Clinical trial NCT02492867
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2016-01-14; Completion date: 2022-04-21
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Successful treatment of lung cancer with radiation therapy requires that the physicians determine exactly where the tumor is in the patient's body and seek to limit any unnecessary radiation to normal parts of the body. This study is designed to apply functional imaging, Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) ("a PET scan") and Ventilation/Perfusion Single Photon Emission Computerized Tomography (V/Q SPECT) ("a perfusion scan"), before treatment and then again during treatment to see if this scanning helps predict how well the treatment works and how well the lung functions during treatment. FDG-PET is a modern technology that uses small amounts of a radioactive glucose (FDG) to make images of the whole body and areas of active cancer. V/Q SPECT is an image mapping tool that helps assess how well the lungs are working. A Computerized Tomography (CT) will also be performed along with both of these procedures to help the researchers see clearly where the cancer or the healthy lung is located.

The researchers are also doing blood and urine tests in this study to look for markers to see if this helps them determine the patient's risk of developing side effects from radiation to the lungs. The researchers hope by using these types of tests that they can have more information to help decrease the amount of toxicity patients have from this type of treatment. The researchers hope that this study will help them in the future to design radiation treatment plans that provide the best treatment for each individual patient.

Detailed description:
This is a pilot study 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.

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. Approximately, 80-85% of lung cancers are NSCLC (Non-small Cell Lung Cancer), and 40% of these are locally advanced (stage II/III) at diagnosis. The current standard of care for these patients is "one size fits all" RT (Radiation Therapy) with concurrent chemotherapy in uniform regimens. Even after concurrent chemoradiation, however, the five year overall survival was still about 15%; almost one half of the patients failed locally. 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.

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.

However, it is challenging to deliver high dose RT in the majority of patients with locally advanced NSCLC without exceeding doses to organs at risk and causing significant side effects.

Investigators hypothesized that they could develop safer and more effective therapy by adapting treatment to the individual patient's response. With respect to the tumor, investigators hypothesized, that they could improve outcome by redistributing dose to the more aggressive regions of the tumor, assessed using mid-treatment FDG-PET (Positron Emission Tomography) scanning. With respect to uninvolved organs, investigators 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.

During-RT FDG-PET/CT potentially can provide important benefits to individual patients by intensifying dose to more resistent tumor, allowing early changes to alternative, more efficacious treatment or by avoiding the unnecessary toxicity related to ineffective therapy.

Patients will also undergo a during treatment V/Q SPECT (Single-photon Emission Computed Tomography) scan, as an adaptive plan based on during-treatment SPECT may further optimize PART (Personalized Adaptive Radiotherapy) to avoid high dose radiation to the well-functioning regions, and would thus decrease RILT (Radiation Induced Lung Toxicity).

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.

Investigators plan to continue to collect data on serum biomarkers to further refine their biophysical model with the ultimate goal of individualizing radiation dose prescription.

By identifying high risk patients and adjusting OAR (Organs at Risk) dose limits to the threshold of tolerance, investigators anticipate a significant reduction in the incidence of toxicity from UMCC 2007.123 (NCT01190527) without compromised tumor control by applying the model to optimize radiation planning.

Arms: arm 1: 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. Patients may also receive concurrent chemotherapy with Carboplatin and Paclitaxel. Patients may receive consolidation chemotherapy (carboplatin and paclitaxel) or immunotherapy (durvalumab) at the discretion of the medical oncologist.
Interventions: intervention 1: Response-driven Adaptive Radiation Therapy intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: FDG-PET intervention 5: V/Q SPECT intervention 6: Durvalumab
Intervention descriptions: intervention 1: None intervention 2: AUC 2 concurrent with RT; AUC 6 during consolidation. Given IV intervention 3: 40 mg/m\^2 IV concurrent with RT; 200 mg/m\^2 during consolidation. Given IV intervention 4: None intervention 5: None intervention 6: 10 mg/kg during consolidation. Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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 


3 
 
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 
 
 


5 
 
 
 
 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) 


6 
 
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.   
 
 
 
 
 
 
 
 
 
 
 


7 
 
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. 
 


8 
 
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 
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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. 
 


