pii]. PubMed PMID: 11240238. 

39 
 
3. 
Aupérin A, Le Péchoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of 
concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(13):2181-90. doi: 
10.1200/JCO.2009.26.2543. PubMed PMID: 20351327. 
4. 
Curran WJ, Jr., Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Sequential vs. concurrent 
chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl 
Cancer Inst. 2011;103(19):1452-60. Epub 2011/09/10. doi: 10.1093/jnci/djr325 
djr325 [pii]. PubMed PMID: 21903745; PubMed Central PMCID: PMC3186782. 
5. 
Perez CA, Stanley K, Rubin P, Kramer S, Brady L, Perez-Tamayo R, et al. A prospective 
randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable 
non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer. 
1980;45(11):2744-53. PubMed PMID: 6991092. 
6. 
Perez CA, Pajak TF, Rubin P, Simpson JR, Mohiuddin M, Brady LW, et al. Long-term observations 
of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with 
definitive radiotherapy. Report by the Radiation Therapy Oncology Group. Cancer. 1987;59(11):1874-81. 
PubMed PMID: 3032394. 
7. 
Vijayakumar S, Chen GT. Implementation of three dimensional conformal radiation therapy: 
prospects, opportunities, and challenges. Int J Radiat Oncol Biol Phys. 1995;33(5):979-83. PubMed PMID: 
7493859. 
8. 
Hayman JA, Martel MK, Ten Haken RK, Normolle DP, Todd RF, 3rd, Littles JF, et al. Dose 
escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a 
phase I trial. J Clin Oncol. 2001;19(1):127-36. PubMed PMID: 11134205. 
9. 
Maguire PD, Marks LB, Sibley GS, Herndon JE, 2nd, Clough RW, Light KL, et al. 73.6 Gy and 
beyond: hyperfractionated, accelerated radiotherapy for non-small-cell lung cancer. J Clin Oncol. 
2001;19(3):705-11. PubMed PMID: 11157021. 
10. 
Rosenzweig KE, Sim SE, Mychalczak B, Braban LE, Schindelheim R, Leibel SA. Elective nodal 
irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy. 
Int J Radiat Oncol Biol Phys. 2001;50(3):681-5. PubMed PMID: 11395236. 
11. 
Bradley JD, Ieumwananonthachai N, Purdy JA, Wasserman TH, Lockett MA, Graham MV, et al. 
Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation 
therapy for non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2002;52(1):49-57. PubMed PMID: 
11777621. 
12. 
Belderbos JS, De Jaeger K, Heemsbergen WD, Seppenwoolde Y, Baas P, Boersma LJ, et al. First 
results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal 
radiotherapy. Radiother Oncol. 2003;66(2):119-26. PubMed PMID: 12648783. 
13. 
Narayan S, Henning GT, Ten Haken RK, Sullivan MA, Martel MK, Hayman JA. Results following 
treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. 
Lung Cancer. 2004;44(1):79-88. PubMed PMID: 15013586. 
14. 
Bogart JA, Aronowitz JN. Localized non-small cell lung cancer: adjuvant radiotherapy in the era of 
effective systemic therapy. Clin Cancer Res. 2005;11(13 Pt 2):5004s-10s. PubMed PMID: 16000604. 
15. 
Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, et al. Toxicity and outcome results 
of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in 
patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2005;61(2):318-28. 
PubMed PMID: 15667949. 
16. 
Kong FM, Ten Haken RK, Schipper MJ, Sullivan MA, Chen M, Lopez C, et al. High-dose radiation 
improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell 
lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys. 
2005;63(2):324-33. PubMed PMID: 16168827. 
17. 
Rosenzweig KE, Fox JL, Yorke E, Amols H, Jackson A, Rusch V, et al. Results of a phase I dose-
escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall 
cell lung carcinoma. Cancer. 2005;103(10):2118-27. PubMed PMID: 15830346. 
18. 
Chen M, Hayman JA, Ten Haken RK, Tatro D, Fernando S, Kong FM. Long-term results of high-
dose conformal radiotherapy for patients with medically inoperable T1-3N0 non-small-cell lung cancer: is 
low incidence of regional failure due to incidental nodal irradiation? Int J Radiat Oncol Biol Phys. 
2006;64(1):120-6. Epub 2005/10/04. doi: S0360-3016(05)01160-0 [pii] 
10.1016/j.ijrobp.2005.06.029. PubMed PMID: 16198503. 
19. 
Kong FM, Pan C, Eisbruch A, Ten Haken RK. Physical models and simpler dosimetric descriptors 
of radiation late toxicity. Semin Radiat Oncol. 2007;17(2):108-20. Epub 2007/03/31. doi: S1053-
4296(06)00108-1 [pii] 

