Personalized Radiation Therapy Through Functional Lung Avoidance and Response-Adaptive Dose Escalation: Utilizing Multimodal Molecular Imaging to Improve the Therapeutic Ratio (FLARE RT)
Phase: PHASE2
Conditions: Stage IIB Lung Non-Small Cell Carcinoma AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7
Sponsor: University of Washington

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FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
Personalized radiation therapy through functional lung avoidance and 
response-adaptive dose escalation: utilizing multimodal molecular 
imaging to improve the therapeutic ratio (FLARE RT)
Principal Investigator:
Jing Zeng, MD
Associate Professor
Department of Radiation Oncology
University of Washington Medical Center
1959 NE Pacific Street, Box 356043
Seattle, Washington 98195-6043
Phone: 206-598-4100 
Fax: 206-598-6218
Email: jzeng13@uw.edu
Co-Investigators:
Stephen R. Bowen, PhD
Shilpen A. Patel, MD
Ramesh Rengan, MD, PhD
Waylene A. Wang, MD
                              
Version date:
Protocol Amendment 4: version February 5, 2020
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Study Summary
Title
Personalized radiation therapy through response-adaptive dose 
escalation and functional lung avoidance: utilizing multimodal 
molecular imaging to improve the therapeutic ratio (FLARE RT)
Short Title
FLARE RT 
Protocol Number
CCIRB 9599
Phase
Phase II
Methodology
Single Arm Open-Label 
Study Duration
5 yrs. 
Study Center(s)
University of Washington Medical Center 
Objectives
To utilize mid-treatment FDG PET/CT tumor response to select 
non-responding patients for dose escalation, while utilizing 
functional lung avoidance to mitigate toxicity. Changes in tumor 
FDG uptake on mid-treatment PET/CT (24 Gy nominal) will divide 
patients into “responders” and “non-responders”. Responders will 
receive 60 Gy to their tumor per standard of care; non-responders 
will undergo dose escalation to 74 Gy.  All patients will receive 
functional lung avoidance radiation treatment via SPECT/CT 
imaging with 
99mTc-MAA and 
99mTc-SULFUR COLLOID to 
accurately identify and preferentially spare functional lung. Primary 
endpoint of this study will be 2-yr. overall survival.  
Number of 
Subjects
The projected enrollment number is 60 in order to meet the study 
goal of 50 evaluable subjects.
Diagnosis and 
Main Inclusion 
Criteria
Patients diagnosed with stage IIB-III non-small cell lung cancer 
receiving definitive chemoradiation.  
Study Product, 
Dose, Route, 
Regimen
All scans are FDA approved for use with patients: 18FFDG-PET/CT 
and SPECT/CT with 99mTc-MAA and 99mTc-Sulfur Colloid
Duration of 
administration
Beyond standard of care imaging, some patients may undergo a 
repeat baseline protocol specific FDG-PET/CT, and be considered 
research, then a PET/CT mid-treatment, and 2 SPECT/CT scans 
(pre-treatment and 3 months post-treatment). 
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Statistical 
Methodology
Primary endpoint of the study will be 2 yr. overall survival, 
compared to the 60 Gy cohort of RTOG 0617 (57% 2yr OS). With 
an estimated improvement to 72% 2yr OS, we will need 49 
patients to test for superiority of FLARE RT at 80% power and 5% 
Type I error. Secondary endpoints will include toxicity, and in 
particular CTCAE v4 grade 2 or higher pneumonitis, and 1 yr. local 
control, progression-free survival, and pulmonary function test 
decline. We will also collect plasma and urine for future correlative 
studies. 
Table of Contents
1. Introduction
1.1.Background
1.2.Local Control Impacts Survival in Locally Advanced NSCLC
1.3.Radiation Dose Escalation Can Improve Local Control in NSCLC, but Uniform 
Dose Escalation Is Detrimental
1.4.FDG PET/CT Can Select For Patients at High Risk of Local Failure and Guide 
Dose Escalation
1.5.Radiation to the Lungs Causes Pulmonary Toxicity and Limits the Deliverable 
Dose
1.6.Current Radiation Planning Methods are Unable to Accurately Predict Which 
Patients Will Develop Pulmonary Toxicity
1.7.SPECT/CT Perfusion/Ventilation Scans can Detect Heterogeneity in Lung 
Function
2. Study Objectives
3. Study Design
3.1.General Design
3.2.Statistical Plan
3.3.Eligibility 
4. Study Registration
5. Radiation Therapy
5.1.Dose Specifications
5.2.Localization, simulation and immobilization
5.3.Target Volumes
5.4.Critical Structures
5.5.Treatment Planning
5.6.Radiation Quality Assurance Reviews
5.7.Radiation Toxicity
5.8.Criteria for Removal/Withdrawal from Treatment 
6. Systemic Therapy
7. Data and Safety Monitoring Plan
7.1.Early Stopping Rules
7.2.Interim Data Review
8. Data Management/Confidentiality 
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1
Introduction
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
1.1 Background
Radiation is a major treatment option for patients with locally advanced non-small cell 