48 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
ID: UMCC 
2015.035 
     
 
 
 
 
 
 
 
A Pilot Study of Response-Driven Adaptive 
Radiation Therapy for Patients With Locally 
Advanced Non-Small Cell Lung Cancer 
    NCT02492867 
 


Study ID: HUM00098202   IRB: IRBMED   Date Approved: 7/24/2020   Expiration Date: 7/23/2021
Page 1 of 14
Consent Subtitle: UMCC 2015.035
Consent Version: 06.08.2018
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
INFORMATION ABOUT THIS FORM
You may be eligible to take part in a research study.  This form gives you important information about the study.  
It describes the purpose of the study, and the risks and possible benefits of participating in the study.  
Please take time to review this information carefully.  After you have finished, you should talk to the researchers 
about the study and ask them any questions you have.  You may also wish to talk to others (for example, your 
friends, family, or other doctors) about your participation in this study.  If you decide to take part in the study, you 
will be asked to sign this form.  Before you sign this form, be sure you understand what the study is about, 
including the risks and possible benefits to you.
1.  GENERAL INFORMATION ABOUT THIS STUDY AND THE RESEARCHERS
1.1 Study title: A Pilot Study of Response-Driven Adaptive Radiation Therapy for Patients with Locally Advanced 
Non-Small Cell Lung Cancer, UMCC 2015.035
1.2 Company or agency sponsoring the study: 
The National Institutes of Health, The University of Michigan Department of Radiation Oncology
1.3 Names, degrees, and affiliations of the researchers conducting the study:
Principal Investigator
Shruti Jolly, MD 
Department of Radiation Oncology, University of Michigan
2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
Successful treatment of lung cancer with radiation therapy requires that the physicians determine exactly where 
the tumor is in your body and seek to limit any unnecessary radiation to normal parts of the body.  This study is 
designed to apply functional imaging, Fluorodeoxyglucose–Positron Emission Tomography (FDG-PET) (“a PET 
scan”) and Ventilation/Perfusion Single Photon Emission Computerized Tomography (V/Q SPECT) (“a perfusion 
scan”), before treatment and then again during treatment to see if this scanning helps predict how well the 
treatment works for your cancer and how well your lung functions during treatment.  FDG-PET is a modern 
technology that uses small amounts of a radioactive glucose (FDG) to make images of your whole body and areas 
of active cancer. V/Q SPECT is an image mapping tool that helps assess how well your lungs are working.  A 
Computerized Tomography (CT) will also be performed along with both of these procedures to help the 
researchers see clearly where your cancer or your healthy lung is located.
The researchers are also doing blood and urine tests in this study to look for markers to see if this helps them 
determine your risk of developing side effects from radiation to the lungs.  The researchers hope by using these 
types of tests that they can have more information to help decrease the amount of toxicity patients have from 
this type of treatment.  The researchers hope that this study will help them in the future to design radiation 
treatment plans that provide the best treatment for each individual patient.
3. INFORMATION ABOUT STUDY PARTICIPANTS (SUBJECTS)
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  You may 
also leave the study at any time.  If you leave the study before it is finished, there will be no penalty to you, and 
you will not lose any benefits to which you are otherwise entitled. 
3.1 Who can take part in this study?
Patients who have stage IIA-IIIB non-small cell lung cancer and considered unresectable or inoperable are eligible 
for this study. All patients must be age 18 or over. Pregnant women cannot participate in this study. Prisoners are 
excluded from this study.  


