Novel Lung Functional Imaging for Personalized Radiotherapy
Phase: NA
Conditions: Lung Cancer
Sponsor: University of California, Davis

Official Study Title:  
Novel Lung Functional Imaging for Personalized Radiotherapy 
ClinicalTrials.gov ID:  NCT02308709    
Secondary ID:  
CCRO030 
Protocol Version:  
Version 19: October 22, 2020 
 

Novel Lung Functional Imaging for Personalized Radiotherapy 
 
Protocol #:  
 
 
 
 
CCRO030 
 
Principal Investigator:                                    Tokihiro Yamamoto, Ph.D. 
 
Assistant Professor 
Department of Radiation Oncology 
UC Davis Comprehensive Cancer Center 
 
 
 
 
 
 
Co-Principal Investigator:                              Megan Daly, M.D. 
 
Assistant Professor 
Department of Radiation Oncology 
UC Davis Comprehensive Cancer Center 
 
 
 
 
 
Co-Investigators:                                           Stanley Benedict, Ph.D. 
 
Professor and Vice Chair of Clinical Physics 
Department of Radiation Oncology 
UC Davis Comprehensive Cancer Center 
Department of Radiation Oncology 
 
 
 
 
 
Ken Y. Yoneda, M.D. 
 
Professor of Clinical Internal Medicine 
Division of Pulmonary and Critical Care 
University of California Davis Medical Center 
 
 
 
Friedrich D. Knollmann, M.D., Ph.D. 
Professor of  Clinical Radiology 
Department of Radiology 
University of California Davis Medical Center 
 
  
  
 
Biostatistics:                                                   Lihong Qi, Ph.D. 
 
Associate Professor 
Department of Public Health Sciences 
University of California Davis 
 
 

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Protocol Version and Date:                           Version 19: October 22, 2020 
Version 18: March 11, 2019 
 
 
 
 
 
 
 
 

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Index 
Schema 
1. Introduction and Background Data 
2. Specific Objectives and Hypotheses 
3. Patient Selection 
4. Imaging Procedures 
5. Radiation Therapy 
6. Pulmonary Function Test, 6-min Walk Test, and BODE Index 
7. Adverse Event Reporting 
8. Data Review and Management 
9. Statistical Considerations 
10. Study Timelines 
11. Patient Assessments 
12. Ethical and Regulatory Considerations 
13. Data Safety and Monitoring 
14. Data Sharing 
15. Potential Benefits to Subjects 
16. Economic Burden to Subjects 
17. Sharing of Results with Subjects 
18. Devices 
References 
Appendix I: 
Zubrod Performance Status 
Appendix II:   Eligibility Checklist 
Appendix III:  Patient Assessments 
Appendix IV: Data Submission Schedule 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Simulation imaging 
1. Pre-treatment free-breathing CT 
2. Pre-treatment four-dimensional (4D) CT scan 
Personalized treatment planning 
4D CT ventilation image-guided optimization to 
preferentially spare functional lung regions 
4D CT ventilation image-guided radiotherapy delivery 
• 
Conventionally-fractionated radiotherapy (CFRT) or hypo-
fractionated stereotactic ablative radiotherapy (SABR) 
• 
Two mid-treatment free-breathing CT and 4D CT scans as 
correlative studies to assess dosimetric significance of 4D CT 
ventilation image-guided adaptive radiotherapy (CFRT only) 
Eligible Lung Cancer Patient 
↓ 
Follow-up 
↓ 
↓ 
↓ 

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Introduction and Background Data 
1.1. Overall survival of lung cancer patients treated with radiotherapy remains 
disappointing with substantial toxicity 
Lung cancer is the leading cause of cancer death in the US and worldwide.  In 2011, 
approximately 221,130 new cases of lung or bronchial cancer were expected to be diagnosed in 
the US, and 156,940 patients (71%) are estimated to die of this disease (Siegel et al., 2011).  
Approximately 64% of non-small-cell lung cancer (NSCLC) patients and 54% of small-cell lung 
cancer (SCLC) patients will require radiotherapy at least once (Tyldesley et al., 2001).  
Stereotactic body radiotherapy (SBRT) has provided excellent clinical outcomes for early stage 
NSCLC, e.g., three-year local control, 98%; three-year survival, 56% in the Radiation Therapy 
Oncology Group (RTOG) 0236 trial (Timmerman et al., 2010).  For advanced stage NSCLC, 
however, Machtay et al. have recently reported a five-year survival rate of 15% for patients treated 
with chemoradiotherapy from seven RTOG trials (Machtay et al., 2012).  The maximum tolerated 
dose is limited by the risk of toxicity, especially for advanced disease.  For example, an attempt 
to escalate the prescribed dose in the early Phase I portion of RTOG 0117 was unsuccessful 
because of severe toxicity, including Grade 3 and 5 radiation pneumonitis (Bradley et al., 2005b).  
Radiation pneumonitis is a common, potentially fatal toxicity that occurs in 5-30% of lung cancer 
patients treated with radiotherapy (Marks et al., 2010; Palma et al., 2013). 
 
1.2. Personalized radiotherapy that avoids high-functional lung regions may reduce 
toxicity and facilitate safe investigations designed to improve tumor control 
To address the critical problem described above, we propose a novel paradigm, i.e., functional 
image-guided personalized radiotherapy that avoids high-functional lung regions.  It may reduce 
toxicity and facilitate safe investigations designed to improve tumor control.  This hypothesis is 
supported by several findings in the literature.  Abratt et al. have found that patients whose 
irradiated lung regions had >35% of the total lung perfusion are significantly more likely to manifest 
post-treatment decreases in diffusing capacity and worsening of dyspnea score (Abratt et al., 1990).  
Seppenwoolde et al. (Seppenwoolde et al., 2004) and Vinogradskiy et al. (Vinogradskiy et al., 2013) 
have demonstrated better correlations between the function-weighted lung dose and pneumonitis 
than those between the physical lung dose and pneumonitis. 
 