lung cancer (NSCLC), but current treatment regimens result in suboptimal tumor control 
with local failures up to 50% and 5-year overall survival (OS) of 10-20%, while carrying 
substantial risk of toxicity, with grade 3+ pulmonary toxicity seen in approximately 20% 
of patients (1-4). We propose to improve the therapeutic ratio by limiting pulmonary 
toxicity risk through radiation dose avoidance of functional lung defined on 
ventilation/perfusion SPECT/CT and increasing local control through FDG-PET/CT 
guided tumor dose escalation in select patients at high risk of local failure. We will 
explore several questions with clinical significance: (1) whether the combination of 
selective tumor dose escalation and functional lung avoidance synergistically impacts 
patient outcomes, (2) whether patient selection based on early FDG PET response can 
improve the potential survival benefit from PET-guided dose escalation, (3) whether 
radiation dose burden to functional lung better predicts clinical lung toxicity than 
radiation dose burden to anatomic lung, and (4) whether image parameters of spatial 
and functional heterogeneity in lung can select patients prior to treatment who are at 
highest risk of pulmonary toxicity. Answers to such questions within the scope of this 
pilot trial will support the launch of a multi-center trial that can definitively assess the 
efficacy of FLARE RT. Development of functional lung imaging heterogeneity tools and 
FLARE RT planning tools will enable radiation oncologists and radiologists to more 
precisely manage and deliver care to cancer patients.
1.2 Local Control Impacts Survival in Locally Advanced NSCLC
Although current treatments have dose limiting toxicities including pulmonary toxicity, 
local control after radiation treatment is still suboptimal at around 50%. When patients 
die from NSCLC, both metastatic sites of disease and disease in the chest contribute to 
the causes of deaths (5). The lack of local control of lung tumor is clearly correlated with 
worse survival, and the death-rate for patients with intra-thoracic disease recurrence is 
similar to death-rate for patients with metastatic disease (6-8). In the CHART 
randomized trial testing different radiation dose/fractionation schemes, improving the 
local control from 20% to 29% resulted in improvement in median survival from 10 
months to 28 months (9). Therefore, local control of lung tumors does impact the overall 
survival in patients with locally advanced lung cancer. 
1.3 Radiation Dose Escalation Can Improve Local Control in NSCLC, but 
Uniform Dose Escalation Is Detrimental
Dose-escalation studies have shown promising local control rates when radiation dose 
is escalated above the standard 60 Gy in conventional fractionation. One study looking 
at 122 patients receiving definitive radiation treatment for lung cancer, without surgery, 
found that each 1 Gy increase in dose resulted in approximately 1.25% improvement in 
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5-year local control (3). For patients treated to 63-69 Gy, 5-year local control was 12%, 
versus 49% for patients treated to >90 Gy. The same trend is seen for 5-year OS, 4% 
versus 28% for the lower dose versus higher dose groups, respectively. Analysis of 
multiple patient series has found that a 1 Gy increase in dose leads to 3-4% 
improvement in survival and local control (10).
The potential survival advantage from dose escalation beyond 60 Gy was tested in a 
randomized trial in RTOG 0617, where patients with locally advanced NSCLC were 
treated to 60 Gy versus 74 Gy (11). Surprisingly, results showed that uniform dose 
escalation to the entire tumor volume in all patients is inferior to standard dose radiation. 
Local control and OS were worse in the 74 Gy arm versus the 60 Gy arm. Exact cause 
of the inferior outcome in the higher dose arm is unclear, but higher heart radiation dose 
was found to be associated with worse outcomes, and heart dose was higher in the 74 
Gy arm compared to the 60 Gy arm. It is unknown if the higher heart dose is truly the 
cause of increased mortality, or a surrogate marker for other poor prognostic variables 
that were unbalanced between the two randomized arms. For example, multiple surgical 
series have found subcarinal lymph node involvement and multi-station mediastinal 
nodal involvement to be associated with poor survival in patients in lung cancer (12-14). 
The same effect is seen in patients treated with chemoradiation (15). Both subcarinal 
disease and multi-station nodal disease are associated with higher radiation dose to the 
heart (16). Therefore, it is possible that the higher heart dose in the higher dose arm is a 
surrogate for mediastinal nodal involvement, which is well known to have a negative 
impact on survival. 
These results highlight the importance of selecting the right patient population for dose 
