Lung Volume Reduction for Severe Emphysema by Stereotactic Ablative Radiation Therapy
Phase: NA
Conditions: Emphysema
Sponsor: Stanford University

 
 
 
 
Lung Volume Reduction for Severe Emphysema by Stereotactic Ablative 
Radiation Therapy 
Study Protocol 
NCT03673176 
November 21, 2017 

 
 
 
 
 
A Phase I Clinical Study of Lung Volume Reduction by Stereotactic Ablative 
Radiotherapy in the Treatment of Severe Emphysema 
 
 
 
Emphysema 
 
Chronic Obstructive Pulmonary Disease (COPD) is a major, worldwide public health 
problem.  Consisting of emphysema, chronic bronchitis, and combinations of the two, 
COPD is the third most frequent cause of death in developed countries, and a major cause 
of morbidity, reduced quality of life, and costs to health care systems.  Severe COPD is 
estimated to be present in 10.1% of the world’s population (1). Even after smoking 
cessation, pulmonary dysfunction resulting from the inflammatory process of COPD 
unfortunately continues to progress, albeit at a slower rate. 
 
 Treatments for COPD are almost entirely palliative, consisting of inhaled 
bronchodilators, inhaled steroids, and sometimes systemic steroids as chronic therapy; 
and antibiotics with or without steroids for acute exacerbations.   Once the forced 
expiratory volume in one second (FEV1, the most standardized measure of severity of 
COPD) falls below 30%, the mean two year survival in emphysema patients is only 
approximately 60%.  The only non-surgical therapy which has been shown to have 
impact on this dismal survival in severe COPD is oxygen therapy for patients who are 
hypoxic.   
 
The pathophysiology of COPD is complex.  In emphysema, however, the major 
component of the pathophysiology, and thus the cause of much of the dyspnea associated 
with the disease, is pulmonary hyperexpansion.  The elastin fibers in emphysematous 
lungs are progressively destroyed, resulting in progressive enlargement of air spaces and 

thus of the entire lung itself.   As the lungs expand, they force the diaphragm and 
accessory respiratory muscles out of their usual, optimized positions.  The diaphragm is 
flattened and its muscle fibers shortened, and the other respiratory muscles are similarly 
able to function far less efficiently.  The resulting increased work of breathing is central 
to emphysema patients’ sensation of dyspnea. Additionally, loss of elastic tethering fibers 
that normally support the airways allows the small to medium sized airways of 
emphysema patients to collapse upon expiration, creating a vicious cycle in which 
exhalation -- normally a passive event -- requires additional respiratory muscle work to 
be achieved. In chronic bronchitis, the hyperexpansion may be somewhat less 
pronounced and less important in the generation of symptoms; an inflammatory 
component, causing relatively fixed narrowing of the airways and mucous 
overproduction, is more prominent. 
 
 
Lung Volume Reduction Surgery 
 
Since medical therapies offer only modest palliation and minimal hopes for improved 
survival to COPD patients, surgical therapies have been designed that may provide 
greater benefits in selected patients.  Lung transplantation, for example, clearly improves 
survival and quality of life in patients with end stage COPD.  This comes at substantial 
economic cost, however, as well as the at the cost of complications that may result from 
the complex surgery and from life-long immunosuppression.  In addition, nearly all lung 
transplants will fail within 5 years as a result of progressive bronchiolotis obliterans, 
which we currently have no way to prevent or treat. 
 
A second operation designed to treat severe COPD patients is lung volume reduction 
surgery (LVRS).  This operation, designed for patients with predominant emphysema 
rather than chronic bronchitis, is among the most carefully studied operations ever 
developed.  The National EmphysemaTreatment Trial (NETT) randomized severe 
emphysema patients (in a CMS-sponsored national study) to bilateral lung volume 
reduction surgery via median sternotomy versus “best medical therapy” (2, 3).  This 

study found that outside of the most severely ill patients enrolled (in whom the risks of 
the surgery outweighed the benefits), 3 out of the 4 remaining ‘non-high-risk’ subgroups 
derived major improvements in pulmonary function and quality of life, and 1 of the 4 
subgroups actually derived a survival benefit from the operation.  On average, 
appropriately selected patients will have a 50% improvement in their FEV1 following the 
operation (4). 
 