1.3. Novel lung ventilation imaging based on 4D CT has high translational potential and 
advantages 
4D CT ventilation imaging is a novel promising technique (Guerrero et al., 2005) (Figure 1) that 
has high translational potential and advantages (e.g., higher resolution, lower cost, and/or greater 
availability) over competing modalities.  Thus, there has been growing interest in using this 
technology for functional avoidance treatment planning (Yaremko et al., 2007; Yamamoto et al., 
2011) and treatment/toxicity assessment (Ding et al., 2010; Vinogradskiy et al., 2012).  Animal 
studies have demonstrated high accuracy, e.g., correlation with xenon (Xe)-CT ventilation as 
reference (Fuld et al., 2008; Reinhardt et al., 2008; Ding et al., 2012) as well as high reproducibility 
(Du et al., 2012).  Human studies have reported relatively inconsistent results (Castillo et al., 
2010; Castillo et al., 2012; Du et al., 2012; Mathew et al., 2012; Yamamoto et al., 2012; Yamamoto 
et al., 2014), but reasonable correlations with PFT parameters (Yamamoto et al., 2014), SPECT 
ventilation (Yamamoto et al., 2014), hyperpolarized 3He MR ventilation (Mathew et al., 2012) and 
SPECT perfusion (Castillo et al., 2012) indicate the potential for 4D CT ventilation imaging to have 
physiological significance. 

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Figure 1. Schematic diagram for 4D CT ventilation imaging through (1) acquisition of 4D CT scans, (2) spatial mapping 
of different respiratory phases of 4D CT images using DIR, deriving a displacement vector field, and (3) analysis of the 
resultant displacement vector field to quantify regional volume change, a surrogate for ventilation. 
 
1.4. We propose a novel paradigm, 4D CT ventilation image-guided personalized 
radiotherapy to improve therapeutic gains 
Many investigators have demonstrated a dosimetric benefit of functional image-guided 
radiotherapy that avoids high-functional lung regions using various modalities, including SPECT 
perfusion (Marks et al., 1995), hyperpolarized gas magnetic resonance (MR) ventilation (Ireland 
et al., 2007) and 4D CT ventilation (Yaremko et al., 2007; Yamamoto et al., 2011).  We have 
demonstrated that 4D CT ventilation image-guided radiotherapy planning reduces the mean dose 
to high-functional lung regions by 2 Gy on average compared to anatomic image-guided planning 
(Yamamoto et al., 2011), indicating that 4D CT ventilation image-guided radiotherapy is estimated 
to reduce pneumonitis by 4%, corresponding to over 5,000 patients/year in the US, based on the 
fact that about 60% (Tyldesley et al., 2001) of 221,130 new lung cancer patients (Siegel et al., 2011) 
are treated with radiotherapy.  It is assumed that the probability of pneumonitis increases with the 
mean dose to high-functional lung regions in a similar manner to the published data on the mean 
dose to the total lung (Marks et al., 2010).  There have been no attempts to assess the 
safety/feasibility or clinical significance of such treatment in human subjects.  In this clinical trial, 
we will assess the safety and feasibility of 4D CT ventilation image-guided personalized 
radiotherapy.  We will deliver personalized radiotherapy treatments for lung cancer patients, and 
follow up patients to assess the safety and feasibility.  The hypothesis to be tested is: 4D CT 
ventilation image-guided personalized radiotherapy can be delivered safely for lung cancer. 
 
2. Specific Objectives and Hypotheses 
2.1. 
Primary objective and hypothesis 
Objective: Assess the safety and feasibility of 4D CT ventilation image-guided personalized 
radiotherapy that selectively avoids irradiating highly-functional lung regions for lung cancer. 
Hypothesis: 4D CT ventilation image-guided personalized radiotherapy can be delivered safely 
for lung cancer. 
 
2.2. 
Secondary objectives 
1) Assess long-term toxicity from 4D CT ventilation image-guided personalized radiotherapy as 
scored by the NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
2) Estimate the clinical significance of 4D CT ventilation image-guided personalized radiotherapy 
by evaluating: (1) clinical and subclinical endpoints for pulmonary toxicity (including 
symptomatic radiation pneumonitis and post-treatment changes in pulmonary function tests 
(PFTs), 6-min walk test, and BODE index); (2) correlation between those endpoints and 
functional dose-volume parameters. 
3) Assess local tumor control after 4D CT ventilation image-guided personalized radiotherapy. 
4) Quantify the dosimetric significance of 4D CT ventilation image-guided adaptive radiotherapy. 
4D CT scan
Displacement 
vector field
Deformable image 
registration (DIR)
Quantitative 
analysis
Ventilation image
Phase

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5) Investigate whether in vivo EPID dosimetry can detect clinically significant anatomic changes 
for patients treated with CFRT. 
 
3. Patient Selection 
3.1. 
Inclusion criteria 
1) Primary lung cancer or metastatic disease to the lungs to be treated with either conventionally-
fractionated radiotherapy (CFRT) or hypo-fractionated stereotactic ablative radiotherapy 
(SABR). 
2) Age restriction and/or gender/ethnic restrictions: Patients must be ≥18 years of age.  There 
are no gender or ethnic restrictions. 
3) Concurrent chemotherapy is allowed, but not required. 
4) Life expectancy with treatment should be ≥6 months in the estimation of the treating 
physicians. 
5) Zubrod performance status ≤2 
6) Adequate marrow and hepatic function defined as Hgb ≥8; platelets ≥100k; ANC≥1500; LFTs 
≤2x upper limit of normal and creatinine ≤2.0 or creatinine clearance of ≥40 
7) Patient must be able to provide study specific informed consent prior to study entry. 
 
3.2. 
Exclusion criteria 
1) Prior radiotherapy for thoracic cancer or other malignancy leading to any overlap of planned 
radiotherapy fields. 
2) For patients undergoing definitive CFRT, patients with distant metastatic disease are not 
eligible. 
3) For patients undergoing SABR, both early stage primary lung cancer patients and those with 
limited metastatic disease to the lungs are eligible; however, patients with oligometastatic 
disease should have a controlled primary and no more than one other involved organ system. 
4) Children (<18 years of age), pregnant women, University of California employees and 
students, and prisoners will be excluded from this study. 
5) We will carefully consider the inclusion of patients with severe artifacts in 4D CT images, 
which deteriorate the accuracy of ventilation computation. 
 