escalation, since not all patients experience local failures after 60 Gy, and only patients 
who would have experienced local failure would potentially benefit from escalated 
radiation dose beyond 60 Gy. Giving more radiation dose uniformly across an entire 
patient population will likely cause as much toxicity as benefit; therefore it is key to 
utilize strategies that can identify patients at high risk of local failure after conventional 
radiation doses of 60 Gy.
1.4 FDG PET/CT Can Select For Patients at High Risk of Local Failure and 
Guide Dose Escalation
Given that up to 50% of patients with NSCLC develop local recurrences after standard 
radiation treatment, methods to improve local control are needed. However, randomized 
data have shown that dose escalation in all patients leads to worse outcomes when 
looking at the entire patient population (11). Strategies to identify patients at high risk of 
local failure are needed to target therapy intensification in the group of patients who will 
benefit. High tumor uptake on mid-radiation treatment FDG PET relative to baseline 
FDG PET is associated with poorer clinical outcomes, and local recurrences after 
radiation treatment tend to occur inside FDG PET avid regions (17-19). It has been 
estimated that 60% of patients were classified as early non-responders on FDG PET 
and that this subpopulation had overall survival rates of 33% compared to 92% in the 
responder subpopulation (van Elmpt, Ollers, et al. 2012). This result highlights both the 
prevalence of poor tumor response early during treatment and its significant impact on 
patient outcomes. Further, high spatial correlation between FDG PET avid areas and 
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recurrent disease (20, 21) help refine the definition of high-risk treatment targets in 
NSCLC.
Ongoing clinical trials are defining targets on FDG PET/CT for concomitant dose 
escalation but do not select patients according to local failure risk. The PET boost trial in 
the Netherlands utilizes discrete dose escalation to FDG PET avid regions (50% SUVmax 
threshold) based on pre-treatment assessment and individualizes integral target dose 
boosts based on mean lung dose, but does not account for patient variability in early 
treatment response (22). RTOG 1106 is investigating whether tumor dose can be 
escalated to improve the local control rate based on FDG-PET/CT imaging at 40-46 Gy 
during treatment, which exploits higher achievable dose escalation following tumor 
volume regression (17). This adaptive dose escalation trial design to concurrently boost 
residual FDG PET avid regions late in therapy poses the following challenges: (1) 
potential for increased toxicity with little survival benefit from dose escalation in patients 
whose tumors have already responded to standard dose radiation therapy, (2) limited 
radiobiological effectiveness with 9/30 radiation treatment fractions available for dose 
escalation during accelerated tumor cell repopulation, and (3) enhancement of 
radiation-induced inflammatory response signal on late mid-therapy FDG PET/CT 
imaging that can confound target definition.
Patients at high local failure risk can be selected according to the quantitative change in 
tumor FDG PET SUVmax and total lesion glycolysis as early as 2-3 weeks into treatment, 
which is predictive of clinical outcomes (23, 24). An earlier assessment of treatment 
response (2-3 week time point instead of waiting until 40-46 Gy during week 4-5) has 
the benefit of allowing earlier implementation of dose escalation to regions at high risk 
of local failure. The 2-3 week mid-treatment PET/CT can select for patients who are at 
high risk of local relapse, and treat this high risk subpopulation with dose escalation to 
improve cancer control, which is another step towards personalized medicine for this 
patient population. 
1.5 Radiation to the Lungs Causes Pulmonary Toxicity and Limits the 
Deliverable Dose
When improving the therapeutic ratio, dose escalation must always be weighed against 
potentially increased toxicity. Radiation to the lungs cause a spectrum of changes, with 
the two most clinically relevant changes being radiation pneumonitis (RP) and radiation 
induced fibrosis. Radiation pneumonitis is a disorder characterized by inflammation 
focally or diffusely affecting the lung parenchyma. It occurs in the subacute phase after 
radiation treatment, from several weeks to several months after completion of therapy. 
Radiation pneumonitis can be mild, causing shortness of breath that does not require 
intervention and resolves spontaneously, to severe, requiring steroids, oxygen, 
ventilation, or, if not treatable even, even death. Radiation pneumonitis is a dose-limiting 
toxicity in lung cancer treatment, causing worsening respiration in patients who often 