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3.2 How many people (subjects) are expected to take part in this study?
Fifty-five evaluable subjects are expected to take part in this research, and we may need to enroll up to seventy 
subjects to reach this goal.  Approximately 40 subjects will be enrolled at the University of Michigan, and 
approximately 30 subjects will be enrolled at the VA Ann Arbor Healthcare System.
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
After agreeing to participate in this study and signing this consent, you will have some pre-treatment procedures 
completed.
Within 6 weeks prior to the start of treatment, you must have a chest and upper abdomen CT and pulmonary 
function tests. You must also have a head CT or MRI within 6 weeks. Within 4 weeks prior to the start of 
treatment, you must have history, physical, and a baseline toxicity evaluation.  Within 4 weeks prior to the start of 
treatment, you must have vitals and blood work completed, including blood counts and liver function tests, and 
have urine collected. These are all standard procedures for people with lung cancer being treated with radiation 
therapy. 
Within 2 weeks prior to or after your treatment planning CT scan, you must also have an FDG-PET-CT scan and 
V/Q SPECT.  This is used to help plan your radiation therapy.  If any of these procedures have already been 
completed in the appropriate timeframes, they will not be repeated for this research.  If your clinical FDG-PET/CT 
scan was completed more than 2 weeks’ prior your treatment planning CT, another scan will be completed for 
updated tumor assessment.  This will be used for research purposes and care.
For the V/Q SPECT, you will be required to lie on a table while the machine creates computer images of your 
lungs.  This procedure will have 3 different parts.  For the first part, you will be required to breathe into a 
radiotracer through a mouthpiece.  A radiotracer is a radioactive chemical that can be seen on the images of your 
body.  This tracer, called [99mTc] DTPA, is in aerosol form and is tasteless.  You will be able to breath normally with 
this mouthpiece.  Once the tracer has gotten into your system, you will be given a small amount of water to drink 
to clear your mouth and throat.  This part of the procedure will last approximately 15-20 minutes.  You will stay in 
the exact same place on the table for the second part of the procedure.  You will then be injected with a different 
radiotracer.  This second tracer is called [99mTc] MAA.  It will be injected into a vein in your arm or leg.  The second 
part of the procedure will last approximately 10 minutes.  For the last part, you will have a CT scan done.  This part 
of the procedure will last less than one minute.  
For University of Michigan patients only, a portion of the tumor tissue collected at the biopsy at 
diagnosis will be analyzed for research purposes.  No additional tissue will be collected for this 
study, beyond what is collected during your standard biopsy.  
Blood and urine will be collected.  For the research blood draw, the researchers will be checking for 
proteins in your blood, to correlate with your treatment side effects. For this test, you will need to 
have four tubes of blood drawn for a total of 40 ml.  This will be similar to 3 tablespoonful’s.  Urine 
will be used for analysis of RNA, DNA, protein, and other biomarkers.  You will have blood and urine 
collected 4 weeks prior to starting radiation.  It will be repeated Day 1 (1 hour post radiation), Day 
2 (prior to radiation), Day 5 (prior to radiation and 1 hour post radiation), thereafter weekly while 
you are receiving radiation, and during follow-up at months 1, 3, every 3 months through 12 
months, then every 6 months through 36 months, and then annually for years 4 and 5 post 
treatment.  The exact number of weeks of radiation therapy you will receive will be determined by 
your doctor. After approximately two-thirds of your radiation treatment has been completed, you 
will have another FDG-PET/CT scan, a V/Q SPECT scan, and a re-planning CT Simulation scan.  
Following the mid-treatment scans, a radiation treatment break of one day will be permitted in the 


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Consent Subtitle: UMCC 2015.035
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event that additional time is needed for treatment planning and QA.  These are all being done only 
because of this research study.  
You will complete Quality of Life questionnaires 4 weeks prior to starting treatment, again during the third week 
of treatment, and also the last week of treatment. 
The researchers hope the active tumor will be smaller on these scans than the previous ones, so the treatment 
fields can be shrunk accordingly.  By doing so, the radiation dose to the tumor and your total radiation dose can 
be increased while the probability of normal tissue toxicity of the lung remains the same.  In the event the tumor 
is not smaller, the information we learn during the scan will also be used to adjust your treatment plan. Similarly, 
the V/Q SPECT will be used to measure the function of the lung and may also impact how the radiation is 
delivered near the end of treatment in order to try to decrease the risk of long term damage to the lung.
 During the study, you will have 2 total V/Q SPECT scans for the purposes of this research protocol.  Each V/Q 
SPECT will last approximately 45 minutes.  You will also have 2 FDG-PET/CT scans.  These scans are used routinely 
for lung cancer patients, but it is not standard of care for patients to have this type of scan during their radiation 
treatment.  Each FDG-PET/CT study will generally take about 2 hours.  You will be injected with the radiotracer 
and then wait about 1 hour before the PET/CT scans begins.  The scan itself will last less than 30 minutes.  The 
amount of radiation you will receive from all of the scans will be a small fraction of the dose of radiation you will 
receive for the treatment of your lung cancer.  
You will receive 30 daily radiation treatments along with chemotherapy.  
You will receive chemotherapy while on study and the drugs you will receive are Carboplatin and Paclitaxel.  You 
will receive one chemotherapy treatment a week for six weeks during radiation treatment.  Following radiation, 
you will receive one chemotherapy dose every three weeks for three additional cycles or one immunotherapy 
dose every two weeks for an additional twenty-six cycles.  The standard risks of Carboplatin and Paclitaxel or 
Durvalumab will be discussed with your physician.  The decision to receive chemotherapy or immunotherapy will 
be at the discretion of the medical oncologist.
After you finish your radiation treatment, you will continue to be followed on a regular basis.  You will be seen in 
the clinic about 1 month following your radiation.  At the visit, you will have a physical exam, CT, and have 
research blood and urine collected.  You will be scheduled to be seen 3, 6, 9, 12, 18, 24, 30, 36, 48, and 60 months 
(5 years) after you finish treatment.  You would be scheduled for follow-up at these time points whether or not 
you take part in this research and they are considered a part of your standard care.  At each time point, you will 
have a clinic visit and research blood and urine collected.  At 3 and 12 months, you will have pulmonary function 
tests.  A chest CT will be done at 6 months, every 6 months through 36 months, and then annually for years 4 and 
5.   You will complete a Quality of Life questionnaire at each follow-up visit.
If you participate in an additional lung study with similar sample collection, only one set of samples will be 
collected.  You will not be double-drawn if you are on two studies. 
4.2 How much of my time will be needed to take part in this study?  
You will have the pre-treatment study procedures within about six weeks prior to your radiation treatment.  The 
duration of your radiation treatment and chemotherapy will be around 6 weeks for a total of 30 daily radiation 
treatments. 
After you complete your treatment, you will be clinically followed for five years and the information collected will 
also be used for purposes of this research.  All of these visits are a part of standard of care.  The only extra time 
needed strictly for research is the time needed for the V/Q SPECT scan prior to treatment, the PET scan and V/Q 
SPECT scan during the treatment, which the total combined time will be about three hours.  The re-planning CT 
Simulation will take about 60 minutes.  Each questionnaire will take about 8 minutes to complete.
4.3 When will my participation in the study be over? 
After you complete your treatment, you will be followed for up to five years.  