4. Imaging Procedures 
4.1. 
Scans to be acquired  
Patients will be positioned in the supine position on a flat tabletop with immobilization (a 
customized thermoplastic immobilization cast or a molded foam cradle for stabilization for CFRT; 
a stereotactic body frame or BodyFIX system for SABR).  Abdominal compression will be used 
for all SABR patients unless tumor motion <1 cm can be reliably demonstrated by fluoroscopy 
and confirmed by 4D CT without compression.  The following scans will be obtained:  
Simulation imaging 
1) Free-breathing CT extending from the angle of the mandible cranially to the inferior extent 
of the liver caudally at a slice thickness of ≤3 mm for CFRT and ≤2 mm for SABR.  IV 
contrast to assist in delineation of the mediastinal nodal regions is permitted but not 
required. 
2) Pre-treatment 4D CT scan to include lungs from apices to diaphragm and full disease 
extent. 
3) If abdominal compression is used, an additional 4D CT scan will be acquired without 
abdominal compression. 
During a course of treatment (CFRT only) 

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1) Two mid-treatment free-breathing CT scans performed at 16-20 Gy and 30-34 Gy to 
include lungs from apices to diaphragm and full disease extent based on the same method 
as simulation. 
2) Two mid-treatment 4D CT scans performed with the mid-treatment free-breathing CT 
scans to include lungs from apices to diaphragm and full disease extent. 
 
4.2. 
4D CT ventilation computation 
4D CT ventilation images at the peak-inhale phase will be created using a software tool developed 
and provided by a collaborator, Dr. Kabus at Philips Research.  This software has not received 
regulatory clearance.  This tool loads anonymized 4D CT images acquired at UC Davis as input, 
and provides ventilation images calculated based on a non-parametric/volumetric DIR algorithm 
(Staring et al., 2010) and two classes of ventilation metric: Hounsfield unit (HU)-change (Simon, 
2000; Fuld et al., 2008) and Jacobian (Reinhardt et al., 2008) as output. 
 
5. Radiation Therapy 
5.1. 
Dose specifications 
CFRT 
Patients undergoing CFRT will receive a total of 60 Gy in 30 fractions.  The plan will be normalized 
such that ≥95% of the PTV receives the prescription dose.  Minimum dose to the PTV (defined 
as the dose to the lowest 0.03 cc) must be ≥90% of the prescription dose (≥85% will be scored 
as a minor deviation) and maximum dose must be ≤115% of the prescription dose to ≤0.03 cc 
(≤120% will be scored as a minor deviation). 
 
SABR 
Patients undergoing SABR will receive a total of 54 Gy in 3 fractions for peripheral tumors or 55 
Gy in 5 fractions for centrally located tumors (defined as within 2 cm of the proximal bronchial tree 
or PTV touching mediastinal structures or pleura; tumors with significant chest wall overlap of 
PTV can also be treated over 5 fractions at treating physician discretion). The prescription isodose 
surface will be chosen such that 95% of the target volume (PTV) is conformally covered by the 
prescription isodose surface and 99% of the target volume (PTV) receives a minimum of 90% of 
the prescription dose.  
5.2. 
Technical parameters 
Radiotherapy will be delivered by intensity-modulated radiotherapy (IMRT) or volumetric 
modulated arc therapy (VMAT) with an Elekta linear accelerator at energies ≥6 MV.  The dose 
behind the patient, i.e., transmission dose images will be acquired with a linear accelerator-
mounted electronic portal imaging device (EPID).  The acquired data will be analyzed with a 
research version of the PerFRACTION software (Sun Nuclear, Melbourne, FL) (not FDA-
approved/cleared). 
 
5.3. 
Immobilization and simulation 
See section 4. 
 
5.4. 
Treatment planning 
Treatment plans will be created using a research version and a clinical version of the Pinnacle 
treatment planning system (Philips Radiation Oncology Systems, Fitchburg, WI).  The research 
version has not received regulatory clearance, whereas the clinical version has a FDA 510(k) 
clearance and is routinely used for treatment planning in the Department of Radiation Oncology.  
First, the research version will be used to create an initial 4D CT ventilation image-guided 
treatment plan.  The initial plan will then be transferred to the clinical version for final dose 
calculation and evaluation by a radiation oncologist to ensure that the plan quality is clinically 
appropriate, i.e., target coverage is adequate and critical structures are spared as necessary. 
 
5.4.1. Target volumes 

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CFRT 
1) GTV: Will include visible tumor as identified by diagnostic and/or treatment planning CT 
or PET, including pathologically enlarged lymph nodes >1 cm in short axis, hypermetabolic 
by PET (SUV >3), or pathologically confirmed to contain malignant cells.  Elective 
treatment of nodal areas is not permitted. 
2) CTV: A CTV margin of 5-10 mm will be added at the discretion of the treating physician to 
account for potential microscopic spread.  This margin may be shaved off overlapping 
adjacent structures including chest wall, heart, esophagus, great vessels, and vertebral 
bodies. 
3) ITV: Will include the full range of tumor motion of the primary tumor and nodal target as 
delineated by 4D CT.  Depending upon tumor location, a maximum intensity projection or 
maximal inhale/exhale scans may be used to identify the ITV. 
4) PTV: An additional margin of 5-10 mm will be added to account for setup error. 
 
SABR 
1) GTV: Will include visible tumor as identified by diagnostic and/or treatment planning CT 
or PET. 
2) CTV: No additional margin for microscopic spread will be used.  For purposes of this 
protocol, ITV=CTV. 
3) ITV: Will include the full range of tumor motion of the primary tumor and nodal target as 
delineated by 4D CT.  Depending upon tumor location, a maximum intensity projection or 
maximal inhale/exhale scans may be used to identify the ITV. 
4) PTV: An additional margin of 5 mm will be added to account for setup error. 
 