Lung volume reduction surgery is performed via either median sternotomy or bilateral 
thoracoscopy.  The goal of the procedure is to remove areas of emphysematous lung in 
order to reduce hyperexpansion, thereby restoring the respiratory muscles closer to their 
normal, efficiently-functioning positions, as well as restoring the lung’s “elastic recoil,” 
thereby increasing expiratory airflow.  The ideal patients, as established in multiple 
studies including the NETT trial, have severe emphysema (FEV1 less than 45% of 
predicted), are markedly hyperexpanded (residual volume greater than 150% of 
predicted, preferably even higher), and have “target zones” – that is, heterogeneous 
distribution of disease such that there are areas of lung that are more severely involved 
and can be targeted for resection and other areas that are less severely involved.  By 
removal of the areas that are more severely involved, one can reduce lung volume 
without removing lung that is contributing substantially to gas exchange (4).   
 
Despite the clear benefits of the operation, it is associated with an approximately 5% 
mortality rate.  Furthermore, because of the complexity of the care of these significantly 
compromised patients following general anesthesia and chest surgery, it can currently be 
performed only in sites that are either lung transplant centers or are certified specifically 
for LVRS, thus limiting access to the procedure.  For these and other reasons, the 
operation is not performed with nearly the frequency that one might expect given its 
carefully documented effectiveness. 
 
As a result, a variety of devices and procedures have been designed to try to create a 
“non-surgical lung volume reduction” -- which might be able to provide the benefits of 
LVRS without engendering the same degree of risk.  These devices have consisted for the 

most part ofendobronchial valves designed to be placed into segmental airways to either 
completely block, or to create one-way flow, through the airways.   The goal of these 
devices is to collapse the targeted segments of the lung.  Unfortunately, although these 
approaches incur less morbidity than surgical LVRS, they are not nearly as successful as 
surgical LVRS in improving pulmonary function and reducing dyspnea.  The several 
pilot studies which have been performed to evaluate these approaches have generally 
demonstrated marginally statistically significant improvements in quality of life and 
pulmonary function but clearly not clinically significant improvements (5, 6). 
 
It is thought that the failure of endobronchial valves to create successful lung volume 
reduction is due to the presence of collateral ventilation between segments and lobes in 
emphysema patients.  Pores are present which allow anatomic regions of the lung to 
exchange air even across fissures.  Thus, even after occluding a segmental bronchus, that 
segment is likely to remain expanded as a result of collateral ventilation from adjacent 
segment and lobes.  This would render any attempt at endobronchial lung volume 
reduction to fail.  Because of the failure of the non-surgical modes of volume reduction 
currently under evaluation, this remains an active area of investigation by a number of 
universities and commercial concerns.   
 
Stereotactic Ablative Radiotherapy 
 
Stereotactic Ablative Radiotherapy (SABR), also called stereotactic body radiation 
therapy (SBRT), is a relatively recent advance in radiotherapy which allows high doses of 
radiation to be transmitted to focused areas (typically malignancies), allowing higher 
rates of tumoricidal activity, generally lower complications, and greater convenience for 
patients since it can be delivered in 1 to just a few sessions.  As the radiation is 
administered from multiple directions according to stereotactic planning, high doses can 
be delivered to the tissues with rapid fall-off to relatively low doses in even nearby, 
surrounding normal tissues.  This technique was initially applied to brain tumors– an 
application which over the years has met with great success.  More recently, it has been 

applied with substantial success and is gaining increasing acceptance as a primary mode 
of therapy for stage I lung malignancies, and malignancies in multiple other body areas. 
 
In the lung, the rate of pneumonitis resulting from SABR is far lower than the rates 
incurred by conventional external beam radiotherapy. In conventional external beam 
radiotherapy reported pneumonitis rates range from 13-37% (7), depending on dose and 
field size. Reported rates of symptomatic pneumonitis after lung SABR are significantly 
lower and generally are ~5% (8).  SABR does, however, typically leave a scar in the area 
of lung that has been treated (9).  Importantly, there appears to be contraction of 
surrounding lung parenchyma into this scar resulting in an effect that is essentially a 
“lung volume reduction.”  One often sees clear loss of lung volume following any form 
of lung radiotherapy.  With SABR, this “volume reduction” is achieved with a far lower 
risk of morbidity – in particular, less risk of pneumonitis.   
 
Stereotactic Ablative Radiotherapy for Emphysema 
 
We hypothesize that we can create a minimally invasive form of LVRS by applying SABR 
to target areas of the lung in severe emphysema patients, creating limited scarring and 
retraction of tissue and thus “volume reduction”.  We believe that by reducing the 
volume of emphysematous lung with the precise target localization made possible by 
image-guided SABR, that we will be able to duplicate the benefits of surgical lung volume 
reduction with far less risk.  We believe that this may represent a major advance in the 
therapy of emphysema – a highly prevalent disease.  It may provide not only palliation 
but also increased survival, as does surgical lung volume reduction, in carefully selected 
patients.   
 