40 
 
10.1016/j.semradonc.2006.11.007. PubMed PMID: 17395041. 
20. 
Bradley JD, Paulus R, Graham MV, Ettinger DS, Johnstone DW, Pilepich MV, et al. Phase II trial 
of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-
small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG 9705. 
J Clin Oncol. 2005;23(15):3480-7. PubMed PMID: 15908657. 
21. 
Rengan R, Rosenzweig KE, Venkatraman E, Koutcher LA, Fox JL, Nayak R, et al. Improved local 
control with higher doses of radiation in large-volume stage III non-small-cell lung cancer. Int J Radiat Oncol 
Biol Phys. 2004;60(3):741-7. PubMed PMID: 15465190. 
22. 
Machtay M, Hsu C, Komaki R, Sause WT, Swann RS, Langer CJ, et al. Effect of overall treatment 
time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: 
analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys. 
2005;63(3):667-71. PubMed PMID: 15927409. 
23. 
Machtay M, Bae K, Movsas B, Paulus R, Gore EM, Komaki R, et al. Higher biologically effective 
dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung 
carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat 
Oncol Biol Phys. 2012;82(1):425-34. Epub 2010/10/29. doi: 10.1016/j.ijrobp.2010.09.004. PubMed PMID: 
20980108. 
24. 
Zhao L, West BT, Hayman JA, Lyons S, Cease K, Kong FM. High radiation dose may reduce the 
negative effect of large gross tumor volume in patients with medically inoperable early-stage non-small cell 
lung cancer. Int J Radiat Oncol Biol Phys. 2007;68(1):103-10. Epub 2007/03/17. doi: S0360-
3016(06)03660-1 [pii] 
10.1016/j.ijrobp.2006.11.051. PubMed PMID: 17363189. 
25. 
Kong FM, Haken RT, Hayman J, Ramnath N, Hassan K, Wang J, et al. Personalized High Dose 
Radiation (>70 Gy) Is Significantly Associated with Better Local Regional Control and Overall Survival in 
Non-small Cell Lung Cancer Treated with Concurrent Chemoradiation. Int J Radiat Oncol Biol Phys. 
2011;81(2, supplement):S594. 
26. 
Hicks RJ, Mac Manus MP, Matthews JP, Hogg A, Binns D, Rischin D, et al. Early FDG-PET imaging 
after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate 
with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys. 
2004;60(2):412-8. Epub 2004/09/24. doi: 10.1016/j.ijrobp.2004.03.036. PubMed PMID: 15380574. 
27. 
Kong FM, Frey KA, Quint LE, Ten Haken RK, Hayman JA, Kessler M, et al. A pilot study of 
[18F]fluorodeoxyglucose positron emission tomography scans during and after radiation-based therapy in 
patients with non small-cell lung cancer. J Clin Oncol. 2007;25(21):3116-23. Epub 2007/07/20. doi: 
10.1200/JCO.2006.10.3747. PubMed PMID: 17634490. 
28. 
Weber WA, Petersen V, Schmidt B, Tyndale-Hines L, Link T, Peschel C, et al. Positron emission 
tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative 
assessment of glucose use. J Clin Oncol. 2003;21(14):2651-7. PubMed PMID: 12860940. 
29. 
Nahmias C, Hanna WT, Wahl LM, Long MJ, Hubner KF, Townsend DW. Time course of early 
response to chemotherapy in non-small cell lung cancer patients with 18F-FDG PET/CT. J Nucl Med. 
2007;48(5):744-51. PubMed PMID: 17475962. 
30. 
Hoekstra CJ, Stroobants SG, Smit EF, Vansteenkiste J, van Tinteren H, Postmus PE, et al. 
Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy-D-glucose positron emission 
tomography in patients with locally advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(33):8362-
70. PubMed PMID: 16293866. 
31. 
de Geus-Oei LF, van der Heijden HF, Visser EP, Hermsen R, van Hoorn BA, Timmer-Bonte JN, et 
al. Chemotherapy response evaluation with 18F-FDG PET in patients with non-small cell lung cancer. J 
Nucl Med. 2007;48(10):1592-8. PubMed PMID: 17873138. 
32. 
Dimitrakopoulou-Strauss A, Hoffmann M, Bergner R, Uppenkamp M, Eisenhut M, Pan L, et al. 
Prediction of short-term survival in patients with advanced nonsmall cell lung cancer following 
chemotherapy based on 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography: a feasibility 
study. Mol Imaging Biol. 2007;9(5):308-17. PubMed PMID: 17623254. 
33. 
van Baardwijk A, Bosmans G, Dekker A, van Kroonenburgh M, Boersma L, Wanders S, et al. Time 
trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in 
locally advanced non-small cell lung cancer (NSCLC) patients. Radiother Oncol. 2007;82(2):145-52. 
PubMed PMID: 17258339. 
34. 
Feng M, Kong FM, Gross M, Fernando S, Hayman JA, Ten Haken RK. Using fluorodeoxyglucose 
positron emission tomography to assess tumor volume during radiotherapy for non-small-cell lung cancer 
and its potential impact on adaptive dose escalation and normal tissue sparing. Int J Radiat Oncol Biol Phys. 
2009;73(4):1228-34. Epub 2009/03/03. doi: S0360-3016(08)03726-7 [pii] 