already have underlying lung disease, such as emphysema. Approximately 15-40% of 
patients develop clinically significant radiation pneumonitis after treatment with 
conventional radiation doses (25). Long term, lung tissue treated with radiation can 
develop fibrosis, and is no longer able to function in gas-exchange. This can lead to a 
permanent reduction in pulmonary function. Symptomatic lung damage is the major 
impediment to safely escalate dose to lung tumors. 
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1.6 Current Radiation Planning Methods are Unable to Accurately Predict 
Which Patients Will Develop Pulmonary Toxicity
Radiation pneumonitis and global pulmonary dysfunction are poorly predicted by current 
radiation planning methods, which consider all lung tissue to be equally important in 
pulmonary gas exchange (and equally vulnerable to radiation damage). Mean radiation 
dose to the lung (mean lung dose=MLD) and percent of lung volume receiving at least 
20 Gy of radiation (V20) are the two most commonly used metrics for estimating risk for 
developing pulmonary toxicity from radiation treatment. Many other studies have tried to 
incorporate other variables into prediction models for radiation pneumonitis and global 
dysfunction, including clinical parameters as well as radiation treatment plan 
parameters, but the most widely used metrics for evaluating a radiation treatment plan 
are still MLD and V20. In a recent large international series of 836 patients, V20 was 
found to be predictive of radiation pneumonitis: 18% of patients receiving V20<20% 
(lowest lung dose group) developing symptomatic RP, 0% fatal; versus 30% 
symptomatic RP in the V20 between 20-30% patient group (intermediate lung dose 
group but still within V20 that is typically considered safe) and 1% fatal RP; versus the 
highest lung dose group with V20>40%, developing 36% RP and 3.5% fatality (25). This 
data emphasizes that even in the lowest lung dose group (according to V20), almost 
20% of patients are still developing radiation pneumonitis; and even in the highest lung 
dose group, more than 60% of patients do not develop RP. This calls for a better 
method of predicting RP than the current parameters of MLD and V20.
1.7 SPECT/CT Perfusion/Ventilation Scans can Detect Heterogeneity in Lung 
Function 
Current standard practice in radiation oncology, relying on MLD and V20 to quantify 
lung dose, treats all lung tissue as if it functions equally. In reality, lung tissue function is 
spatially heterogeneous, especially in patients with baseline lung disease such as 
smoking-induced COPD where ventilation and perfusion-mediated gas exchange 
becomes compromised. Perfusion and ventilation SPECT/CT imaging using 99mTc-
labeled MAA and SULFUR COLLOID, respectively, is commonly performed as a non-
invasive diagnostic imaging test of pulmonary function, is utilized by surgeons to predict 
post-operative lung function, and has strong potential for use in RT planning (26). 
Conventional RT planning based on anatomic lung dose constraints yielded large 
variability in dose to functional lung across patients (27) that can be accounted for in 
functional avoidance planning. Prior studies using planar scintigraphy and MAA SPECT 
perfusion scans with long-term follow-up provided strong rationale for modeling regional 
perfusion reduction as a function of delivered radiation dose (28, 29). Independent 
investigations were able to link perfusion SPECT-weighted dose to post-RT pulmonary 
toxicity (30, 31). However, no link was established between regional perfusion deficits 
and pulmonary toxicity in part due to existing technical limitations in spatial resolution 
and quantitative accuracy that are now achievable with modern SPECT/CT imaging 
techniques (32). The technical feasibility of incorporating lung function imaging 
heterogeneity into treatment planning has been well-established (33-37) and can be 
readily implemented once an imaging surrogate for radiation-induced pulmonary toxicity 
risk is identified.
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The established clinical utility and widespread availability of perfusion and ventilation 
imaging using 99mTc-labeled MAA and SULFUR COLLOID SPECT/CT, respectively, 
make this approach most feasible for eventual incorporation of functional lung 
avoidance into routine radiation oncology practice.
2
Study Objectives
Primary Objective
The primary endpoint of the study will be 2 year overall survival.  The primary objective 
will be to test the superiority of 2yr OS in the FLARE RT patient cohort over the 60 Gy 
cohort of RTOG 0617 (57% 2yr OS) for historical control. Based on an estimated 
improvement to 72% 2yr OS, we will enroll at least 49 patients to test for superiority of 
FLARE RT at 80% power and 5% Type I error. 
Secondary Objective