LVRS via SABR (or Stereotactic Ablatic Volume Reduction – SAVR) should avoid 
the problem of collateral ventilation, described above, which appears to underlie the 
failure of other attempts at minimally invasive forms of LVRS.  Like surgical LVRS, 
SAVR will actually ablate areas of lung, resulting in their essential disappearance.  
Surgical LVRS allows actual surgical excision of these areas of lung; SAVR would 

shrink these areas of lung into small scars which would take up far less space within the 
chest than the untreated lung.   We hope that this will engender all the benefits of surgical 
lung volume reduction.   
 
Although surgical LVRS is often carried as a bilateral procedure (upon both lungs) under 
a single anesthetic, many centers perform the operation unilaterally, reserving the 
opposite side to be operated upon only subsequently, if indicated.  Given that this 
unilateral approach has also been demonstrated to result in major improvements in 
pulmonary function and quality of life, we are electing to carry out unilateral SAVR for 
the first 5 patients in this protocol, extending this to bilateral SAVR in the last 5 patients 
if there are no major adverse events through the initial 5..  
 
Preliminary Data 
 
Fibrosis in lung tissue irradiated to a high dose is a well-known phenomenon after 
conventional radiotherapy. More recently, studies have characterized this phenomenon 
more systematically in patients treated with SABR (9, 10).  These fibrotic changes 
develop over time in 99% of patients treated with SABR for lung tumors, 73% within one 
year (10).  Of note, this occurs despite the usual attempt to minimize the volume of lung 
tissue irradiated in the context of treating early stage lung cancer. A greater effect can be 
anticipated if lung tissue is deliberately targeted for ablation,  as the development of 
fibrosis is known to be related to the irradiated volume. 
 
Actual intentional volume reduction as a result of a fibrotic response to SABR, and 
concomitant expansion of the remaining portions of the lung, has not been previously 
reported to our knowledge. We have, however, observed this phenomenon in several 
patients in our own experience at Stanford. Figure 1 shows an example of a patient 
treated with SABR for an early stage lung cancer of the right upper lobe. After treatment, 
the right lung apex was replaced with fibrosis where the tumor had been located, and the 
change in the position of the major fissure clearly reflects both volume loss in the right 
upper lobe and volume expansion of the right lower lobe – precisely what is achieved by 

surgical LVRS. Again, this effect was not the intent of the treatment, which in this and all 
other patients treated to date, was focused on the tumor.  If, however, volume reduction 
by shrinkage of lung tissue became the goal of the SABR, this effect could presumably be 
optimized by appropriate targeting of lung tissue. 
 
 
Figure 1. Lung volume reduction after SABR for a right upper lobe tumor. Coronal and 
sagittal sections demonstrate that following SABR, there is fibrosis of the right lung apex 
where the radiation has been delivered to tumor (large yellow arrow), and volume loss 
within the right upper lobe, indicated by craniad deviation of the major fissure, with 
corresponding expansion of the right lower lobe (small white arrows). Note also that the 
mediastinum is deviated to the side of the treatment. 
 
Intriguingly, in the 1970’s a pilot study used now antiquated radiation therapy 
technologies to attempt to induce lung fibrosis in emphysematous lung regions in order to 
improve overall lung function (11).  The treatment was found to be safe and achieved 
subjective improvement in dyspnea in all ten patients, but it did not achieve clear, 

objective improvements in lung volumes. It stands to reason that precise radiotherapy to 
specifically targeted lung volumes should achieve more impressive results. 
 
Study Design 
 
We propose a 10 patient, phase I study to determine safety and feasibility of SAVR.. All 
patients will each be treated with approximately  the same SABR dose, unilaterally (with 
minor modifications based on the precise anatomy of the emphysematous changes in their 
parenchyma).  The primary outcome will be the occurrence of grade 3 or higher adverse 
events, as listed below.   Secondary outcome measures, in order to determine initial 
effectiveness of the procedure, will include post-procedure pulmonary function, exercise 
capacity, and quality of life.   
 
Study subjects may be candidates for surgical LVRS, and all subjects who are good 
candidates for surgical LVRS will be offered the surgical procedure as well as entry into 
the study.  We therefore expect that most subjects enrolled will be individuals who are 
not optimal candidates for surgical LVRS.  
 