41 
 
10.1016/j.ijrobp.2008.10.054. PubMed PMID: 19251094. 
35. 
Kong FM, Mahasittiwat P, Yuan S, Xie C, Ritter T, Shen Z, et al. Define tumor volume during 
radiotherapy to individualize adaptive radiation dose escalation in non-small cell lung cancer. Imaging for 
Treatment Assessment in Radiation Therapy( ITART) 2010;Abstract 14327. 
36. 
Kong FP, Ten Haken RK, Hayman JA, Cease K, Ramnath N, Arenberg D, et al. Can We Deliver 
High Dose Radiation in 6 Weeks with Concurrent Chemotherapy in Stage III Non-small Cell Lung Cancer? 
Int J Radiat Oncol Biol Phys. 2010;78(3, Supplement):S35. 
37. 
Shioyama Y, Jang SY, Liu HH, Guerrero T, Wang X, Gayed IW, et al. Preserving functional lung 
using perfusion imaging and intensity-modulated radiation therapy for advanced-stage non-small cell lung 
cancer. Int J Radiat Oncol Biol Phys. 2007;68(5):1349-58. Epub 2007/04/21. doi: S0360-3016(07)00310-0 
[pii] 
10.1016/j.ijrobp.2007.02.015. PubMed PMID: 17446001. 
38. 
Lavrenkov K, Christian JA, Partridge M, Niotsikou E, Cook G, Parker M, et al. A potential to reduce 
pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of 
non-small cell lung cancer. Radiother Oncol. 2007;83(2):156-62. PubMed PMID: 17493699. 
39. 
Seppenwoolde Y, Engelsman M, De Jaeger K, Muller SH, Baas P, McShan DL, et al. Optimizing 
radiation treatment plans for lung cancer using lung perfusion information. Radiother Oncol. 
2002;63(2):165-77. PubMed PMID: 12063006. 
40. 
McGuire SM, Zhou S, Marks LB, Dewhirst M, Yin FF, Das SK. A methodology for using SPECT to 
reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung. Int J Radiat Oncol Biol Phys. 
2006;66(5):1543-52. Epub 2006/11/28. doi: S0360-3016(06)02757-X [pii] 
10.1016/j.ijrobp.2006.07.1377. PubMed PMID: 17126212. 
41. 
Gayed IW, Chang J, Kim EE, Nunez R, Chasen B, Liu HH, et al. Lung perfusion imaging can risk 
stratify lung cancer patients for the development of pulmonary complications after chemoradiation. J Thorac 
Oncol. 2008;3(8):858-64. Epub 2008/08/02. doi: 10.1097/JTO.0b013e31818020d5 
01243894-200808000-00008 [pii]. PubMed PMID: 18670303. 
42. 
Christian JA, Partridge M, Nioutsikou E, Cook G, McNair HA, Cronin B, et al. The incorporation of 
SPECT functional lung imaging into inverse radiotherapy planning for non-small cell lung cancer. Radiother 