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4.4 What will happen with my information and/or biospecimens used in this study? 
Your biospecimens and collected information may be shared with NIH and the University of Michigan Department 
of Radiation Oncology. With appropriate permissions, your samples and collected information may also be shared 
with other researchers, here, around the world, and with companies. Your identifiable private information or 
identifiable biospecimens may be stripped of identifiers and used for future research studies or distributed to 
another researcher for future research studies without additional informed consent. 
5.  INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me against these 
risks?
The known or expected risks are:
Risks Associated with Radiation Therapy to the Chest:
Listed below are toxicities that a patient could experience by receiving standard radiation to the lung.  Because 
you may receive an intensified form of radiation by participating in this study (in combination with 
chemotherapy), there may be side effects other than those listed below that we cannot predict. 
Very Likely (> 10% of patients) 
Difficulty, pain, or burning sensation when swallowing, which is temporary
Fatigue, which is temporary
Tanning, redness of skin, and hair loss within the treatment area, which is temporary 
Skin in treatment area may remain permanently dry, and chest hair may not grow back
Decrease in blood counts while undergoing treatment that may result in bleeding and bruising easily
Scarring in radiated normal tissue, particularly in the lung
Less Likely, But Serious (< 10% of patients)
Cough and some difficulty in breathing (or shortness of breath) due to lung inflammation or scarring, which may 
be severe at times (Radiation Pneumonitis)
Coughing up blood
Irritation of the heart sac (Pericarditis)
Irritation of the heart muscle (Myocarditis)
Esophageal Injury
Very Unlikely (< 1% of patients)
Inflammation of the spinal cord (Transverse Myelitis)
A second cancer caused by radiation
Permanent damage to the lung tissue
Death
Risks Associated with Paclitaxel:
Very Likely (> 10% of patients)
 Loss of hair, lower blood counts which can lead to a risk of infection and bleeding, gastrointestinal discomforts, 
skin redness or rash, fatigue
Less Likely (< 10% of patients)
Nausea and/or vomiting, diarrhea, anemia, headaches, blurred vision, skin or nail darkening, aches and pains in 
muscle and joints, swelling, mouth sores, low pulse, low blood pressure, tingling, numbness, burning pain in hands 
and feet.
Less Likely, But Serious (< 1% of patients)
Irregular heartbeat and heart palpitations, seizures, severe allergic reactions, non-itching lesions in mouth and/or 