5.4.2. Lungs 
We will create 4D CT ventilation image-guided personalized radiotherapy plans that selectively 
avoid irradiating highly-functional lung regions.  The peak-inhale 4D CT ventilation image will be 
aligned with the free-breathing CT image (primary image set for treatment planning) by rigid image 
registration.  The overlapped lungs between the free-breathing CT and peak-inhale 4D CT images 
will be contoured.  Note that the final total lung volume for dose-volume analysis will include 
combined right and left lungs, excluding the GTV, trachea, and main and lobar bronchi.  IMRT or 
VMAT optimization will be performed by setting higher weights to highly-functional lung regions 
than poorly-functional regions to meet the dose-volume constraints shown below. 
 
CFRT 
Tissue 
Constraints 
Lung (right and left 
minus CTV) 
V20 <37% (<40% will be scored as a minor deviation) 
Mean lung dose (MLD) <20 Gy (<21 Gy will be scored as a minor deviation) 
Functional V20 <30% (Vinogradskiy et al., 2013) (<33% will be scored as a minor 
deviation) 
Functional MLD <19 Gy (Vinogradskiy et al., 2013) (<20 Gy will be scored as a 
minor deviation) 
 
SABR 
Tissue 
3 fraction 
5 fraction 
Volume 
Vol Max 
Max to 
0.03 cc 
Volume 
Vol Max 
Max to 
0.03 cc 
Lung (right and left 
minus CTV) 
<1500 cc 
<1000 cc 
10.5 Gy* 
11.4 Gy* 
 
NA 
<1500 cc 
<1000 cc 
12.5 Gy* 
13.5 Gy* 
 
NA 
Functional V20 <4% (Barriger et al., 2012) (<7% will be scored as a minor 
deviation) 
Functional MLD <4 Gy (Barriger et al., 2012) (<5 Gy will be scored as a minor 
deviation) 

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*Constraints marked by asterisk are guidelines and will not be scored as a protocol deviation if not achieved.  
For SABR in patients with more than one target, the lung dose-function constraints (functional MLD and V20) 
are guidelines and will not be scored as a protocol deviation if not achieved. Other constraints represent 
absolute limits and treatment delivery that cannot meet these constraints will constitute a major 
protocol violation. 
 
5.4.3. Other critical structures 
The following other critical structures will be contoured on the free-breathing CT image for both 
CFRT and SABR patients. 
1) Spinal Cord: The spinal cord should be contoured on every axial CT slice as the bony 
limits of the spinal canal, extending from at least 10 cm superior to the superior-most 
extent of the PTV, and caudally 10 cm below the inferior-most extent of the PTV. 
2) Heart: The heart, along with the pericardial sac, should be contoured from its base to apex, 
beginning superiorly at the level of the inferior aspect of the aortic arch (aorto-pulmonary 
window) and extending inferiorly to the apex of the heart. 
3) Esophagus: The entire circumference of the esophagus including the outermost fatty 
dventitia should be contoured based on mediastinal windowing, and should be contoured 
on every axial CT slice at least 10 cm cranial and caudal to the PTV. 
4) Brachial Plexus: The right and left brachial plexi should be contoured separately.  The 
defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamina on the involved side from around C5 to T2.  However, for the purposes of 
this protocol, only the major trunks of the brachial plexus will be contoured using the 
subclavian and axillary vessels as a surrogate for identifying the location of the brachial 
plexus.  This neurovascular complex will be contoured starting proximally at the bifurcation 
of the brachiocephalic trunk into the jugular/subclavian veins (or carotid/subclavian 
arteries) and following along the route of the subclavian vein to the axillary vein ending 
after the neurovascular structures cross the second rib. 
5) Proximal bronchial tree: Should extend from 2 cm above the carina and include the right 
and left main bronchi, extending distally to the first bifurcation of the named bronchi. 
6) Trachea: Should include the tracheal and cartilage rings extending at least 10 cm superior 
to the superior extent of the PTV. 
7) Great Vessels: Should include the aorta, right and left pulmonary arteries, and superior 
vena cava at least 10 cm superior and inferior to PTV. 
8) Skin: The skin will be defined as a rind encompassing the outer 0.3 cm of the body surface. 
 
CFRT 
Tissue 
Max Dose to 
0.03 cc (Gy) 
Other Constraints 
Spinal cord 
47 Gy 
 
Esophagus 
70 Gy 
Mean <34 Gy* 
Brachial Plexus 
66 Gy* 
 
Heart/Pericardium 
70 Gy 
60 Gy to <33%; 45 Gy to <66% 
Great Vessels 
70 Gy* 
 
Trachea  
70 Gy 
 
Central Airways 
68 Gy 
 
 
SABR 
Tissue 
3 fraction 
5 fraction 
Volume 
Vol Max 
Max to 
0.03 cc 
Volume 
Vol Max 
Max to 
0.03 cc 
Spinal cord 
<0.35 cc 
18 Gy 
21.9 Gy 
<0.35 cc 
23 Gy 
30 Gy 
Esophagus 
<5 cc 
17.7 Gy* 
25.2 Gy 
<5 cc 
19.5 Gy 
35 Gy 
Brachial Plexus 
<3 cc 
20.4 Gy* 
24 Gy* 
<3 cc 
27 Gy* 
30.5 Gy* 

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Heart/Pericardium 
<15 cc 
24 Gy* 
30 Gy 
<15 cc 
32 Gy* 
38 Gy 
Great Vessels 
<10 cc 
39 Gy* 
45 Gy 
<10 cc 
47 Gy* 
53 Gy 
Trachea  
<4 cc 
15 Gy* 
30 Gy 
<4 cc  
16.5 Gy* 
40 Gy 
Central Airways 
<0.5 cc 
18.9 Gy* 
23.1 Gy 
<0.5 cc 
21 Gy* 
33 Gy 
Skin 
<10 cc 
30 Gy* 
33 Gy* 
<10 cc 
36.5 Gy* 
39.5 Gy* 
*Constraints marked by asterisk are guidelines and will not be scored as a protocol deviation if not achieved.  
Other constraints represent absolute limits and treatment delivery that cannot meet these 
constraints will constitute a major protocol violation. 
 