CTCAE v4 grade 2 or higher pneumonitis incidence from FLARE RT compared 
to historical controls (non-inferiority test)

1 yr local control, progression-free survival, and pulmonary function test decline

Identification of baseline FDG PET/CT and mid-treatment FDG PET/CT imaging 
biomarkers for predicting patient survival

Identification of baseline perfusion SPECT/CT imaging biomarkers for predicting 
G2+ pneumonitis and PFT decline

Collection of plasma and urine samples for future correlative studies between 
imaging biomarkers and cytokine biomarkers of radiation response in both tumor 
and normal tissue
3
Study Design
3.1General Design
This is a phase II study that will deliver personalized radiation treatment plans by 
combining differential tumor dose escalation based on residual tumor SUV of mid-
treatment FDG-PET/CT in select patients classified as early FDG PET non-responders, 
and functional pulmonary avoidance based on perfusion SPECT/CT.  The long-term 
goal is to improve patient survival without increasing toxicity of treatment.  
Trial schema is shown below in Figure 1. All patients will undergo imaging at 3 time 
points: 1) baseline FDG PET/CT and SPECT/CT for tumor imaging and functional lung 
avoidance treatment planning; 2) mid-radiation treatment (24 Gy nominal) FDG PET/CT 
to assess tumor response to therapy; 3) 3 months post-radiation FDG PET/CT and 
SPECT/CT, to assess cancer response to treatment and functional lung tissue 
response.  Based on tumor response at the mid-treatment PET/CT, patients will either 
be classified as responders (receive 60 Gy per standard of care with functional lung 
avoidance), or non-responders (dose escalation to 74 Gy while keeping overall 
treatment constant at 30 fractions and avoiding functional lung). Follow up of all patients 
will also include standard of care evaluations (see Table 1 for study calendar).
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Figure 1. Clinical trial schema for FLARE RT.
Table 1. Study Calendar
Pre-screen
Baseline
Mid-RT
3-Months 
Post-RT
1-year Post-
RT
Prior to RT 
Start
20-30 Gy
2-4 mo.
9-18 mo.
Informed Consent
X
Medical History
X
X
X
Physical Exam
X
X
X
X
ECOG Performance 
Status 
X
X
X
X
Lab Work***
X
Pulmonary Function 
Tests (PFTs) including 
FEV1
X
X
X
Brain CT or MRI
X
18F-FDG PET/CT Scan#
X
Xa
Xc
X
SPECT/CT with 99mTc-
MAA and 99mTc-
SULFUR COLLOID# 
performed at UWMC
Xb
*b
Xb
Blood and urine 
collection for future 
correlative studies
X**
X**
X**
X  Required for study
*   Optional for study
** Optional but highly encouraged 
***CBC with absolute neutrophil count and platelet count; Serum chemistries include BUN, creatinine, 
sodium, potassium, bicarbonate, chloride, glucose, total
protein, total bilirubin, AST, ALT, alkaline phosphatase, and albumin
# Scans should ideally be performed in the treatment position with treatment immobilization
a Baseline PET/CT scans will be done as part of routine clinical care for lung cancer staging and radiation 
treatment planning. For patients whose clinical scans are >1 month old or do not meet research scan 
quality standards, a repeat research PET/CT will be done around the time of simulation, which will be 
paid for by the study.
b All SPECT/CT scans performed will be paid for by the study.
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c Mid-Treatment PET/CT performed will be paid for by the study. Ideally, mid-RT PET/CT to be performed 
between treatment fraction #12 and #13 (~24 Gy). 
3.2. Statistical Plan
The primary endpoint of the study will be 2-year overall survival (OS). The primary 
objective will be to test the superiority of the 2-year overall survival rate in patients 
enrolled on the FLARE RT trial compared to the 60 Gy cohort of RTOG 0617 (57% 2yr 
OS) for historical control (11). RTOG 0617 was a randomized phase III trial for patients 
with unresectable non-small cell lung cancer (NSCLC), testing two radiation doses (60 
Gy versus 74 Gy), and addition of cetixumab to standard chemoradiation. Results of 
RTOG 0617 established the current standard of care for NSCLC: concurrent 
chemoradiation to 60 Gy.
The expected 2yr OS and effect size of FLARE RT was derived from a weighted 
average of mid-treatment FDG PET responders (2 yr. OS = 92%, 41% of patient 
population) and non-responders (2 yr. OS = 33%, 59% of patient population) identified 
in a prospective patient series with 2 yr. OS rate (56%) in strong agreement with the 60 
Gy cohort of RTOG 0617 (23).  Based on data from a dose escalation meta-analysis 
(10) and the University of Michigan experience tumor dose escalation to 74 Gy in non-
responders are expected to produce 4% relative improvement in overall survival per Gy 
(3). Combined with functional lung avoidance to reduce mean perfused lung dose from 
20 Gy to 10 Gy and risk of clinical grade radiation pneumonitis, we predict a 72% 2yr 
OS in patients receiving FLARE RT.
The FLARE RT trial features a non-randomized design that selectively assigns patients 
to one of two arms based on early treatment response assessment on FDG PET/CT. In 
order to assess whether this selection strategy leads to superior 2yr OS compared to 
the historical control, we will perform a one sample proportionality test using all patients 
who complete either FLARE RT treatment arm (standard dose arm in responders + 
dose escalation arm in non-responders). In our cohort of at least 49 patients, the test is 
expected to detect a 2yr OS rate improvement relative to historical control from 57% to 
72%, under assumptions of 5% Type I error rate (α=0.05), 80% power (β=0.20), and 1% 
margin of superiority (δ=0.01).
Secondary objectives will feature a non-inferiority proportionality test of pulmonary 
toxicity incidence, defined as CTCAE v4 grade 2 or higher pneumonitis, between 
patients receiving FLARE RT and historical rates. Interim and final statistical analyses of 
the clinical endpoints (local control, progression-free survival, overall survival) will 
consist of Kaplan-Meier estimation and Cox proportional hazard regression. We will not 
conduct formal subset analyses due to insufficient statistical power. However, we will 
assess the relative strengths of hazard ratio estimates (and 95% confidence intervals) 
from a few predictors, including pre-treatment and mid-treatment imaging metrics 
extracted from PET/CT and SPECT/CT data. The degree of correlation amongst the 
variables will be evaluated. We will conduct linear regression of post-treatment lung 
perfusion SPECT/CT changes and decline in standard pulmonary function tests (FEV1, 
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DLCO, etc.). Lastly, we will perform ROC analysis to associate pre-treatment lung 
perfusion SPECT/CT parameters with dichotomous incidence of pneumonitis.
3.3. Eligibility 
Conditions for patient eligibility:

Pathologically proven (either histologic or cytologic) diagnosis of Stage IIB-IIIB non-
small cell lung cancer (NSCLC); according to AJCC Staging, 7th edition.  
o
Staging workup must include: brain imaging (CT head or MRI brain) and 
PET/CT.
o
Pleural effusions must have cytology to rule out malignant involvement unless 
too small to undergo thoracentesis per radiology

Patients must be considered unresectable or inoperable

Patient must not have received prior radiation for this lung cancer

Patients must be having concurrent chemotherapy

Nodal recurrences can be treated on this protocol but prior curative surgery for lung 
cancer must have been at least 6 months prior to the nodal recurrence.

Patients must have measurable or evaluable disease that is FDG avid with SUV>3 
on PET/CT

Zubrod Performance Status 0-1;

Age ≥ 18;

PFTs including FEV1 within 26 weeks prior to registration; for FEV1, the best value 
obtained pre- or post-bronchodilator must be ≥ 0.8 liters/second or ≥ 50% predicted.

CBC/differential obtained within 8 weeks prior to registration on study, with adequate 
bone marrow function defined as follows:
o
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
o
Platelets ≥ 100,000 cells/mm3;
o
Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 10.0 g/dl is acceptable.)

Serum creatinine within normal institutional limits or creatinine clearance ≥40 ml/min;

Bilirubin must be within or below normal institutional limits;

AST and ALT < 2.5 x the IULN;

Patient must sign study specific informed consent prior to study entry.
Conditions for patient ineligibility:

>10% unintentional weight loss within the past month

Prior invasive malignancy (except non-melanomatous skin cancer) unless disease 
free for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of 
the breast, oral cavity, or cervix are all permissible.

Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields;

Pregnancy or women of childbearing potential and men who are sexually active and 
not willing/able to use medically acceptable forms of contraception.
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4
Study Registration
Subjects will be registered by the FHCRC/UW Study Coordinator and entered into 
OnCore at seattlectms.org. A complete, signed, study consent and HIPAA consent are 
required for registration.
5
Radiation Therapy
5.1Dose Specifications
All patients will undergo treatment planning at initial simulation to 60 Gy at 2.0 Gy per 
fraction, using perfusion SPECT/CT to guide functional lung avoidance (details below).  
At 24 Gy (20-30 Gy acceptable), mid-treatment FDG PET/CT will be performed, and 
changes in tumor SUV and total lesion glycolysis (TLG) will be assessed to divide 
patients into metabolic responders and metabolic non-responders (details below).  
Patients classified as metabolic non-responders will receive dose escalation to 74 Gy, 
completed in 30 fractions (starting fraction 16, there will be hypofractionated dose 
escalation, dividing the additional 44 Gy into the remaining 15 fractions).
5.2Localization, simulation, and immobilization 

Volumetric treatment planning CT study will be required to define gross tumor 
volume (GTV), clinical target volume (CTV), and planning target volume (PTV) (see 
definitions below). Each patient will be positioned in an immobilization device in the 
treatment position on a flat table.