Oncol. 2005;77(3):271-7. Epub 2005/11/09. doi: S0167-8140(05)00428-7 [pii] 
10.1016/j.radonc.2005.08.008 [doi]. PubMed PMID: 16274762. 
43. 
Lavrenkov K, Singh S, Christian JA, Partridge M, Nioutsikou E, Cook G, et al. Effective avoidance 
of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung 
cancer (NSCLC): an update of a planning study. Radiother Oncol. 2009;91(3):349-52. Epub 2008/11/11. 
doi: S0167-8140(08)00539-2 [pii] 
10.1016/j.radonc.2008.10.005. PubMed PMID: 18995919. 
44. 
Das SK, Miften MM, Zhou S, Bell M, Munley MT, Whiddon CS, et al. Feasibility of optimizing the 
dose distribution in lung tumors using fluorine-18-fluorodeoxyglucose positron emission tomography and 
single photon emission computed tomography guided dose prescriptions. Med Phys. 2004;31(6):1452-61. 
Epub 2004/07/21. PubMed PMID: 15259648. 
45. 
Yuan S, Kirk FA, Gross MD, Morris DE, Hayes DN, Halle J, et al. Semi-quantification and 
classification of local pulmonary function by V/Q SPECT in patients with non-small cell lung cancer. J 
Thorac Oncol. 2011;6(1):pending. Epub 2011/02/20. doi: 10.1097/JTO.0b013e3181915028 
01243894-200901000-00012 [pii]. PubMed PMID: 19096310. 
46. 
Yuan S, Frey KA, Gross M, Hayman J, Arenberg D, Cai X. Changes in global function and regional 
ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung 
cancer. Int J Radiat Oncol Biol Phys. 2012;82(4):e631-8. 
47. 
Mascarenhas F, Silvestre ME, Sa da Costa M, Grima N, Campos C, Chaves P. Acute secondary 
effects in the esophagus in patients undergoing radiotherapy for carcinoma of the lung. Am J Clin Oncol. 
1989;12(1):34-40. Epub 1989/02/01. PubMed PMID: 2536215. 
48. 
Choy H, LaPorte K, Knill-Selby E, Mohr P, Shyr Y. Esophagitis in combined modality therapy for 
locally advanced non-small cell lung cancer. Semin Radiat Oncol. 1999;9(2 Suppl 1):90-6. Epub 1999/04/21. 
PubMed PMID: 10210546. 
49. 
Belderbos J, Heemsbergen W, Hoogeman M, Pengel K, Rossi M, Lebesque J. Acute esophageal 
toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy. Radiother Oncol. 
2005;75(2):157-64. Epub 2005/05/14. doi: S0167-8140(05)00128-3 [pii] 
10.1016/j.radonc.2005.03.021. PubMed PMID: 15890421. 
50. 
Maguire PD, Sibley GS, Zhou SM, Jamieson TA, Light KL, Antoine PA, et al. Clinical and dosimetric 
predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys. 1999;45(1):97-103. 
PubMed PMID: 10477012. 