Inclusion Criteria 
 
These criteria are modified from those established by the NETT and other single-
institution studies establishing the criteria for relative safety and effectiveness of surgical 
LVRS. 
 
 
 
Pulmonary Function 
 
 
Severe COPD with severe reduction in quality of life due to dyspnea 
 
 
Moderate to Severe emphysematous destruction of lung parenchyma on 
chest CT 
 
 
FEV1 < 45% predicted and >18% predicted 
 
 
FEV1/FVC < .7 
 
 
DLCO > 18% predicted 

 
 
Residual Volume > 160% predicted (by plethysmography) 
 
Arterial Blood Gas 
 
 
paO2>40 on room air at rest 
 
 
paCO2<55 
 
 
General 
Successful completion of 16 sessions of pulmonary rehabilitation 
 
 
Exclusion Criteria 
 
 
Left ventricular ejection fraction below 40% 
Predominate chronic bronchitis (none or mild emphysematous destruction 
of lung on chest CT) 
 
 
Pulmonary function tests / lung volumes that do not meet above criteria. 
 
 
Active coronary ischemia (stress test required if clinical symptoms). 
 
 
Inability to complete 16 sessions of pulmonary rehabilitation. 
Recent (less than 3 months) hospitalization with or without the COPD 
exacerbation. 
Recent (less than 3 months) pulse dose steroids usage. 
 
 
 
Pregnancy. Presence of lung cancer. 
 
 
 
 
Procedures:  Initial Evaluation and Pre-procedural preparation 
 
1. Initial evaluation – Patients will be evaluated by the PI and study coordinator in 
the thoracic surgery clinic of the PI.  Evaluation will include the standard 
evaluation for surgical LVRS, which includes history and physical examination, 
and the CT chest as well as PFT studies required to evaluate for fulfillment of the 
inclusion/exclusion criteria. 
The option of surgical LVRS, if the patient is a candidate for surgical LVRS, 
will be discussed, as well as the option of entering this study of LVRS by SABR. 

 
Studies to be completed to determine suitability for protocol enrollment: 
 
CT Chest 
 
Pulmonary function testing including spirometry, DLCO, 
plethysmographic lung volumes 
 
Arterial Blood Gas (room air, at rest) 
 
Patients who meet inclusion/exclusion criteria will sign informed consent to 
enroll in the study. 
 
2. Pre-procedural preparation - All patients who are enrolled in the study must, in 
addition to the above studies, undergo the following prior to SABR therapy: 
a. 16 sessions of pulmonary rehabilitation 
b. 6 minute walk test 
c. SF36 quality of life assessment and St George's questionnaire. 
d. . EKG test 
 
Procedures: SABR Administration and Radiation Treatment Planning  
 
1. 
Simulation 
 
During radiotherapy simulation, customized immobilization devices will 
be formed for each patient, and 4-dimensional CT (4-D CT) will be 
acquired in the treatment position.  
 
 
2. 
Treatment planning 
 
The PI (surgeon) and one of the co-PIs (radiation oncologist) will together 
contour the area of lung to be targeted.  This will consist of the region of 
greatest parenchymal destruction by emphysema, which could be as large 
as an entire lobe if normal tissue constraints are met, and will be 

designated as the clinical target volume (CTV). Breathing-induced target 
motion will be assessed using the 4-D CT data and managed by respiratory 
gating or motion-inclusive technique, and the internal target volume (ITV) 
will be designed accordingly. There will be no additional set-up margin 
and therefore the planning target volume (PTV) will be identical to the 
ITV. 
Treatment will be delivered using 6 MV photons on the Trilogy or 
TrueBeam platforms (Varian Medical Systems, Palo Alto, CA), using 
daily kilovoltage (kV) x-ray portal imaging and cone-beam CT for 
anatomy-based matching. The analytical anisotropic algorithm (AAA) will 
be used for dose calculations (or Acuros XB when available), and 
treatments will be delivered by either dynamic conformal arc therapy 
(DCART) or volumetric modulated arc therapy (VMAT, RapidArc, 
Varian).  
 