 
6. Pulmonary Function Test, 6-min Walk Test, and BODE Index 
We will perform PFTs (including spirometry, lung volumes and diffusing capacity) at pre-treatment 
and at 6-month follow-up, 6-min walk test (recommended but optional at pre-treatment and follow-
up), and calculate the BODE (body mass index, airflow obstruction, dyspnea, exercise capacity) 
index for those who complete the 6-min walk tests. 
 
7. Adverse Event Reporting 
7.1. 
Adverse event monitoring 
Subjects will be carefully monitored for adverse events.  This monitoring includes clinical and 
laboratory tests.  This study will utilize the NCI-CTCAE version 4.0 for toxicity and Adverse Event 
Reporting.  A copy of the NCI-CTCAE version 4.0 can also be downloaded from 
http://ctep.cancer.gov/reporting/ctc.html.  Adverse events will be assessed each cycle, and the 
highest grade according to NCI-CTCAE version 4.0 will be recorded.  Adverse events will be 
assessed in terms of seriousness, severity, and relationship to the study procedures. 
 
7.2. 
Adverse Event Definitions 
Adverse Events (AEs) 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medical treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure (attribution of unrelated, 
unlikely, possible, probable, or definite). 
 
Serious Adverse Events (SAEs) 
Any adverse experience occurring during any part of the protocol treatment and 30 days after that 
results in any of the following outcomes: 
• 
Results in death. 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. 
 
Intensity (Severity) of the Adverse Event 
The intensity or severity of AEs will be graded according to the NCI-CTCAE version 4.0 criteria. 
 
Adverse Event Documentation 

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All AEs occurring after the subject has received the first dose of investigational treatment will be 
fully recorded in the subject’s case record form.  Documentation will be supported by an entry in 
the subject’s file.  Each event will be described in detail along with start and stop dates, severity, 
relationship to study treatment, action taken and outcome. 
 
7.3. 
Study Procedure Adverse Events 
Treatment-related AEs will be categorized and graded based on the NCI-CTCAE version 4.0.  
Treatment should be interrupted for Grade 4 in-field toxicity and resumed when that toxicity has 
decreased to Grade ≤2 as detailed below.  If treatment is interrupted for >2 weeks, the patient 
should be removed from study treatment.  Expected AEs include reversible or permanent 
alopecia, bone marrow toxicity, skin pigmentation, esophagitis and radiation pneumonitis.  
Radiation-induced myocarditis or transverse myelitis rarely occurs at doses <50 Gy.  
Radiographic evidence of density change and subsequent fibrosis of the lung will occur within 
lung volume receiving ≥20 Gy, usually within the first six months after initiation of treatment. 
 
Esophagitis 
Esophageal complaints are common with thoracic radiotherapy.  Esophagitis typically 
manifests as dysphagia, odynophagia, and reflux symptoms.  Acute esophagitis occurs 
during a course of treatment and often persists for several weeks after treatment (Werner-
Wasik et al., 2010).  The symptoms of severe esophagitis (Grade ≥3) typically peak 4-8 
weeks from the beginning of treatment.  Late esophageal damage, typically stricture and 
associated dysphagia, develops ~3-8 months after treatment.  Esophagitis does not 
constitute a reason to interrupt or delay radiotherapy provided oral intake is sufficient to 
maintain hydration.  If Grade 3 or 4 esophagitis occurs, and a treatment interruption is 
being considered, every effort should be made to limit it to 3 treatment days or less. 
 
Acute esophageal toxicity should be pharmacologically managed with the following 
approach and should be initiated at the first signs or symptoms of esophageal toxicity.  
Recommended treatments are as follows: 
1) Patients should be advised to avoid alcoholic, acidic, or spicy foods or beverages.  
2) Ketoconazole 200 mg PO q day OR Fluconazole 100 mg PO q day until completion 
of radiation. 
3) Mixture of: 2% viscous lidocaine: 60 cc, Mylanta: 30 cc, sucralfate (1 gm/cc): 10 
cc; Take 15-30 cc PO q3-4 hrs prn (Contraindications: pts on Dilantin, Cipro, 
Digoxin). 
4) Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such as 
omeprazole) until the completion of radiation. 
5) Grade 4 esophagitis: hold radiotherapy until Grade ≤2.  
6) Occasionally, narcotics may be required. 
 
Radiation pneumonitis 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of 
the end bronchioles and alveoli.  Approximately 80% of radiation pneumonitis is clinically 
manifest within 10 months of treatment (Marks et al., 2010).  The clinical picture may be 
very similar to acute bacterial pneumonia, with fatigue, fever, shortness of breath, 
nonproductive cough, and a pulmonary infiltrate on chest x-ray.  The infiltrate on chest x-
ray should include the area treated to high dose, but may extend outside of these regions.  
The infiltrates may be characteristically “geometric” corresponding to the radiation portal, 
but may also be ill defined. 
 
Patients reporting symptoms as above will be promptly evaluated and treated.  Mild 
radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid 
inhalers.  More significant pneumonitis will be treated with systemic steroids, 

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bronchodilators, and pulmonary toilet.  Supra- and concurrent infections should be treated 
with antibiotics.  Consideration of prophylaxis of opportunistic infections should be 
considered in immunocompromised patients. 
 
It is unlikely that symptomatic pneumonitis will occur during the weeks radiation is actually 
delivered to the patients.  However, if a patient experiences pneumonitis before 
completing therapy, therapy will be put on hold until symptoms resolve.  At that point, a 
clinical decision whether to finish therapy will be made by the treating physicians. 
 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures 
must be reported to Co-PI, Dr. Daly (or designee). 
 
Reporting Forms: 
• 
SAE Report Form 
• 
Reporting to the FDA: US FDA MedWatch 3500A 
(http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm)  
 
Each serious AE will be followed up until resolution or stabilization, by submission of updated 
reports to the Co-PI, Dr. Daly.  Both serious and non-serious AEs will be reported in accordance 
with UCD Institutional Review Board (IRB) Administration and UCD Cancer Center policies.  The 
UC Davis IRB can be reached at (916) 703-9151. 
 