42 
 
51. 
Takeda K, Nemoto K, Saito H, Ogawa Y, Takai Y, Yamada S. Dosimetric correlations of acute 
esophagitis in lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62(3):626-
9. Epub 2005/06/07. doi: S0360-3016(05)00605-X [pii] 
10.1016/j.ijrobp.2005.04.004. PubMed PMID: 15936536. 
52. 
Challand T, Thureau S, Dubray B, Giraud P. [Esophageal toxicity of radiation therapy: clinical risk 
factors 
and 
management]. 
Cancer 
Radiother. 
2012;16(5-6):364-71. 
Epub 
2012/08/29. 
doi: 
10.1016/j.canrad.2012.07.180 
S1278-3218(12)00337-X [pii]. PubMed PMID: 22925486. 
53. 
Bradley J, Deasy JO, Bentzen S, El-Naqa I. Dosimetric correlates for acute esophagitis in patients 
treated with radiotherapy for lung carcinoma. Int J Radiat Oncol Biol Phys. 2004;58(4):1106-13. Epub 
2004/03/06. doi: 10.1016/j.ijrobp.2003.09.080 
S0360301603020236 [pii]. PubMed PMID: 15001251. 
54. 
Wei X, Liu HH, Tucker SL, Liao Z, Hu C, Mohan R, et al. Risk factors for acute esophagitis in non-
small-cell lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal 
radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(1):100-7. Epub 2006/07/15. doi: S0360-
3016(06)00701-2 [pii] 
10.1016/j.ijrobp.2006.04.022. PubMed PMID: 16839700. 
55. 
Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related 
pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Semin Oncol. 2005;32(2 Suppl 3):S42-
54. PubMed PMID: 16015535. 
56. 
Yi ES, Bedoya A, Lee H, Chin E, Saunders W, Kim SJ, et al. Radiation-induced lung injury in vivo: 
expression of transforming growth factor-beta precedes fibrosis. Inflammation. 1996;20(4):339-52. PubMed 
PMID: 8872498. 
57. 
Anscher MS, Kong FM, Marks LB, Bentel GC, Jirtle RL. Changes in plasma transforming growth 
factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis. Int J Radiat 
Oncol Biol Phys. 1997;37(2):253-8. PubMed PMID: 9069294. 
58. 
Bai YH, Wang DW, Cui XM, Long JY, Cui CB, Jia CY, et al. Expression of transforming growth 
factor beta in radiation interstitial pneumonitis. J Environ Pathol Toxicol Oncol. 1997;16(1):15-20. PubMed 
PMID: 9256927. 
59. 
Rube CE, Uthe D, Schmid KW, Richter KD, Wessel J, Schuck A, et al. Dose-dependent induction 
of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic 
irradiation. Int J Radiat Oncol Biol Phys. 2000;47(4):1033-42. PubMed PMID: 10863076. 
60. 
Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated 
with radiation-induced lung toxicity. Semin Radiat Oncol. 2000;10(4):296-307. PubMed PMID: 11040330. 
61. 
Kong FM, Anscher MS, Sporn TA, Washington MK, Clough R, Barcellos-Hoff MH, et al. Loss of 
heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus 
predisposes patients to radiation-induced lung injury. Int J Radiat Oncol Biol Phys. 2001;49(1):35-41. 
PubMed PMID: 11163495. 
62. 
De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. 
Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. 
Int J Radiat Oncol Biol Phys. 2004;58(5):1378-87. PubMed PMID: 15050313. 
63. 
Stenmark M, Cai X, Shedden K, Hayman J, Yuan S, Ritter T, et al. Combining Physical and Biologic 
Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer 
Treated With Definitive Radiotherapy. Int J Radiat Oncol Biol Phys. In press. 
64. 
Xu H, Zhao L, Bi N, Wang J, Wang L. The Combination of Elevation of Plasma TGF-β1 During 
Radiation Therapy and Preradiation Cyfra21-1 Level Predicts Radiation-induced Lung Toxicity in Patients 
With Non-small Cell Lung Cancer int J Radiat Oncol Biol Phys. 2012;83(3 (suppl)):S611. 
65. 
Hart JP, Broadwater G, Rabbani Z, Moeller BJ, Clough R, Huang D, et al. Cytokine profiling for 
prediction of symptomatic radiation-induced lung injury. Int J Radiat Oncol Biol Phys. 2005;63(5):1448-54. 
Epub 2005/08/24. doi: 10.1016/j.ijrobp.2005.05.032. PubMed PMID: 16115739. 
66. 
Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung 
toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer Control. 2008;15(2):140-50. 
Epub 2008/04/01. PubMed PMID: 18376381. 
67. 
Dillman RO, Herndon J, Seagren SL, Eaton WL, Jr., Green MR. Improved survival in stage III non-
small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl 
Cancer Inst. 1996;88(17):1210-5. PubMed PMID: 8780630. 
68. 
Sause W, Kolesar P, Taylor SI, Johnson D, Livingston R, Komaki R, et al. Final results of phase III 
trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, 