 
3. SABR Treatment Delivery: 
The prescribed dose will be 45 Gy in three fractions of 15 Gy, on each 
side that is treated.  In the first 5 patients we will treat only 1 lung 
(unilateral SAVR); if there are no major treatment-related adverse 
events in the first 5 patients, we will plan bilateral LVRS, if 
anatomically appropriate, in the last 5 patients. 
Prescription Dose Constraints and Conformality 
Prescription Isodose Surface Coverage: The prescription isodose 
surface will be chosen such that 95% of the target volume (PTV) is 
conformally covered by the prescription isodose surface (PTV 
V100%RX = 95%).  The global maximum dose point should be within 
the PTV and ideally within the CTV. 

We will exclude prescription-dose planning target volumes (PTV) that 
overlap with the proximal bronchial tree (carina to lobar bronchi) and 
mediastinal structures (heart, esophagus, aorta, SVC, main pulmonary 
artery). 
Conformality parameters: Treatment plans should be as conformal as 
possible.  For targets located far from critical structures, a very 
conformal distribution should be obtained.  For targets close to critical 
structures, dose distributions may be somewhat asymmetric, with a 
sharper fall-off on the side(s) of the target that are closest to the critical 
structure(s) at risk. The following conformality criteria must be met: 
 
Ratio of Prescription 
Isodose Volume to the 
PTV Volume 
Maximum Dose @ 2 cm 
from PTV (in % of dose 
prescribed) 
Ideal 
Required 
Ideal 
Required 
<1.2 
<1.5 
<60 
<75 
 
Critical organ dose constraints 
The following tables list dose constraints to critical structures. 
Exceeding these dose limits by more than 5% constitutes an 
unacceptable protocol deviation. 
 
Critical structures with absolute volume and absolute point dose 
limits: Exceeding any of these limits constitutes a major protocol 
violation. 
Critical structure 
Volume dose limits (3 fractions) 
Maximum 
Point dose 
limit (<0.035 
mL) 
 
Dose 
Volume 
Dose 
Spinal cord 
18 Gy 
12.3 Gy 
<0.35 mL 
<1.2 mL 
21.9 Gy 

Brachial plexus 
20.4 Gy 
<3 mL 
24 Gy 
Skin 
30 Gy 
<10 mL 
33 Gy 
Lungs-PTV (i.e. 
non-targeted lung) 
11.4 Gy 
10.5 Gy 
20 Gy 
<1000 mL 
<1500 mL 
<10% (require <15%) 
NA 
Stomach 
16.5 Gy 
<10 mL 
22.2 Gy 
Small bowel 
16.5 Gy 
11.4 Gy 
<5 cc 
<10 cc 
22.2 Gy 
 
Critical structures with relative volume and absolute point dose 
limits: The volume dose limits are suggested limits for these structures.  
Exceeding these limits is not a protocol violation. The recommended 
maximum point dose limits are also suggested limits that may not be 
met.  However, exceeding any of the required maximum point dose 
limits constitutes a major violation. 
 
Critical 
structure 
Volume dose 
limits 
(3 fractions) 
Maximum point dose limit 
(<0.035 mL) 
 
Dose 
Volume 
Recommended 
Required 
Esophagus* 
17.7 
Gy 
<5 mL 
25.2 Gy 
105% of 
PTV 
prescription 
dose 
Heart/pericardium 
24 
Gy 
<15 mL 
30 Gy 
105% of 
PTV 
prescription 
dose 
Great vessels* 
39 
Gy 
<10 mL 
45 Gy 
105% of 
PTV 
prescription 
dose 
Trachea and 
ipsilateral 
bronchus* 
15 
Gy 
<4 mL 
30 Gy 
105% of 
PTV 
prescription 
dose 

Chest wall# 
30 
Gy 
<10cc 
(<30cc 
required) 
NA 
105% of 
PTV 
prescription 
dose 
Liver 
17.7 
Gy 
<700 mL 
NA 
105% of 
PTV 
prescription 
dose 
* Avoid circumferential radiation 
# Chest wall limitsmay be exceeded for an otherwise excellent plan. This 
will not be considered a violation. 
 
 
All study data will be stored securely in a Stanford-hosted red cap 
database.  
 
 
 
Post-SABR Follow-up 
 
Patients will be followed for 1.5 years following the experimental treatment, 
according to the following follow-up schedule.  Attention at each visit will be 
directed to the presence of clinical signs or radiographic changes suggesting 
pneumonitis or other adverse events.  All adverse events will be recorded and 
scored: 
 
2 months     CXR and office visit 
6 months     CT chest, office visit, PFTs, SF 36 QOL assessment, 6 minute walk  
12 months   CT chest, office visit, PFTs 
18 months   CT chest, office visit, PFTs, SF 36 QOL assessment, 6 minute walk 
 
Data Analysis 
 
 
PFTs (FEV1, DLCO, RV) will be compared preop vs. each postop time point 
 
6 minute walk test will be compared preop vs. each postop time point 
 
SF36 and Borg dyspnea scores will be compared preop vs. each postop time point 
 
Evaluation for Adverse Events 
 
Toxicity will be scored according to the NCI CTCAE v4.0.   
 