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mucous membranes, fever, temporary changes in blood tests that measure liver function, temporary “blind spots” 
in vision, severe rash called Steven-Johnson syndrome which can cause fever and red sores in your mouth and 
eyes.
Risks Associated with Carboplatin:
Very Likely (> 10% of patients)
Lower blood counts which can lead to a risk of infection and bleeding, nausea and/or vomiting, fatigue, loss of hair
Less Likely (< 10% of patients)
Weakness, loss of strength, pain, mouth sores, tingling, numbness, burning pain in hands and feet,  
Less Likely, But Serious (< 1% of patients)
Allergic reactions, cardiovascular changes, respiratory changes, temporary changes in blood tests which measure 
kidney and liver function, blurred vision, hearing loss
While these side effects may occur during standard chest radiation therapy and chemotherapy, participating in 
the study could place you at higher risk for the known or expected side effects listed above.   Because you may 
receive more intensified radiation therapy, and will also get chemotherapy, there may be side effects that the 
researchers cannot predict. You should discuss these with the researcher and/or your regular doctor. Your 
physician will see you weekly while you are on treatment to monitor any side effects and will continue to see you 
following treatment on a regular basis.  Your doctor will treat you for any side effects as is medically appropriate.  
Other drugs will be given to make side effects less serious and uncomfortable. Many side effects will go away 
shortly after the radiation therapy or chemotherapy is stopped, but in some cases side effects can be serious and 
long-lasting or permanent.
Risks Associated with Durvalumab:
Likely (These side effects occur in approximately 10% or more of people receiving durvalumab): 
• Diarrhea 
• Rash / dry itchy skin 
• Liver problems – Increases in the blood level of substances called enzymes found within your liver cells may 
occur. The enzyme changes are unlikely to make you feel unwell. However, if these blood enzyme levels become 
very high, your study doctor may need to stop the study medication. A person may develop inflammation of the 
liver called hepatitis; however, this is uncommon. Signs and symptoms of this include yellowing of the skin or 
whites of the eyes, dark urine, severe nausea and vomiting, pain in the upper right side of your abdomen, skin 
itchiness, not feeling hungry, and bleeding or bruising more easily than normal. 
• Fatigue; feeling tired 
• Nausea 
• Vomiting 
• Decreased appetite 
• Shortness of breath 
• Cough 
• Fever 
• Pain in muscles and joints. 
Less Likely (These side effects occur in approximately 1-9% of people receiving durvalumab):
• Inflammation in the lungs (pneumonitis) – Symptoms may include, but are not limited to, a new or worsening 
cough, and shortness of breath possibly with fever. Pneumonitis can be fatal. Tell your study doctor right away if 
you have any of these symptoms as it may need to be treated urgently. 
• Low thyroid (hypothyroidism) – This is when the thyroid gland produces less thyroid hormone than it should 
which causes the metabolism to run too slow. Symptoms may include, but are not limited to, fatigue, increased 


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sensitivity to cold, constipation, dry skin, unexplained weight gain, puffy face, muscle weakness, slow heart rate, 
thinning hair, and impaired memory. The condition can be treated with replacement thyroid hormone. 
• High thyroid (hyperthyroidism) – This is when the thyroid gland produces too much thyroid hormone. Symptoms 
include anxiety or nervousness, weight loss, frequent and loose bowel movements, 
breathlessness, feeling hot, and possibly having heart palpitations. Depending on the severity of the symptoms, 
treatment may include just monitoring the symptoms, treating the symptoms themselves, and/or giving medicine 
to block the thyroid hormone. 
• Kidney problems – You may have an increase of creatinine levels in a blood test (creatinine is a protein marker 
that measures kidney function) but not have any symptoms or feel unwell. Less commonly a person may 
experience nephritis which is an inflammation of the kidneys that stops the kidneys from working properly. 
• Nervous system problems – Symptoms can include unusual weakness of legs, arms, or face, numbness or 
tingling in hands or feet. In rare situations there is the potential for the inflammation of the nervous system to be 
severe. Tell your study doctor right away if you have problems swallowing, if you start to feel weak very quickly, 
and you are having trouble breathing. 
• Infusion related reactions – Reactions may occur during or after the infusion of study medication. The reaction 
may cause fever or chills and a change in blood pressure or difficulty in breathing which might be serious. Tell 
your study doctor right away if you experience any of these symptoms even if it has been several days after the 
infusion has been completed. 
• Inflammation of the intestine (colitis) – It may cause abdominal pain and diarrhea with or without blood. Fever 
may be present. It may require you to receive additional fluids. If left untreated, this may lead to a tear in the wall 
of the intestine which can be serious and life threatening. Tell your study doctor right away if you have any of 
these symptoms. 
Rare but Serious (These side effects occur in less than 1% of people receiving durvalumab): 
• Inflammation of the pancreas (pancreatitis) – Pancreatitis usually causes symptoms of persistent upper 
abdominal pain (sometimes made worse by eating and drinking), nausea, vomiting, and general weakness. 
Pancreatitis usually settles with simple measures but it can be a serious condition and can be fatal. You should 
immediately tell your study doctor if you develop any unusual symptoms. You may get an increase of lipase and 
amylase levels in a blood test (related to the pancreas) but not have any symptoms or feel unwell. Lipase and 
amylase are enzymes or protein markers that measure the function of your pancreas. Uncommonly these 
increases may be associated with pancreatitis. 
• Type 1 diabetes mellitus which may cause increased blood glucose levels (called ‘hyperglycemia’) – Symptoms 
may include weight loss, increased urination, increased thirst, and increased hunger. Type 1 diabetes will require 
replacement of insulin through injection. Tell your study doctor right away if you have any of these symptoms. 
• Problems with your adrenal glands (adrenal insufficiency) – May cause stomach pains, vomiting, muscle 
weakness and fatigue, depression, low blood pressure, weight loss, kidney problems, nausea, and changes in 
mood and personality. These complications may be permanent and may require hormone replacement. 
• Allergic reactions – These can cause swelling of the face, lips and throat, breathing difficulties along with hives 
or nettle-like rash. You should immediately tell your study doctor if you develop any of these symptoms. 
• Problems with the pituitary gland (hypopituitarism) – Hypopituitarism refers to decreased output of hormones 
from the pituitary gland in the brain and may be caused by inflammation of the pituitary gland (hypophysitis). 
Symptoms may include headaches, thirstiness, and trouble seeing or double vision, leakage of breast milk or 
irregular periods in women. These complications may be permanent and may require hormone replacement. 
• Inflammation of the heart (myocarditis) – In rare cases, myocarditis has been reported. Symptoms may include 
irregular heart rhythm, chest pain, increasing shortness of breath during regular activities, and decrease in the 
hearts ability to pump blood. Myocarditis can be life threatening. Tell your doctor if you have or have had any 
heart problems in the past. 