8. Data Review and Management 
8.1. 
Patient Registration 
Once signed, informed consent has been obtained and all pre-treatment evaluations have been 
performed, patients will be entered on study according to UCD Cancer Center policy.  To register 
a patient, the research nurse or data manager will complete the Eligibility Checklist and the Patient 
Registration Form.  A patient accession number will then be assigned.  Study biopsy and 
administration of study drug may not be initiated until the patient is registered.  An original signed 
and dated participant Informed Consent document will reside in a secured location within the UCD 
Department of Radiation Oncology.  Copies of the signed and dated Informed Consent document 
will be provided to the study participant and UCD Health System Information Management for 
inclusion in the participant’s UCD Health System Medical Record. 
 
8.2. 
Data Collection 
All data will be collected using the UCD Database System (eVELOS) forms.   
 
9. Statistical Considerations 
9.1. 
Study endpoints 
Primary endpoints 
(1) Grade ≥3 radiation pneumonitis, (2) grade ≥3 esophagitis, (3) other grade ≥3 AEs that occur 
≤12 months after treatment and drop-out defined as definitely, probably, or possibly related to the 
protocol treatment. 
 
 
Secondary endpoints 
1) Long-term toxicity, as scored by the NCI-CTCAE version 4.0. 
2) Clinical and subclinical endpoints for pulmonary toxicity (including radiation pneumonitis and 
post-treatment changes in PFTs, 6-min walk test, and BODE index). 
3) Correlation between the clinical/subclinical endpoints for pulmonary toxicity and functional 
dose-volume parameters. 

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4) Local tumor control. 
5) Lung functional dose-volume metrics, including the functional Vx (fVx) (% volume receiving ≥x 
Gy) and functional mean lung dose (fMLD). 
 
9.2. 
Patient accrual 
We aim to accrue 34 patients over 1.5 years.  Patient accrual will continue until either the projected 
sample of 34 patients has been enrolled, or the number of patients developing Grade ≥3 AEs or 
drop-out due to intolerance of treatment exceeds five.  Patient follow-up will continue until all 
patients have at least two years of follow-up, to allow for assessment of longer-term AEs. 
 
9.3. 
Analysis plan 
Primary endpoints: (1) Grade ≥3 radiation pneumonitis, (2) grade ≥3 esophagitis, (3) other grade 
≥3 AEs that occur ≤12 months after treatment and drop-out defined as definitely, probably, or 
possibly related to the protocol treatment. 
We will estimate the rates of AEs and tolerability with exact 95% confidence intervals.  4D CT 
ventilation image-guided personalized radiotherapy will be considered safe if AE rates are lower 
than the following acceptable rates (determined based on the published toxicity data for locally 
advanced lung cancer patients): (1) grade ≥3 radiation pneumonitis, 13% (Jiang et al., 2012), (2) 
grade ≥3 esophagitis, 21% (Wei et al., 2006), and (3) other grade ≥3 AEs and drop-out, 20% 
(Bradley et al., 2015). 
 
Secondary endpoints 
Analyses of secondary endpoints will be primarily descriptive rather than hypothesis testing.  
 
Toxicity will be summarized by frequency and exact 95% confidence intervals, overall and 
separately by grade and organ system. 
 
The clinical significance of 4D CT ventilation image-guided personalized radiotherapy will be 
estimated by evaluating: (1) clinical and subclinical endpoints for pulmonary toxicity (including 
radiation pneumonitis, PFTs, 6-min walk test, and BODE index); (2) correlation between those 
endpoints and functional dose-volume parameters.  Radiation pneumonitis will be assessed at 
follow-up every 3 months for a minimum of 2 years after treatment using the NCI-CTCAE version 
4.0.  Post-treatment changes in PFTs (including spirometry, lung volumes and diffusing capacity), 
6-min walk test, and the BODE index will be evaluated at the time of 6-month follow-up.  Using 
composite treatment plans, the following lung functional dose-volume parameters will be 
calculated: functional mean lung dose (fMLD), functional V20 (fV20) and functional effective dose 
(fDeff) (Vinogradskiy et al., 2013), which will be correlated with the endpoints for pulmonary toxicity. 
 
To quantify the dosimetric significance of 4D CT ventilation image-guided adaptive radiotherapy, 
we will create: (1) 4D CT ventilation image-guided adaptive radiotherapy plan, (2) 4D CT 
ventilation image-guided non-adaptive radiotherapy plan, and (3) anatomical image-guided non-
adaptive radiotherapy plan.  We will evaluate the lung functional dose-volume parameters, 
including the functional Vx (fVx) (% volume receiving ≥x Gy) and functional mean lung dose (fMLD) 
for each plan.  The lung functional dose-volume parameters of the 4D CT ventilation image-guided 
adaptive radiotherapy plans will be compared with those of the 4D CT ventilation image-guided 
non-adaptive radiotherapy plans and anatomical image-guided non-adaptive radiotherapy plans 
using a paired t-test.  Furthermore, we will also investigate sensitivity to the number (1 or 2) and 
time (16-20 Gy and/or 30-34 Gy) of plan adaptation to design an optimal adaptive radiotherapy 
strategy, e.g., when and how many time(s) to adapt the original plan. 
9.4. 
Sample size 
We will examine the safety of 4D CT ventilation image-guided personalized radiotherapy based 
on AEs during the first 12 months of follow-up and toxicity-related drop-out.  With a sample size 
of 34 patients, we will be able to see grade ≥3 radiation pneumonitis, grade ≥3 esophagitis and 
other grade ≥3 AEs at least once with 94%, 99% and 99% probabilities, respectively, assuming 

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true rates of 13%, 21% and 20%, respectively.  We can also estimate these AE rates with a 
standard error of 8%, 9% and 9%, respectively. 
 
Approximately 37% of patients are estimated to die over the first 12 months of follow-up according 
to the published survival data for patients with locally advanced NSCLC (Machtay et al., 2012).  
Also 1% of patients are estimated to drop out for reasons unrelated to the protocol treatment.  To 
compensate for possible loss of patients for such reasons, a sample size of 34 (increased by 38% 
from 20) will be used. 
 
9.5. 
Interim analysis to monitor study progress 
Interim reports will be prepared twice yearly until the final analysis has been completed. In 
general, reports will describe accrual, projected completion date, pre-treatment characteristics of 
patients, and frequency and severity of adverse events.  
 