Serious adverse events (SAE’s) will be reported to the Stanford PI and to 
the IRB, and DSMB as per the Cancer Clinical Trials Office Standard 
Operating Procedure for SAE reporting.  
 
Definition of adverse event:  any unfavorable and unintended sign, 
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).   
 
Definition of serious adverse event:  any adverse experience that results in 
any of the following outcome: death, a life-threatening experience, 
inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.  Important medical events that may not result in 
death, be life threatening, or require hospitalization may be considered a 
serious adverse event when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Definition of unanticipated problems involving risks to participants or 
others (UPs):   events (including internal or external events, death, life-
threatening experiences, injuries, breaches of confidentiality, or other 
problems) that occur any time during or after the research study, which in 
the opinion of the PD are:  
1. 
Unexpected - not in the consent form, protocol, package insert, or 
label; or unexpected in its frequency, severity, or specificity, AND 
2. 
Related to the research procedures – caused by, or probably caused 
by research activity, or, if a device is involved, probably caused by, or 
associated with the device, AND 
3. 
Harmful – caused harm to participants or others, or placed them at 
increased risk of harm (including physical, psychological, economic, or 
social harm). 
 
 
Definition of reportable information:   
 1.    New information that indicates a change to the risks or potential 
benefits of the research, in terms of severity or frequency. 
 2.  Complaints that are unresolved by the research team, or that indicates 
increased or unexpected risks. 
 3.   Unanticipated adverse device effect.  New information about the 
effect on health or safety. 
 
 
  
 
Adverse events:  

Pulmonary, esophageal, chest wall, skin, vascular, cardiac/pericardial, and 
brachial plexus/neurologic toxicity will be scored by the CTCAE 4.0 
criteria. 
 
The following grade 3 or higher adverse events will be reported to the 
protocol director. 
These will be reported as definitely, probably, or possibly related to 
treatment:  
• Grade 3-5 Cardiac Disorders 
- Pericardial effusion 
- Pericarditis 
- Restrictive cardiomyopathy 
• Grade 4-5 Gastrointestinal Disorders 
- Dysphagia 
- Esophagitis 
- Esophageal fistula 
- Esophageal obstruction 
- Esophageal perforation 
- Esophageal stenosis 
- Esophageal ulcer 
- Esophageal hemorrhage 
• Grade 3-5 Injury, Poisoning, and Procedural Complications 
- Fracture (to be limited to rib fractures only) 
• Grade 3-5 Nervous System Disorders 
- Brachial plexopathy 
- Recurrent laryngeal nerve palsy 
- Myelitis 
• Respiratory, Thoracic, and Mediastinal Disorders, Grade 3-5, except as 
noted below 
- Atelectasis (grade 4-5 only) 
- Bronchopulmonary hemorrhage 
- Mediastinal hemorrhage 
- Pleural hemorrhage 
- Tracheal hemorrhage 
- Bronchial fistula 
- Pulmonary fistula 
- Bronchopleural fistula 
- Tracheal fistula 
- Hypoxia (provided grade 3 is worse than baseline) 
- Bronchial obstruction 
- Tracheal obstruction 
- Pleural effusion 
- Pneumonitis 
- Pulmonary fibrosis 
• Grade 3-5 Skin and Subcutaneous Disorders 
- Skin ulceration (thorax only) 

• Any Grade 5 adverse event attributed to treatment 
 
Data Safety Monitoring Board (DSMB) 
This study’s data analysis will be performed by Dr. Max Diehn, who has no conflicts of 
interest. 
We have constituted a DSMB consisting of Dr. Leah Backhus (thoracic surgery), Dr. 
Arthur Sung (pulmonary medicine), and Dr. Daniel Chang (radiation oncology).  They 
will review the collected clinical data after 3 patients have been treated and followed for 
6 months and determine if the study should be continued to completion.  An adverse 
event definitely or probably related to the treatment which causes death (within the first 3 
patients treated) would dictate termination of the study. The following findings would 
dictate termination of the study at the scheduled interim DSMB review: 
-3 treatment-related grade 3 or higher adverse events 
 
 
 
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