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• Inflammation of the skin – In rare cases, severe dermatitis has been reported to show as Stevens-Johnson 
syndrome, toxic epidermal necrolysis or rashes complicated by cell injury or cell death, blisters or hemorrhaging. 
These events can be life-threatening. 
• People with previous history of bleeding and/or who are taking anticoagulant medications or "blood thinners" 
may have a higher risk of bleeding while on durvalumab. Tell your doctor if you are taking any of these 
medications. Your doctor may need to monitor you for any bleeding more closely than usual. 
Other rare but serious side effects include inflammation of the sac around the heart called pericarditis (symptoms 
that may include irregular heart rhythm, chest pain, increasing shortness of breath during regular activities) and a 
form of eye inflammation called uveitis that affects the middle layer of tissue in the eye wall (uvea) (symptoms 
include eye redness, pain and blurred vision). Uveitis can be serious, leading to permanent vision loss. Tell your 
doctor if you are having any of these symptoms. Early diagnosis and treatment are important to prevent the 
complications of uveitis. It is possible that an inflammatory or immune system reaction could occur in nearly all 
organs of the body which may require more frequent monitoring and may require treatment. 
For more information about risks and side effects, ask your study doctor.
Study Procedure Risks:
There is an unlikely risk that the outcome of the study therapy could be worse than standard therapy since the 
use of FDG-PET/CT-adapted radiation therapy with targeted therapy is experimental.
Radioactivity
During the course of this study, you will be exposed to radiation from the PET radiotracer [18F]FDG, and from the 
CT portion of the PET/CT scanner. The biological effect of radiation in humans is measured in terms of Sieverts (Sv) 
or mSv (1/1000 Sv), which is a unit of uniform whole body exposure. The total radiation you will be exposed to from 
this research project will be approximately 42 mSv from internal and external exposures for the PET/CT scans, and 
the SPECT V/Q scans. The effects on the body of this radiation exposure will be added to your overall lifetime 
radiation risk. Your life-time radiation risk includes the background radiation you are exposed to naturally like 
everyone else living on this planet, which is on the average 3 mSv per year; the maximum radiation you will be 
exposed to in this study is about 14 times this average yearly background radiation. In terms of radiation a person 
may get exposed to during medical care, the maximum amount you could receive in this study is less than the 
radiation received in 6 routine X-ray CT scans (CAT scan) of the chest. The US Federal Government requires that the 
annual amount of radiation exposure of radiation workers does not exceed 50 mSv per year; the radiation you will 
be exposed to in this study is 84% of this amount. 
Your lifetime radiation risk also includes any radiation you may have received in the past for diagnosis or treatment, 
and any such radiation you may be exposed to in the future. Please inform the investigators if you have had any 
major radiation exposure in the past, particularly in the past year, such as medical treatment with X-rays or 
radioactivity, or diagnostic X-rays, CT-scans or nuclear medicine scans.
No PET studies will be performed on pregnant, nursing, or potentially pregnant women, as determined by 
pregnancy testing within 48 hours prior to PET the scanning session.  
To reduce the risk of external radiation exposure we take as short of a picture as possible to define the size and 
shape of your body. To reduce the risk of internal radiation exposure we inject as little radioactivity as possible.
V/Q SPECT:  These scans are an established diagnostic test and are conventionally performed for evaluation of 
pulmonary embolism (a blood clot in the lung) and involve only minimal risk.  There is a very small amount of 
radiation you will receive from these scans.  The radiation dose from these scans are insignificant in comparison 
to the dose you will receive as therapy for your lung cancer (less than 1/1000th of your treatment dose). You may 