10. 
Study Timelines 
Task 
Year 1 
Year 2 
Enroll 34 patients and deliver 4D CT ventilation image-guided personalized 
radiotherapy 
 
 
 
 
Assess the safety/feasibility of 4D CT ventilation image-guided personalized 
radiotherapy 
 
 
 
 
Estimate the clinical significance of 4D CT ventilation image-guided 
personalized radiotherapy 
 
 
 
 
 
11. 
Patient Assessments 
11.1. Pre-treatment assessments 
Staging workup will include PET/CT, MRI of the brain (this is only required for locally advanced 
patients and for other patients, it is optional), and CT of the chest and upper abdomen performed 
with contrast (recommended, but not required) within 8 weeks prior to registration, as well as 
histologic or cytologic documentation of lung cancer.  PFT to include routine spirometry, lung 
volumes, and diffusing capacity should be performed within 8 weeks before treatment.  CBC with 
differential and comprehensive metabolic panel will be obtained within 14 days of enrollment to 
ensure adequate marrow reserve and end organ function.   
 
11.2. Evaluation during treatment 
In an effort to improve the capture and consistency of AE reporting, essential AEs commonly 
associated with lung cancer radiotherapy, including but not limited to esophagitis, pneumonitis, 
pericarditis, dermatitis, hematologic toxicity, and chest wall pain are to be assessed at baseline 
and weekly during treatment using the NCI-CTCAE version 4.0.  Additional AE terms and grading 
criteria can be accessed online at http://ctep.cancer.gov/reporting/ctc.html.  Guidelines for 
management of AEs are outlined in section 7.  History, physical examination, Zubrod performance 
status, and body weight will also be obtained weekly during treatment. 
 
 
 
11.3. Discontinuation of protocol treatment  
Protocol treatment may be discontinued for any of the following reasons: 
• 
Progression of disease 
• 
Unacceptable adverse events [at the discretion of the treating physician(s)] 
• 
Patient refusal 
• 
If protocol treatment is discontinued, follow-up and data collection will continue as 
specified. 
 
11.4. Post-treatment evaluations 

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In an effort to improve the capture and consistency of AE reporting, essential AEs commonly 
associated with lung cancer radiotherapy, including esophagitis, pneumonitis, pericarditis, 
dermatitis, hematologic toxicities, spinal cord injury, chest wall pain, and are to be assessed at 
follow-up every 3 months for a minimum of 2 years after treatment using the NCI-CTCAE version 
4.0. 
 
Additional 
AE 
terms 
and 
grading 
criteria 
can 
be 
accessed 
online 
at 
http://ctep.cancer.gov/reporting/ctc.html.  Post-treatment PFTs will be performed at 6 months 
post-treatment, to include routine spirometry, lung volumes, diffusing capacity and diffusing 
capacity. 
 
Disease response and progression will be monitored by the use of contrast-enhanced CT of the 
chest every 3 months for the first 2 years post-treatment.  PET/CT will be obtained at the discretion 
of the treating physician or to follow up suspicious findings on CT.  Patient assessments are 
outlined in Appendix III. 
 
11.5. Discontinuation of follow-up assessments 
Follow-up assessments may be discontinued for either of the following reasons: 
• 
Patient refusal 
• 
Patient’s withdrawal of consent; Data for these patients will not be used for analysis. 
• 
Otherwise, patients will be followed at least every three months for two years following 
treatment. 
 
12. 
Ethical and Regulatory Considerations 
12.1. Ethical conduct of the study 
This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical 
Practice (GCP) according to (International Conference on Harmonization) ICH guidelines.  
Specifically, the study will be conducted under a protocol reviewed by the IRB; the study will be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study do not find the hazards to outweigh the potential benefits; and each subject 
will give his or her written, informed consent before any protocol-driven tests or evaluations are 
performed. 
 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected.  Master files will be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations. 
 
12.2. Informed consent procedures 
Informed consent will be obtained before conducting any study-specific procedures (i.e., all of the 
procedures described in the protocol).  The process of obtaining informed consent will be 
documented in the patient source documents. 
 
All patients will have signed an informed consent for participation in research activities in 
accordance with all institutional, NCI and Federal regulations, and will have been given a copy of 
the Experimental Subject’s Bill of Rights. 
 
12.3. Protocol deviations 
PI, Dr. Yamamoto and Co-PI, Dr. Daly will discuss all protocol waivers and/or treatment deviations 
immediately, and will submit an amendment to the protocol if the deviation is likely to occur again.  
All protocol deviations will be reported in accordance with UCD IRB Administration and UCD 
Cancer Center policies. 
 
13. 
Data Safety and Monitoring 

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In addition to the requirements for AE reporting as outlined in section7, this protocol is also subject 
to the UC Davis Cancer Center’s (UCDCC) Data and Safety Monitoring Plan.  The UCDCC is 
committed to pursuing high-quality patient-oriented clinical research and has established 
mechanisms to ensure both scientific rigor and patient safety in the conduct of clinical research 
studies.  The UCDCC relies on a multi-tiered committee system that reviews and monitors all 
cancer clinical trials and ensures the safety of its participants, in compliance with institutional and 
federal requirements on AE reporting, verification of data accuracy, and adherence to protocol 
eligibility requirements, treatment guidelines, and related matters.  The Scientific Review 
Committee (SRC) assumes overall oversight of cancer studies, with assistance and input from 
two independent, but interacting, committees: the Quality Assurance Committee and the Data 
Safety Monitoring Committee.  A multi-level review system strengthens the ability of the UCDCC 
to fulfill its mission in conducting high quality clinical cancer research. 
 
14. 
Data Sharing 
The anonymized pre- and mid-treatment CT image data acquired in this study will be shared with 
external investigators upon request for other research activities.  To date we have received a 
request from Dr. Rene Werner (University Medical Center Hamburg-Eppendorf, Germany) who 
will develop a repeat 4D CT image database that will be publicly accessible for various 
developments and investigations such as respiratory motion modeling.  Anonymized CT image 
data 
will 
be 
transferred 
through 
cloud-based 
secure 
file 
sharing, 
e.g., 
Box 
(https://ucdavis.app.box.com). 
 
