Pulmonary Functional Imaging for Radiation Treatment Planning
Phase: NA
Conditions: Lung Carcinoma, Malignant Neoplasm
Sponsor: University of Washington

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UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version: 10/31/2013 
 
Title of Protocol: 
Pulmonary Functional Imaging for Radiation Treatment Planning for Lung Cancer 
 
 
 
Principal Investigator: 
Jing Zeng, MD 
 
Assistant Professor 
Department of Radiation Oncology 
206-598-4100 
Co-Investigator List: 
Adam M. Alessio, PhD 
 
Associate Professor 
Department of Radiology 
206-543-2419 
Stephen R. Bowen, PhD 
 
Assistant Professor 
Department of Radiation Oncology & Radiology 
206-598-1128   
Robert S. Miyaoka, PhD 
 
Associate Professor 
Department of Radiology 
206-598-2084 
Matthew J. Nyflot, PhD 
 
Acting Instructor 
Department of Radiation Oncology 
206-598-6657 
Shilpen A. Patel, MD 
 
Associate Professor 
Department of Radiation Oncology 
206-598-4100 
Ramesh Rengan, MD, PhD 
 
Associate Professor 
Department of Radiation Oncology 
206-598-4100 
Lauren Toney, MD 
 
Resident 
Department of Radiology 
206-543-3320 
Hubert Vesselle, MD, PhD 
 
Professor  
Department of Radiology 
Director, Division of Nuclear Medicine 
206-616-5781 
Research Staff: 
Jennifer Revall 
 
Research Coordinator 
206-598-8629 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION 
3 
 
 
2.0 
BACKGROUND 
 
2.1 
Study Disease 
3 
2.2 
Rationale for Use of SPECT/CT 99mTc-MAA and 99mTc-DTPA Scans 
 
2.3 
Clinical Data to Date 
 
2.4 
Risks/Benefits 
 
 
 
3.0 
STUDY OBJECTIVES 
5 
3.1 
Primary Objectives  
 
3.2 
Secondary Objectives 
 
3.3  Exploratory Objectives 
 
 
 
4.0 
STUDY DESIGN 
6 
4.1 
General Design 
 
4.2 
Endpoints 
 
 
 
5.0 
SUBJECT SLECTION 
7 
5.1 
Inclusion Criteria 
 
5.2 
Exclusion Criteria 
 
5.3  Recruitment 
 
 
 
6.0 
SUBJECT REGISTRATION 
8 
 
 
7.0 
TREATMENT PLAN/STUDY CALENDAR 
8 
7.1 
Imaging Protocol 
7.2 
Criteria for Removal/Withdrawal from Study 
 
 
8.0 
DATA AND SAFETY MONITORING PLAN 
10 
 
 
9.0 
DATA MANAGEMENT/CONFIDENTIALITY 
10 
 
 
REFERENCES 
10 
 

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1.0 INTRODUCTION 
 
Title 
Pulmonary Functional Imaging for Radiation Treatment Planning for 
Lung Cancer  
Short Title 
SPECT/CT for Radiation in Lung Cancer 
Phase 
Pilot Study 
Methodology 
Single Arm Open-Label  
Study Duration 
2 years  
Study Center(s) 
University of Washington Medical Center  
Objectives 
To utilize SPECT/CT imaging with 99mTc-MAA and 99mTc-DTPA to 
accurately identify functional lung in patients receiving radiation 
treatment for lung cancer, and characterize tissue response to radiation. 
The long-term goal being to use functional imaging to guide radiation 
treatment planning, so functional lung tissue can be preferentially 
avoided, which will reduce radiation induced pulmonary toxicity 
allowing for increased dose delivery to the primary tumor. 
Number of Subjects 
20 evaluable subjects 
Diagnosis and Main 
Inclusion Criteria 
Patients diagnosed with non-metastatic lung cancers receiving radiation 
treatment, with impaired pulmonary function 
Study Product, Dose, 
Route, Regimen 
99mTc-MAA and 99mTc-DTPA SPECT/CT scans 
Duration of 
administration 
Drug administration will consist of 3 SPECT/CT scans with 99mTc-MAA 
and 99mTc-DTPA (one baseline scan which is standard of care, two 
follow up scans which are experimental and paid for by departmental 
research funds).  The two experimental scans will be at mid-radiation 
treatment and approximately 3 months post-treatment. 
Statistical 
Methodology 
Outside the radiation field, normal lung tissue ventilation and perfusion 
over serial imaging will be assessed for stability using regression 
analysis, Pearson correlation, and Dice coefficient. Inside the radiation 
field, dose response curves will be developed for radiation dose versus 
changes in ventilation and perfusion. Gradient search algorithm in MIM 
6.0. will be used to identify perfused and ventilated lung.    
 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international regulations, applicable government regulations and Institutional research policies and 
procedures.  
 