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experience some bruising, swelling, or infection at the site of the injection of the radiotracers.  Rarely, some 
patients may experience a severe allergic reaction to the radiotracers.
FDG-PET/CT scans:  The risks associated with an FDG-PET/CT scan are minimal.  FDG is considered safe, and there 
has not been a report of an adverse event with this type of use.  This scan is an established diagnostic test and is 
often performed for detecting, staging and monitoring many kinds of cancers.  Despite this information there is 
still a possibility of a rare allergic reaction, such as hives or difficulty breathing.  There is a risk of discomfort, 
bruising, bleeding, fainting or infection with the placement or removal of the needle used for drawing blood and 
injecting the FDG.  Some persons may find it uncomfortable to lie still on their back for 30 minutes.  Rarely, some 
patients may experience a severe allergic reaction to the radiotracers.
Adaptive Therapy:    There is a rare risk that the outcome of the therapy could be worse for the subject.  The use 
of PET scan results during therapy is experimental and could present a situation where there are false negative 
areas of the tumor, so, the possibility exists that the tumor volume to be modified could be completed to under 
dose part of the tumor.  In this case, that part of the tumor would still be treated with a radiation dose which is 
within the standard range that you would receive even if you were not on the study.
Research Blood Draw:  The risks involved with having blood drawn for this test are the same as those with any 
blood draw.  You may experience some bruising, swelling, infection at the site of the blood draw, pain, and, rarely, 
lightheadedness.  
Reproductive Risks:
If there is ANY chance that you can get pregnant, you must either agree to not have vaginal intercourse or you 
must use TWO types of birth control (one from each list below) AT THE SAME TIME all during treatment (including 
during temporary breaks from treatment), and for 90 days after treatment has stopped.  You must talk to the 
doctor before changing any birth control methods you have already agreed to use.
Primary forms: 
Secondary forms:
• tubal sterilization (tubes tied)
• male latex condom with or without spermicide
• partner’s vasectomy 
 
• diaphragm with spermicide
• intrauterine device 
• cervical cap with spermicide
• vaginal sponge with spermicide
Any birth control method can fail. The reports of birth control failing are more frequent for female patients who 
use only a single form of birth control.  Using two forms of birth control at the same time greatly reduces the 
chance of pregnancy. 
MEN
All men must use an acceptable form of birth control while taking part in the study because the effects on sperm 
are not known.  Acceptable forms of birth control are male latex condom (with or without spermicide) or 
vasectomy.  Men should not donate sperm or semen while taking part in the study because the effects on sperm 
are not known.
Genetic Information Nondiscrimination Act (GINA):
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information.  This law does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance.  Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums


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
Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment
GINA does not apply to the following groups; however, these groups have policies in place that provide similar 
protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service
Federal employees receiving care through the Federal Employees Health Benefits Plans
As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 about 
any injuries, side effects, or other problems that you have during this study.  You should also tell your regular 
doctors.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you.  
It may also affect the results of the studies.  You should not take part in more than one study without approval 
from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may not receive any personal benefits from being in this study. It is possible that you may have better control 
of your cancer and have longer survival by taking part in this research instead of getting standard treatment, but 
this is not guaranteed.  The researchers will use the information learned from this study to help with treating 
patients with lung cancer.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
6.  OTHER OPTIONS
6.1 If I decide not to take part in this study, what other options do I have?
If you do not take part in this study, you will continue to receive the same treatment that you would receive if you 
were not on the study.  There will be no penalty to you by not participating in this research.
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to tell the researchers 
why you are leaving the study, your reasons for leaving may be kept as part of the study record. If you decide to 
leave the study before it is finished, please tell one of the persons listed in Section 10 “Contact Information” 
(below).
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
Although there is no specific known risk to leaving the study early, it is in your best interest to discuss your 
decision to leave the study with the researchers at the time that you decide to leave to make sure that you are 
not at any specific risk.  