15. 
Potential Benefits to Subjects 
Potential benefits from this study include a potentially lower risk to experience pulmonary toxicity 
by 4D CT ventilation image-guided personalized radiotherapy compared to standard anatomic 
image-guided radiotherapy.  However, there is no guarantee that the patient will benefit directly 
from participating in this study. 
 
16. 
Economic Burden to Subjects 
There will be no additional costs to subjects because of participation in this study. 
 
17. 
Sharing of Results with Subjects 
The results of this study will not be shared with subjects or subjects’ primary care physicians. 
 
18.      Devices 
In vivo EPID dosimetry with the PerFRACTION software calculates the dose of the day 
reconstructed from EPID measurements in patient anatomy using the treatment plan CT image 
data.  The calculated dose of the day will be compared with the plan dose to estimate changes in 
patient anatomy.  The performance of in vivo EPID dosimetry will be evaluated by comparing the 
PerFRACTION analysis results with the dose of the day calculated with the mid-treatment CT 
image data as reference.  This device poses no additional risk to subjects. 
 
 
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APPENDIX I: 
 
 
 
 
ZUBROD PERFORMANCE SCALE 
 
0  
Fully active, able to carry on all pre-disease activities without restriction (Karnofsky 90-
100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry work of a light 
or sedentary nature. For example, light housework, office work (Karnofsky 70-80). 
 
2  
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours (Karnofsky 50-60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 
(Karnofsky 30-40). 
 
4  
Completely disabled. Cannot carry on self-care. Totally confined to bed or (Karnofsky 10-
20). 
 
5  
Death (Karnofsky 0). 
 

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APPENDIX II: 
 
 
Eligibility Checklist 
 
____________ (Y) 
1. 
Does the patient have histologically documented primary lung 
cancer (NSCLC or SCLC)? or histologically documentation of a solid 
tumor with clear radiographic evidence of spread to the lungs amenable 
to SBRT (for SBRT patients only; if CT-guided lung biopsy is deemed 
unsafe by interventional radiology, documented multidisciplinary review 
confirming radiographic diagnosis of early stage lung cancer or lung 
metastasis may be used) 
____________ (Y) 
2. Is definitive thoracic radiotherapy planned? 
• 
Conventionally-fractionated radiotherapy (CFRT) (with or without 
concurrent chemotherapy)  
• 
Stereotactic ablative radiotherapy (SABR) 
____________ (Y) 
3. Is the patient ≥18 years of age? 
____________ (Y) 
4. Is the life expectancy with treatment ≥6 months? 
____________ (Y) 
5. Is the Zubrod performance status 0-2? 
____________ (Y) 
6. Does the patient have adequate marrow reserve defined as an ANC 
≥1500, plt ≥100,000, Hgb ≥8 g/d? 
____________ (Y) 
7. Does the patient have adequate end organ function defined as LFTs 
≤2x upper limit of normal and creatinine ≤2.0 or creatinine clearance 
≥40? 
____________ (Y) 
8. Is the patient able to provide study specific informed consent? 
____________ (N) 
9. Has the patient had prior radiotherapy or other malignancy leading to 
any overlap of planned radiotherapy fields? 
____________ (Y/N) 
10. Is concurrent chemotherapy planned? 
____________ (Y/N) 
11. Was a CT with contrast of lung and upper abdomen performed within 
8 weeks of registration? (Recommended) 
____________ (Y) 
 
____________ (Y) 
12. Was an FDG-PET performed for staging within 8 weeks of 
registration? 
13. Does the patient have locally advanced disease? 
____________ (Y) 
14. If yes on #13, was an MRI or CT of the brain performed for staging 
within 8 weeks of registration?  

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____________ (N) 
15. Does the patient have any evidence of malignant pleural or 
pericardial effusion? 
____________ (N) 
16. Does the patient have radiographic evidence of distant metastases? 
____________ (Y/NA) 17. Has the patient agreed to use an effective method of contraception? 
____________ (N) 
18. If female, is the patient pregnant or lactating? 

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APPENDIX III: 
 
Patient Assessments 
 
Assessments 
Pre-study 
entry 
At time of 
simulation 
Mid-RT 
(8-10 fx) 
Mid-RT 
(15-17 fx) 
Weekly 
during RT 
Q3 months for 2 
years post-RT 
Evaluations 
 
 
 
 
 
 
History/Physical 
≤21 days 
 
 
 
X 
X 
Zubrod, weight 
≤21 days 
 
 
 
X 
X 
Histologic or 
cytologic tumor 
evaluation**** 
No Time 
Limit  
 
 
 
 
 
Protocol-specific 
AE evaluation 
≤21 days 
 
 
 
X 
X 
Pulmonary 
function test 
≤3 months 
 
 
 
 
X* 
6-min walk test 
≤42 days 
 
 
 
 
X† 
BODE index 
≤42 days 
 
 
 
 
X‡ 
Imaging (staging) 
 
 
 
 
 
 
CT w/ contrast of 
lung/upper 
abdomen 
≤56 days 
††† 
 
 
 
 
X 
MRI brain*** 
≤56 days 
 
 
 
 
As clinically 
indicated 
PET/CT 
≤56 days 
 
 
 
 
As clinically 
indicated 
Imaging (RT 
planning and 
study) 
 
 
 
 
 
 
Free-breathing CT 
 
X 
X§ 
X** 
 
 
4D CT 
 
X 
X†† 
X‡‡ 
 
 
Labs 
 
 
 
 
 
 
CBC with 
differential 
≤14 days 
 
 
 
X 
X 
Comprehensive 
metabolic panel 
including LFTs 
and creatinine 
≤14 days 
 
 
 
 
X 
 
* At 6-month post-RT follow-up only.  
† At 6-month post-RT follow-up only. 
‡ At 6-month post-RT follow-up only. 
§ CFRT only. 
** CFRT only. 
†† CFRT only. 
‡‡ CFRT only. 
 
***Required for locally advanced patients only 
††† Recommended 
****Biopsy mandatory for CFRT only 
CT w/ contrast for SBRT Q3 months for 1 year, then as clinically indicated 

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