Contiguous CT slices, having 3 mm thickness through the regions harboring gross 
tumor and grossly enlarged lymph nodes and 8-10 mm thickness of the remaining 
regions are to be obtained starting from the level of the cricoid cartilage and 
extending inferiorly through the entire liver volume. The GTV, CTV, and PTV and 
normal organs will be outlined on all appropriate CT slices.

A treatment planning FDG PET/CT scan and SPECT/CT scan with the patient in the 
treatment position is strongly encouraged for treatment planning.

4-dimensional radiation treatment planning is required.
5.3Target Volumes

Definition of the GTV: The primary tumor and clinically positive lymph nodes seen 
either on the planning CT (> 1 cm short axis diameter) or pretreatment PET scan 
(SUV > 3) will constitute the GTV.

The ITV includes the envelope that encompasses the tumor motion for a complete 
respiratory cycle.

Definition of the CTV: The CTV is defined to be the ITV plus a 0.5 cm to 1 cm margin 
as appropriate to account for microscopic tumor extension. 

Definition of the PTV: PTV margin should account for setup uncertainties and may 
be individualized but should not be less than 0.5 cm with daily imaging guidance.

Definition of the metabolic tumor volume (MTV): the MTV is defined as the FDG PET 
avid volume for response assessment of total lesion glycolysis (TLG = 
SUVmean*MTV) between baseline and mid-treatment scans.
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5.4Critical Structures
Anatomic based clinical objectives will be prioritized first in treatment planning, to 
ensure that functional lung avoidance radiation treatment will be at least as safe as 
current standard of care (details on functional lung avoidance planning below).  