43 
 
Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 2000;117(2):358-64. 
PubMed PMID: 10669675. 
69. 
Marino P, Preatoni A, Cantoni A. Randomized trials of radiotherapy alone versus combined 
chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer. A meta-analysis. Cancer. 
1995;76(4):593-601. PubMed PMID: 8625152. 
70. 
Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in 
the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis. Ann Intern 
Med. 1996;125(9):723-9. PubMed PMID: 8929005. 
71. 
Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Douillard JY, et al. Radiotherapy alone 
versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung 
Cancer. 1994;10 Suppl 1:S239-44. PubMed PMID: 8087515. 
72. 
Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, 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(9):2692-9. PubMed PMID: 
10561343. 
73. 
Curran WJ SC, Langer CJ, Komaki R, Lee JS, Hauser S, et al. Long-term benefit is observed in a 
phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresected stage III 
NSCLC: RTOG 9410 [abstract]. Proc Am Soc Clin Oncol. 2003; 22:621. 
74. 
Zatloukal P, Petruzelka L, Zemanova M, Havel L, Janku F, Judas L, 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(1):87-98. PubMed PMID: 15364136. 
75. 
Rosenman JG, Halle JS, Socinski MA, Deschesne K, Moore DT, Johnson H, et al. High-dose 
conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and 
results of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2002;54(2):348-56. PubMed PMID: 12243807. 
76. 
Vokes EE. Induction chemotherapy followed by concomitant chemoradiotherapy for non-small cell 
lung cancer. Oncologist. 2001;6 Suppl 1:25-7. PubMed PMID: 11182002. 
77. 
Albain KS, Crowley JJ, Turrisi AT, 3rd, Gandara DR, Farrar WB, Clark JI, et al. Concurrent cisplatin, 
etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest 
Oncology Group phase II study, SWOG 9019. J Clin Oncol. 2002;20(16):3454-60. PubMed PMID: 
12177106. 
78. 
Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, et al. Combined chemoradiotherapy 
regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase 
II locally advanced multi-modality protocol. J Clin Oncol. 2005;23(25):5883-91. PubMed PMID: 16087941. 
79. 
Gandara DR, Chansky K, Albain KS, Leigh BR, Gaspar LE, Lara PN, Jr., et al. Consolidation 
docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest 
Oncology Group Study S9504. J Clin Oncol. 2003;21(10):2004-10. PubMed PMID: 12743155. 
80. 
Vokes EE. Optimal therapy for unresectable stage III non-small-cell lung cancer. J Clin Oncol. 
2005;23(25):5853-5. PubMed PMID: 16087940. 
81. 
Vokes E, Herndon, JE, Kelley, MJ, Watson, D, Cicchetti, MG, Green, MR. Induction chemotherapy 
followed by concomitant chemoradiotherapy versus chemoradiotherapy alone for regionally advanced 
unresectable non-small cell lung cancer: initial analysis of a randomized phase III trial. J Clin Oncol. 
2004;22(14S):suppl; abstr 7005. 
82. 
Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, et al. Phase III study of 
cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with 
inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin 
Oncol. 2008;26(35):5755-60. Epub 2008/11/13. doi: JCO.2008.17.7840 [pii] 
10.1200/JCO.2008.17.7840. PubMed PMID: 19001323. 
83. 
Auperin A, Le Pechoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-analysis of 
concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin 
Oncol. 2010;28(13):2181-90. Epub 2010/03/31. doi: JCO.2009.26.2543 [pii] 
10.1200/JCO.2009.26.2543. PubMed PMID: 20351327. 
84. 
Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body 
radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-6. Epub 2010/03/18. 
doi: 303/11/1070 [pii] 
10.1001/jama.2010.261. PubMed PMID: 20233825; PubMed Central PMCID: PMC2907644. 
85. 
Arrieta O, Gallardo-Rincon D, Villarreal-Garza C, Michel RM, Astorga-Ramos AM, Martinez-
Barrera L, et al. High frequency of radiation pneumonitis in patients with locally advanced non-small cell 
lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and 