2.0 BACKGROUND 
 
2.1 Study Disease 
 
Lung cancer is the most common cause of cancer related mortality in the US.  Radiation therapy 
is a main treatment modality for lung cancer: for resectable tumors, radiation can be given pre-
operatively or post-operatively to improve local tumor control and outcomes; for unresectable tumors, 
radiation can be given as definitive treatment for the cancer, either alone or in combination with 
chemotherapy.   
 

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Local recurrence remains a main cause of treatment failure in lung cancer.  For stage III lung 
cancer treated with definitive chemoradiation, local failure rates range from 30% to 50% [1, 2].  
Escalating radiation dose is one approach that may improve local control [3-5]. However, this approach 
has seen little success in recent dose escalation trials [6].  One potential limitation to radiation dose 
escalation is radiation induced toxicity.  In the thoracic region, pulmonary toxicity is one major source 
of dose limitation.  Many lung cancer patients are smokers and have poor baseline pulmonary function 
secondary to pulmonary co-morbidities, such as COPD.  Moderate to severe radiation induced 
pulmonary toxicity occurs in 10-20% of patients receiving definitive treatment to a therapeutic dose of 
60Gy and is fatal in 2-3% of these patients.[7]   
 
Due to the prevalence of tobacco use in the lung cancer population, a significant percentage of 
patients have underlying parenchymal lung disease, which frequently has heterogeneous involvement.  
Differences in perfusion and ventilation leads to regional variations in pulmonary function. Perfusion 
imaging is an established technique to identify functional and non-functional zones within normal lung 
and is routinely used to predict post-operative pulmonary function in patients planned for pulmonary 
resection [8]. Current radiation treatment planning treats the lung as a homogenously functioning organ 
and does not take regional variances in pulmonary function into account. Recent advances in radiation 
treatment planning and delivery, such as 3-D conformal radiation therapy and intensity modulated 
radiotherapy allow for preferential sparing of anatomic substructures in close proximity to the primary 
tumor.  Other radiation treatment modalities, such as proton radiation therapy, provide greater ability to 
carefully choose radiation beam path, to selectively avoid lung regions.  
  
2.2 Rationale for Use of SPECT/CT 99mTc-MAA and 99mTc-DTPA Scans  
 
SPECT imaging is a sensitive method of detecting regional lung function such as ventilation and 
perfusion.  Radiation has been shown to affect both lung ventilation and perfusion.  Data from Duke 
University and NKI using SPECT imaging have suggested a dose-response relationship between 
decrease in lung ventilation and perfusion and radiation dose delivered [9].  With more advanced 
imaging methods and the addition of CT scan to SPECT imaging, it is possible to improve contrast 
resolution relative to planar scintigraphy, and quantitative accuracy from attenuation correction [10, 11].  
By integrating SPECT/CT scans into the radiation planning process, it is also possible to obtain scans in 
the radiation treatment position, allowing for more accurate calculation of radiation dose and functional 
image intensity at the voxel scale, leading to more precise dose-response characterization.   
 
2.3 Clinical Data to Date 
 
SPECT/CT 99mTc-MAA and 99mTc-DTPA scans are both in use clinically for evaluating lung 
perfusion and ventilation, respectively.  A landmark study showed that intravenous 99mTc 
macroaggregates were shown to accurately predict functional loss (FEV 1) 3 months 
postpneumonectomy [12].  Radionuclide-labeled tracers for perfusion scanning remains the gold 
standard for predicting postoperative lung function [13].  The radiation oncology community has not 
adopted the use of functional imaging to aid in radiation planning.  The standard of care in radiation 
oncology is to treat all lung tissue as identical when calculating radiation dose and probability of 
complications.   
 
2.4 Risks/Benefits 
 
The only risk to patients in this study is the risk associated with the two additional SPECT/CT 99mTc-
MAA and 99mTc-DTPA scans.  The radiation treatment patients receive will be standard of care.  Risks 
associated with the two SPECT/CT 99mTc-MAA and 99mTc-DTPA scans include: patient time; radiation 
dose from radioactive tracers and scans (~ 30 mSv per session, which is about 0.1% of the usual 

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radiation dose for lung cancer treatment, typically around 60 Gy), and intravenous injection and 
potential for bleeding, pain, infection, and injection site reaction.  Please see consent form for further 
details on potential risks. 
 