Definition of perfused lung-CTV: the structure is derived by applying a fixed 
threshold of 70% of maximum intensity on MAA SPECT/CT (rigidly aligned to the 
planning CT) within the lung-CTV structure
5.5Treatment Planning
Following the trial schema, we will deliver functional lung avoidance RT plans that meet 
pre-treatment functional lung objectives and PTV coverage. The treatment plans will be 
subsequently adapted to dose escalate after 3 weeks of RT based on a mid-treatment 
PET/CT (image after 24 Gy, between fraction 12-13 nominal) in select patients 
classified as FDG non-responders based on change in SUVmax (< 15% nominal) and 
total lesion glycolysis (< 15% nominal) reported from prior patient series with validation 
against local control and survival (23-24). FLARE RT plans will maintain 60 Gy base 
dose to the pre-treatment PTV, while delivering a concomitant boost to mid-treatment 
PTV (defined by 3 week PET/CT) during weeks 4-6 up to a total mean dose of 74 Gy in 
30 fx. The 14 Gy mid-treatment PTV boost will be distributed according to relative mid-
treatment FDG PET SUV. Patients who are classified as FDG responders (as defined 
above) at 3 weeks mid-RT will continue receiving functional lung avoidance RT to a total 
dose of 60 Gy, without plan adaptation.
The FLARE RT plans will be generated from unique FDG PET/CT and perfusion 
SPECT/CT objectives that redistribute dose at every image voxel away from functional 
lung regions and towards FDG-avid tumor regions. This combined differential avoidance 
[38] and differential tumor dose escalation [39-41] is a form of dose painting that creates 
continuous dose gradients rather than sharp dose gradients, which increases the 
robustness of FLARE RT to target motion and patient setup-induced uncertainties. In 
effect, the low spatial resolution PET and SPECT images acquired over many patient 
respiratory cycles define blurred targets and avoidance regions that help mitigate the 
effects of motion and risk of geographic miss during delivery of FLARE RT. 
Mathematically, FLARE RT objectives for FDG PET/CT-based dose escalation levels 
and MAA perfusion SPECT/CT-based dose avoidance levels are tabulated in the 
planning system as part of the cost function for plan optimization.   
All FLARE RT planning clinical goals are listed in Table 2.
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Table 2. FLARE RT adaptive planning objectives in select high local failure risk NSCLC 
patients classified as FDG PET non-responders. The composite dose of the functional 
avoidance RT plan administered in weeks 1-3 (15 fx) and the FLARE RT plan 
administered in weeks 4-6 (15 fx) would meet the following key objectives: (1) dose 
escalate residual FDG avid regions through linear dose redistribution at each FDG PET 
SUV-based dose level Li about 74 Gy mean dose to the mid-treatment PTV, (2) 
maintain perfused mean lung dose below 15 Gy, (3) redistribute each MAA perfusion 
SPECT uptake U-based dose level Li about 20 Gy mean dose to the anatomic lung. 
FLARE RT planning objectives will also include conventional dose-volume limits in 
accordance with standard clinical practice to heart, esophagus, spinal cord, etc. With 
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the exception of the mid-treatment PTV boost objectives, the same objectives will be 
applied to all remaining structures for patients selected to the functional lung avoidance 
arm (no dose escalation). All dosimetric objectives refer to radiation dose in units of 
Gray for photon therapy and Cobalt Gray Equivalent (CGE) for particle therapy. 
5.6Radiation Quality Assurance Reviews 
All patients treated on this protocol will undergo standard review in the Department of 
Radiation Oncology.  At least two physicians will review the patient history, imaging 
findings, tumor contours, and radiation plan.  
5.7 Radiation Toxicity
Toxicity will be graded based on CTCAE 4.0.  Grade 3 and higher AE’s will be recorded 
as well as AE’s that require a treatment interruption.  One exception is pulmonary AE’s 
which will be recorded at Grade 2 and higher.  In accordance with institutional policy, all 
adverse events which in the opinion of the principal investigator are unexpected and 
related or possibly related to the research and serious or suggest that the research 
places research participants or others at greater risk of physical or psychological harm 
than was previously known or recognized be reported to the IRB within 10 calendar 
days of learning of the problem.
5.8 Criteria for Removal/Withdrawal from Treatment
Patients will be withdrawn from treatment if their clinical conditions decline so they are 
no longer able to tolerate x-ray / proton radiation, or are unlikely to clinically benefit from 
further therapy.
Patients will still receive follow up care per standard of care even if they withdraw from 
the study.  If a subject withdraws consent to participate in the study or aspects of the 
study, attempts will be made to obtain permission to record at least survival data up to 6 
months post-treatment.  
6
Systemic Therapy
All patients must receive cytotoxic (not targeted agents) systemic therapy concurrent 
with radiation, but exact agent and dosing are at discretion of medical oncology.  
7
Data and Safety Monitoring Plan
Institutional support of trial monitoring will be in accordance with the FHCRC/University 
of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under 
the provisions of this plan, FHCRC Clinical Research Support coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or 
FHCRC employees unaffiliated with the conduct of the study.  Independent monitoring 
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visits occur at specified intervals determined by the assessed risk level of the study and 
the findings of previous visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by the Consortium 
Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/University of Washington Cancer Consortium Institutional 
Review Board (IRB).  The review committees evaluate accrual, adverse events, 
stopping rules, and adherence to the applicable data and safety monitoring plan for 
studies actively enrolling or treating patients.  The IRB reviews the study progress and 
safety information to assess continued acceptability of the risk-benefit ratio for human 
under the provisions of the DSMB, the Cancer Consortium Clinical Trial Support Office 
subjects.  Approval of committees as applicable is necessary to continue the study.
The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines.
7.1Early Stopping Rules
Early stopping of this trial will be any grade 5 adverse events (AEs) occurring within ≤ 
30 days after the end of treatment defined as possibly, probably, or definitely related to 
treatment (per CTCAE, v.4.0).  All AEs will be immediately monitored and reviewed by 
PI.  
7.2Interim Data Review
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented or published. In general, the interim reports will 
contain the following information:

Patient accrual rate with a projected completion date (while the study is still 
accruing)

Total patients accrued

Frequencies and severity of adverse events 

Compliance rates of treatment delivery
8
Data Management/Confidentiality 
The investigator will ensure that data collected conform to all established guidelines. 
Each subject is assigned a unique patient number to assure subject confidentiality. 
Subjects will not be referred to by this number, by name, or by any other individual 
identifier in any publication or external presentation. The licensed medical records 
department, affiliated with the institution where the subject receives medical care, 
maintains all original inpatient and outpatient chart documents.
Subject research files are stored in a secure place (or database). Access is restricted to 
authorized personnel.
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