44 
 
carboplatin. J Thorac Oncol. 2009;4(7):845-52. Epub 2009/06/03. doi: 10.1097/JTO.0b013e3181a97e17. 
PubMed PMID: 19487963. 
86. 
Yom SS, Liao Z, Liu HH, Tucker SL, Hu CS, Wei X, et al. Initial evaluation of treatment-related 
pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy 
and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68(1):94-102. Epub 2007/02/27. 
doi: S0360-3016(06)03637-6 [pii] 
10.1016/j.ijrobp.2006.12.031. PubMed PMID: 17321067. 
87. 
Chopra RR, Bogart JA. Radiation therapy-related toxicity (including pneumonitis and fibrosis). 
Hematol Oncol Clin North Am. 2010;24(3):625-42. Epub 2010/05/22. doi: S0889-8588(10)00060-2 [pii] 
10.1016/j.hoc.2010.03.009. PubMed PMID: 20488358. 
88. 
Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus 
chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III 
randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. doi: S0140-6736(09)60737-
6 [pii] 
10.1016/S0140-6736(09)60737-6. PubMed PMID: 19632716. 
89. 
Fournel P, Robinet G, Thomas P, Souquet PJ, Lena H, Vergnenegre A, 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(25):5910-7. Epub 2005/08/10. doi: 
JCO.2005.03.070 [pii] 
10.1200/JCO.2005.03.070. PubMed PMID: 16087956. 
90. 
Cox JD, Pajak TF, Asbell S, Russell AH, Pederson J, Byhardt RW, et al. Interruptions of high-dose 
radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell 
carcinoma of the lung: analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials. Int 
J Radiat Oncol Biol Phys. 1993;27(3):493-8. Epub 1993/10/20. PubMed PMID: 8226140. 
91. 
Yuan ST, Frey KA, Gross MD, Hayman JA, Arenberg D, Curtis JL, et al. Semiquantification and 
classification of local pulmonary function by V/Q single photon emission computed tomography in patients 
with non-small cell lung cancer: potential indication for radiotherapy planning. J Thorac Oncol. 2011;6(1):71-
8. Epub 2010/12/02. doi: 10.1097/JTO.0b013e3181f77b40. PubMed PMID: 21119546; PubMed Central 
PMCID: PMC3351273. 
92. 
Nijkamp J, Rossi M, Lebesque J, Belderbos J, van den Heuvel M, Kwint M, et al. Relating acute 
esophagitis to radiotherapy dose using FDG-PET in concurrent chemo-radiotherapy for locally advanced 
non-small cell lung cancer. Radiother Oncol. 2012. Epub 2012/12/12. doi: S0167-8140(12)00490-2 [pii] 
10.1016/j.radonc.2012.09.024. PubMed PMID: 23219463. 
93. 
Fernando S, Zhao L, Brown RKJ, Gross M, Feng M, Hayman JA, et al. Changes of Esophageal 
FDG Activity During Fractionated Radiation May Be Associated With Radiation Esophagitis. Int J Radiat 
Oncol Biol Phys. 2006;66(3 (suppl)):S485. 
94. 
Antonia SJ1, Villegas A1, Daniel D1, Vicente D1, Murakami S1, Hui R1, Yokoi T1, Chiappori A1, 
Lee KH1, de Wit M1, Cho BC1, Bourhaba M1, Quantin X1, Tokito T1, Mekhail T1, Planchard D1, Kim 
YC1, Karapetis CS1, Hiret S1, Ostoros G1, Kubota K1, Gray JE1, Paz-Ares L1, de Castro Carpeño J1, 
Wadsworth C1, Melillo G1, Jiang H1, Huang Y1, Dennis PA1, Özgüroğlu M1; PACIFIC Investigators. 
Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 
16;377(20):1919-1929doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8. 
95. 
Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. 
Nature 545, 60, doi:10.1038/nature22079 
96. 
Demaria, S., Golden, E. B. & Formenti, S. C. Role of Local Radiation Therapy in Cancer 
Immunotherapy. JAMA Oncology 1, 1325, doi:10.1001/jamaoncol.2015.2756 (2015). 
97. 
Galon, J. et al. Towards the introduction of the 'Immunoscore' in the classification of malignant 
tumours. The Journal of pathology 232, 199-209, doi:10.1002/path.4287 (2014). 
98. 
Fujimoto, D. et al. Alteration of PD-L1 expression and its prognostic impact after concurrent 
chemoradiation therapy in non-small cell lung cancer patients. Scientific Reports 7, 11373, 
doi:10.1038/s41598-017-11949-9 (2017). 
99. 
Kallinteris, N. L. et al. New method for immunoprofiling of the tumor microenvironment of cancer 
patients by opal multiplex quantitative 
 