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7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study?  
The study will pay for research-related items or services that are provided only because you are in the study.  If 
you are not sure what these are, see Section 4.1 above or ask the researchers for a list.  If you get a bill you think 
is wrong, call the researchers’ number listed in section 10.1.
You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services.
If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
The study team has given you instructions about this research study. It is important that you follow these 
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the 
study, call Dr. Jolly immediately, at telephone 734-936-4302. The doctor will either treat you or send you to 
another doctor for treatment.
You will get free medical care at the UMHS hospitalization or ER visits directly caused by the study drug, device, or 
procedure. The UMHS and the study doctor are responsible for determining whether your condition was the 
result of your participation in the study.
The UMHS will pay for your treatment only if the need for treatment has been caused by the study drug, device or 
procedure. This means that you or your health plan must pay for any treatment that is part of your usual medical 
care or that is related to a medical condition you had before participating in the study.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
8.2 Will I be paid or given anything for taking part in this study?
You will not get paid for taking part in this research.  
8.3 Who could profit or financially benefit from the study results?
No person or organization has a financial interest in the outcome of this study.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the use of the data or discoveries. You will not 
have rights to these discoveries or any proceeds from them. 
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study.


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9.1 How will the researchers protect my privacy?
Information collected about you will be put in a research records.  This record will show your name and will have 
codes that will allow the information to be linked to you.  This research record will be stored in a secure, non-
public area of the Department of Radiation Oncology.  Any electronic research data will be kept in a password 
protected database.  The researchers will keep your records confidential to the fullest extent provided by local, 
state, and federal laws.  No one will see your research record other than people who have a right to see it like the 
study investigators and their research staff.  You will not be identified in any reports on this study.
9.2 What information about me could be seen by the researchers or by other people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.  Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

All records relating to your condition, the treatment you have received, and your response to the 
treatment

Billing information
There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University, Food and Drug Administration (FDA), and/or other government officials may need the 
information to make sure that the study is done in a safe and proper manner.   

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular UMHS medical record.

If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, social security number, payment amount, and related 
information for tax reporting purposes. 

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.3 What happens to information about me after the study is over or if I cancel my permission?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it secure until it 
is destroyed.  Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over.  


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Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help University and government officials make sure that the study was conducted properly
As long as your information is kept within the University of Michigan Health System, it is protected by the Health 
System’s privacy policies.  For more information about these policies, ask for a copy of the University of Michigan 
“Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa. Note that once your information has been shared 
with others as described under Question 9.2, it may no longer be protected by the privacy regulations of the 
federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
9.4 When does my permission expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your permission at 
any time by writing to the researchers listed in Section 10 "Contact Information" (below).  
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator:
Shruti Jolly, MD
Mailing Address:
UM Department of Radiation Oncology 
B2C490 University Hospital SPC 5010
Ann Arbor, MI 48109-5010
Telephone:
734-936-4302
You may also express a concern about a study by contacting the Institutional Review Board listed below.
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies:  US Country Code: 001)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help University 
officials to look into your concern.  When reporting a concern, you do not have to give your name unless you want 
to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?


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Your signature in the next section means that you have received copies of all of the following documents:

This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you receive, 
copies of this document will be stored in a separate confidential research file and may be entered into your 
regular University of Michigan medical record.)

Other (specify):


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12.  SIGNATURES
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential 
benefits, and my other choices with __________________________.  My questions so far have been 
answered.  I understand that if I have more questions or concerns about the study or my 
participation as a research subject, I may contact one of the people listed in Section 10 (above).  I 
understand that I will receive a copy of this form at the time I sign it and later upon request.  I 
understand that if my ability to consent or assent for myself changes, either I or my legal 
representative may be asked to re-consent prior to my continued participation in this study.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
For use only if required by sponsor: 
Date of Birth (mm/dd/yy): ____________________________
ID Number: ________________________________________
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information 
about this study that I believe to be accurate and complete.  The participant and/or his/her legally 
authorized representative(s) indicated that he or she understands the nature of the study, including 
risks and benefits of participating.
Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________


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UMCC # 2015.035
PERSONAL CENSUS FORM
Name _______________________________________________
Date ____________________
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer Center 
report race and ethnicity information about people who participate in clinical research to ensure that all 
populations are offered the opportunity to participate. 
 Check here if you do not wish to provide some or all of the information below.
1. What race do you consider yourself to be?

American Indian/Alaska Nativea
(Please select one or more)

Asianb

Black or African Americanc

Native Hawaiian or Other
Pacific Islanderd

Whitee

More than one racef
2. Do you consider yourself to be Hispanicg?
 Yes
 No
________________________________________________________________________
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or South America, 
and who maintains tribal affiliation or community attachment.
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, 
including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and 
Vietnam.
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as “Haitian” or 
“Negro” are sometimes used in addition to “Black” or “African American.”)
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or 
other Pacific Islands.
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed above, but 
this may also be solely selected.)
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, 
regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or “Latino.”