The benefit gained from this study is the knowledge of whether SPECT/CT 99mTc-MAA and 99mTc-
DTPA scans can identify functional lung tissue that remains ventilated and perfused over time.  If we are 
able to reliably identify functional lung tissue, we can preferentially protect those lung regions from 
radiation, which can decrease radiation induced lung injury.  We will also learn about the effect of 
radiation on the spatial and temporal dynamics of lung ventilation and perfusion, which can better help 
us design radiation treatments to safely treat tumors while minimizing lung toxicity.   
 
3.0 STUDY OBJECTIVES 
 
3.1 Primary Objective 
 
To utilize SPECT/CT imaging with 99mTc-MAA and 99mTc-DTPA to identify functional lung on serial 
imaging in patients receiving radiation treatment for lung cancer, as well as to characterize 
reproducibility of perfusion and ventilation in non-irradiated lung tissue. 
 
Hypothesis:  For lung tissue outside the radiation field, perfusion and ventilation as defined by 
SPECT/CT imaging with 99mTc-MAA and 99mTc-DTPA will exhibit smaller changes over time than 
tissue inside the radiation field.  Compared to the pre-radiation scan, lung tissue receiving radiation dose 
below the 20th percentile of total lung will have perfusion and ventilation that remain constant or 
increase at the mid-radiation treatment scan and 3-months post-treatment scans.  By contrast, lung tissue 
receiving radiation dose above the 80th percentile of total lung will have perfusion and ventilation that 
decrease at the mid-radiation treatment scans and 3-months post-treatment scans. 
 
3.2 Secondary Objective 
 
a) To estimate the dose response relationship on multiple spatial scales (global lung, regional lung, lung 
image voxel) between radiation dose and changes in lung ventilation and perfusion, both acutely (mid-
radiation treatment) and long term (3 months post-treatment), using SPECT/CT imaging with 99mTc-
MAA and 99mTc-DTPA. 
 
Hypothesis:  Compared to the current models of radiation dose response for lung tissue, using CT in 
addition to SPECT imaging acquired in the radiation treatment position, a more accurate regional dose 
response relationship between radiation dose and changes in lung function can be generated with 
superior volumetric and quantitative data.   
 
b) To estimate the degree of radiation response in lung tissue with varying levels of function (i.e. 
compare radiation dose response of well ventilated and well perfused tissue against lung tissue with poor 
perfusion and ventilation).  This may establish a threshold of lung tissue that would be “safe” to treat 
without significantly affecting lung function.  
 
Hypothesis: Well-perfused and ventilated lung tissue has a different radiation dose response curve than 
lung tissue that receives poor ventilation and perfusion (upper quartile versus lower quartile of perfused 
and ventilated tissue image intensity distributions). The dose-response relationship can be modeled 
either as a linear or sigmoid function.  
 
3.3 Exploratory Objective 

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To evaluate proton radiation therapy for functional lung sparing in lung cancer through treatment 
planning comparisons to conventional photon radiation therapy.  
 
Hypothesis:  Unique physical characteristics of proton radiation allow for fewer external radiation beam 
pathways through normal tissue to achieve similar tumor dose coverage with photon radiation, leading 
to superior functional lung sparing. 
 
4.0 STUDY DESIGN 
 
4.1 General Design 
 
This is a pilot study of utilizing SPECT/CT imaging with 99mTc-MAA and 99mTc-DTPA to 
accurately identify functional lung tissue on serial imaging in patients receiving radiation treatment for 
lung cancer. The long-term goal being to use functional imaging to help with radiation planning, which 
can preferentially spare functional lung tissue, leading to reduced pulmonary toxicity.  Conversely, this 
has the potential for allowing increased radiation dose to the tumor while keeping normal tissue dose the 
same as conventional photon radiation therapy. 
 
Patients will have a total of 3 SPECT/CT imaging with 99mTc-MAA and 99mTc-DTPA.  The first 
scan will be routine medical care (not experimental) and will take place prior to initiation of radiation 
treatment.  Two follow up scans will be part of the protocol, one at mid-radiation treatment, and one 
about 3 months post-radiation treatment. 
 
4.2 Endpoints 
 
4.2.1 Primary Endpoint 
 
In this study, patients with lung cancer will undergo SPECT/CT imaging with 99mTc-MAA and 
99mTc-DTPA at the time of radiation treatment planning. All image datasets will be imported into MIM 
6.0, and fused with the radiation treatment planning CT and radiation plan.  Lung tissue will be divided 
into tissue outside the radiation field (dose < 20th percentile of total lung dose) and tissue inside the 
radiation field (dose > 80th percentile of total lung dose).  This process will be repeated for the mid-
treatment scan and 3 months post-treatment scan.  Lung tissue outside the radiation field will be 
compared on serial scans and their perfusion and ventilation quantified.  There should be insignificant 
changes in perfusion and ventilation in >80% of lung tissue outside the radiation field. Lung tissue 
inside the radiation field will also be compared, and should yield significant differences in ventilation 
and perfusion between pre, mid, and post-treatment scans. 
 