 
 
 

45 
 
17.0   APPENDICES 
 

46 
 
Appendix A: SOPs for blood and urine collection 
1)       Obtaining, handling, and delivery of blood specimens in Red Top 
tube for blood cells and tumor DNA/RNA analysis, collected at clinic 
 
1. To avoid skin cell contamination, collect samples for this study after at 
least 2 mL of blood is collected into a separate "discard" tube (or 
alternatively after collecting tube(s) of blood for a clinical draw). 
2. Draw aseptically 1 x 10 mL of venous blood into one red top serum 
tube, and immediately mix by gentle inversion 10 times (do not shake).  
3. Tubes should be labeled with study number, subject de-identified study 
number, date, and time of collection. 
4. Store and transport samples at ambient, indoor temperature 
(typically 18-25 °C) until delivery.  
 
2) Obtaining, handling, and delivery of blood specimens in EDTA for blood 
cells and tumor DNA analysis, collected at clinic 
 
1. To avoid skin cell contamination, collect samples for this study after at 
least 2 mL of blood is collected into a separate "discard" tube (or 
alternatively after collecting tube(s) of blood for a clinical draw). 
2. Draw aseptically 2 x 10 mL of venous blood into 10 mL BD Vacutainer 
purple top EDTA Blood Collection tubes and gently invert 5 times (do 
not shake).  
3. Tubes should be labeled with study number, subject de-identified study 
number, date, and time of collection. 
4. Store and transport EDTA tubes at ambient, indoor temperature 
(typically 18-25 °C). 
3) Obtaining, handling, and delivery of blood specimens in Streck tubes for 
blood cells and tumor DNA/RNA analysis, collected at clinic 
1. Draw aseptically 1 x 10 mL of venous blood into one Streck brown 
top cell-free DNA BCT tube, and immediately mix by gentle 
inversion 10 times (do not shake).  
2. Tubes should be labeled with study number, subject de-identified 
study number, date, and time of collection. 
3. Store and transport samples at ambient, indoor temperature 
(typically 18-25 °C) until delivery.  
 
Deliver to Dr. Muneesh Tewari's lab as soon as possible (within 60 min of 
collection). 
4) Obtaining, handling, and delivery of urine specimens at clinic 
1. Ask subject to provide urine specimen in a urine hat or urinal, using 
the Simple Urine Collection subject instructions. (Please see below 
for Subject Instructions for urine collection at clinic.) 

47 
 
2. Preferably within 10 minutes of urination, pour urine into one urine 
collection container that has EDTA solution in it. Urine should be 
added to the collection container no more than 30 minutes after 
urination. 
3. Screw cap on tightly and invert container twice to mix urine and 
EDTA. 
4. Fill in the provided ID Labels (study number, patient de-identified 
study number, date, time of collection, and method of collection) 
and affix to the container with the preserved urine samples. 
5. Store and deliver the urine specimens with ambient temperature 
packs in a Styrofoam container in light protected conditions, to Dr. 
Muneesh Tewari's lab within 1 hr of urine collection. 
 
 
Appendix B: Instructions for Collecting a Urine Sample 
 
1. Read the instructions carefully, and follow each of the steps to ensure you 
collect the correct specimen for the study.  
 
2. Use the urine hat or urinal provided to you for collection.  
 
3. Lift toilet seat and place hat on top of the toilet rim, then lower toilet seat.  
Make sure the hat is in the correct orientation to collect urine, not stool.  
Urinate into the hat.  If you need to have a bowel movement, collect the urine 
separately.  
 
 
 
 
 
 
 
 
 
 
 
Important: 
Do not allow bowel movement to fall into the hat. 
Do not place toilet paper into the hat. 
 
4. A study team member will receive the urine sample from you and provide 
additional instructions if needed. 
 

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