We will analyze the perfusion and ventilation data through multiple methods.  Image sets from 
all 3 time points (before radiation, mid-radiation, 3-months post-radiation) will be fused using rigid 
registration.  Regions of interest within the lung will be defined using automated and semi-automated 
methods, including simple thresholds and gradient-search algorithms.  For each tracer, uptake value will 
be calculated for each voxel.  For lung tissue outside the radiation field, summary statistics such as total 
regional uptake and mean regional uptake by lobe will be compared across the time points using 
parametric and non-parametric statistical testing.  Voxel-based correlation, including Pearson linear and 
Spearman rank, will be performed to measure the stability of uptake between time points. Lastly, metrics 
of ventilation and perfusion volume overlap between time points will be estimated using the Dice 
coefficient.  
 
 

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4.2.2 Secondary Endpoint 
 
For the second aims (a) and (b) looking at lung tissue inside the radiation field, the images will 
be process similar to primary endpoint. For lung tissue inside the radiation field, changes in tracer 
uptake at the global lung, regional lung, and lung image voxel scales (compared to baseline scan) will be 
plotted against the radiation dose at the same scales to generate multiscale radiation dose response 
curves.  These curves will be fit to linear and sigmoid dose-response functions. We will also separate out 
lung regions in the upper quartile and lower quartile of ventilation and perfusion, and generate separate 
radiation dose response curves per region, to assess for potential differences in radiation dose response 
of functional lung versus non-functional lung.   
 
4.2.3 Exploratory Endpoint 
 
 
Comparison planning with proton radiation will also be performed, to explore whether superior 
functional lung sparing can be achieved with proton radiation, compared with conventional photon 
radiation therapy.  Two planning paradigms will be utilized: (1) fixed tumor dose objectives and 
comparison of normal tissue dose sparing, (2) fixed normal tissue objectives and comparison of tumor 
dose escalation. 
 
 
5.0 SUBJECT SELECTION 
 
5.1 Inclusion Criteria  
 
5.1.1 Lung cancer patients receiving radiation treatment to the thorax to at least 45 Gy.  Both non-
small cell and small cell patients are eligible.  Patient must have pathologic confirmation of 
diagnosis, or have an enlarging lung mass on at least two scans spaced 3 months apart, and FDG 
avidity on PET scan.   
 
5.1.2 All stages of lung cancer are eligible, but patients must be planned for at least 45 Gy of radiation. 
 
5.1.3 Patients are not required to have measurable disease.  Post-operative patients (patients who have 
had surgical resection of lung cancer) are eligible.   
 
5.1.4 Patients must have pulmonary function as defined below: 
5.1.4.1 Abnormal pulmonary function test within 3 months of study entry 
5.1.4.2  Prior radiation to the lungs 
5.1.4.3 Prior surgical resection of lung tissue (i.e. wedge resection, lobectomy, or 
pneumonectomy) 
5.1.4.4 Clinical diagnosis of COPD or emphysema 
5.1.4.5 Ongoing oxygen use 
 
5.1.5 There are no limits on prior therapy.  Patients are allowed to have prior chemotherapy, radiation 
therapy, and surgery.  Patients are allowed to have concurrent chemotherapy with radiation 
treatment.  Patients are allowed to have chemotherapy after radiation treatment.  Patients are not 
allowed to have planned lung resection after radiation.   
 
5.1.6 Patients >18 years old.   
 
5.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 

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5.1.8 Patients will typically be enrolled on this trial prior to beginning the radiation treatment course.  
However, if a patient has had a SPECT/CT 99mTc-MAA and 99mTc-DTPA scan as part of routine 
medical care within 6 weeks prior to initiation of radiation treatment, he/she is eligible for trial 
enrollment up to the last day of the radiation treatment course. 
 
5.2 Exclusion Criteria 
 
5.2.1 Patients must not be planned for lung resection after radiation therapy.   
 
5.2.2 Patients receiving < 45 Gy radiation.  
 
5.2.3 Patients who received radiation to the chest within the past 6 months.  
 
5.2.4 Patients unable to tolerate a SPECT/CT 99mTc-MAA and 99mTc-DTPA scan.   
 
5.2.5 Patients who are not planning to adhere to the required follow up schedule as outlined in this 
protocol.   
 
5.2.6 Pregnant women 
 
5.2.7 Women of childbearing potential and men who are sexually active and not willing/able to use 
medically acceptable forms of contraception. 
 
5.2.8 Patients unable to provide informed consent.   
 
5.3 Recruitment 
 
Subjects will be recruited from investigator clinical practices and include men and women with lung 
cancer who will be receiving radiotherapy to at least 45 Gy.  Subjects will undergo an informed consent 
process in accordance with GCP (see section 11 Ethical Considerations). Informed consent will be 
obtained prior to the performance of any screening procedures. 
 
6.0 SUBJECT REGISTRATION 
  
Subjects will be registered by the FHCRC/UW Study Coordinator and entered into the Protocol Accrual 
Tracking System (PATS). Information regarding the PATS system is available at 
http://www.cancerconsortiumorg/rto/protocol_office/pats/. A complete, signed, study consent and 
HIPAA consent are required for registration. 
 
 
7.0 TREATMENT PLAN 
 
All patients will receive radiation treatment per standard of care.  As part of this study, all patients will 
undergo 3 SPECT/CT scans: 1) first scan will be at the time of radiation treatment planning, in the 
treatment position.  This scan will be standard of care clinically for patients with compromised lung 
function (such as COPD); 2) second scan will be mid-radiation treatment (up to 1 week post-completion 
of radiation is acceptable), to assess the acute response of functional lung to radiation; 3) third scan will 
be 3 months post-radiation (up to 6 months is acceptable), to assess the longer term response of 
functional lung tissue.  Follow up of all patients will occur via standard clinical follow-up by treating 
physician. This clinical follow-up may include clinical exam, pulmonary function test (PFT), and FDG 
PET/CT scan. Research staff will review clinical record at 3 months post-treatment.  See Table 1 below 
for summary. 

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Table 1. Study Calendar. 
 
 
Screening 
Prior to Start of 
Radiation 
Treatment 
Mid-
Radiation 
Treatment 
3-Months Post-
Radiation 
Treatment End 
Informed Consent 
X* 
 
 
 
Physical Exam 
X 
 
X 
X 
Medical History 
X 
 
 
X 
Pulmonary Function 
Tests (PFTs) 
X 
 
 
X 
Serum Pregnancy 
Test** 
X 
 
 
 
FDG PET/CT Scan 
X*** 
 
 
X, X# 
SPECT/CT with 
99mTc-MAA and 
99mTc-DTPA  
 
X 
X* 
X* 
* Denotes a Research Procedure, all others are standard of care 
**For women of child bearing potential only 
***FDG PET/CT simulation scan preferred over CT simulation scan, but both are acceptable   
#CT scan only is also acceptable in the follow-up period 
 
7.1 Imaging Protocol 
 
SPECT/CT with 99mTc-MAA and 99mTc-DTPA will be performed per standard protocol, which is 
currently in routine clinical use.  The imaging session is comprised of an inhalation of the 99mTc-DTPA 
tracer and SPECT static acquisition, followed by intravenous injection of the 99mTc-MAA tracer and 
second SPECT static acquisition.  This rapid serial process ensures the efficient imaging of ventilation 
and perfusion in the same imaging session. An initial scan at the time of radiation planning will identify 
functional lung that is ventilated and perfused.  This scan will be in the radiation treatment position 
which can be fused precisely with the radiation treatment planning scan, and will be used to identify 
functional lung tissue both inside and outside the radiation fields.  Two follow up scans will track lung 
response to radiation (one scan at mid-treatment for acute radiation response, and one scan at 3-months 
post-treatment for longer term assessment).  Detailed ventilation and perfusion dose response curves will 
be generated from this data.  Comparison planning with proton radiation will be performed to evaluate 
the feasibility of improved functional lung sparing with proton beam radiation. 
 
7.2 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 SPECT/CT with 99mTc-MAA and 99mTc-DTPA.  They will be withdrawn from treatment if 
they are enrolled with hospice.   
 
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.   
 
 
 

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8.0 DATA AND SAFETY MONITORING PLAN 
 
Oversight for this study at UWMC will be provided by the Principal Investigator with delegation of 
appropriate responsibilities to sub-investigators and designated study personnel.  They will ensure all 
entry criteria are met prior to the initiation of the protocol and all study procedures and reporting of 
adverse events are performed according to the IRB-approved protocol.  
 
 
9.0 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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Cox, J.D., Are the results of RTOG 0617 mysterious? Int J Radiat Oncol Biol Phys, 2012. 82(3): p. 1042-4. 
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