STARS Revised Clinical Trial Protocol: Stereotactic Ablative Radiotherapy (SABR) in Stage I Non-small Cell Lung Cancer Patients Who Can Undergo Lobectomy
Phase: NA
Conditions: Lung Cancer
Sponsor: M.D. Anderson Cancer Center

Protocol 2007-0870 
Revised Oct 28,2020 
Page 1 of 26 
 
 
 
 
STARS Revised Clinical Trial Protocol: Stereotactic Ablative Radiotherapy 
(SABR) in Stage I Non-small Cell Lung Cancer Patients Who Can Undergo 
Lobectomy. 
 
 
 
 
Principal Investigator: Jack A. Roth, M.D. 
Department of Thoracic and Cardiovascular Surgery 
MD Anderson Cancer Center 
 
Co-Principal Investigator: Joe Y. Chang, M.D., Ph.D. 
Department of Radiation Oncology 
MD Anderson Cancer Center 
 
Co-Principal Investigator: Reza J. Mehran, M.D. 
Department of Thoracic and Cardiovascular Surgery 
MD Anderson Cancer Center 
 
Co-Principal Investigator: Stephen McRae, M.D. 
Department of Diagnostic Radiology 
MD Anderson Cancer Center 
 
Co-Principal Investigator: Peter Balter, Ph.D. 
Department of Radiation Physics 
MD Anderson Cancer Center 
 
Co-Investigator: Lei Feng, MS 
Principal Statistical Analyst 
Department of Biostatistics 
MD Anderson Cancer Center 
 
Co-Investigator: Donald Berry, Ph.D. 
Department of Biostatistics 
MD Anderson Cancer Center 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 2 of 26 
 
Suspected recurrence 
Biopsy 
 
SCHEMA 
 
 
Operable with lobectomy 
NSCLC 
Stage IA by PET/CT and EBUS or mediastinoscopy 
 
 
 
 
Stereotactic Ablative Radiotherapy (SABR): 
50Gy in 4 fractions (central tumor) or 54Gy 
in 3 fractions (peripheral tumor) 
 
Adjuvant chemotherapy 
is not permitted 
 
 
 
 
Follow for recurrence with PET/CT and use 
RECIST and SUV criteria 
 
 
 
 
No recurrence 
Follow 
Negative 
Continue to 
Follow 
 
Positive 
 
Surgically resect primary tumor with 
Mediastinal dissection. Consider 
additional radiation therapy and 
chemotherapy 
 
Follow patient for local control, toxicity, and survival 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 3 of 26 
 
 
 
Objectives: 
 
Primary Goal: Overall survival at 3 years. 
Secondary goals: 
1. Local recurrence free survival (LRFS). 
2. Time to local recurrence (TTLR). 
3. Grade 3 and above acute and/or chronic toxicities. 
4. To evaluate predictive value of pre and post treatment PET scan in clinical 
outcome. 
 
Introduction: 
 
Lung cancer remains the most frequent cause of cancer death in both men and women 
in North America. There are over 1,000,000 new cases of lung cancer annually world- 
wide. Seventy-five percent of patients with bronchogenic carcinoma will be diagnosed 
with non-small cell lung cancer (NSCLC). Approximately 15-20% of NSCLC patients 
present with early or localized disease (1-2). The number of patients diagnosed with 
stage I NSCLC is expected to rise significantly in the next several decades due to 
widespread screening with spiral CT. Surgical resection using lobectomy with 
mediastinal lymph node dissection or sampling in stage I (T1-2, NO) NSCLC results in 
five-year survival rates of approximately 60-70% (1-2) and remains the treatment of 
choice for this population. 
 
Primary radiotherapy for early stage non-small lung cancer is considered reasonable 
non-surgical therapy for patients who cannot tolerate surgery. Conventional fractionated 
radiotherapy (60–66 Gy in 1.8- or 2.0-Gy fractions) in these patients with stage I/II 
disease has resulted in 5-year local control rates of 30% to 50% and overall survival 
rates of 10% to 30% (3-4). Modern three-dimensional (3-D) conformal radiotherapy, 
however, may improve clinical outcome compared with two-dimensional radiotherapy 
(6). Several studies have reported a benefit from such a dose escalation, suggesting a 
dose-response relationship from the standpoint of both survival and local disease 
control in these patients (7, 8). Because early-stage NSCLC is not inherently a systemic 
disease at the time of diagnosis and because local control is poor after conventional 
radiotherapy, research directed toward improving survival should put more emphasis on 
improving local tumor obliteration. 
 
The development of 3-D conformal radiotherapy (3-DCRT) and stereotactic ablative 
radiation therapy (SABR), allows precise targeting and delivery of radiotherapy. SABR 
for lung cancer utilizes elements of 3-DCRT and also incorporates a variety of systems 
for taking cancer motion into consideration and decreasing set-up uncertainty using 
image guided radiotherapy techniques (9). These systems allow reduction of treatment 
volumes facilitating hypofractionation with markedly increased daily doses (>10 GY) and 
a significantly reduced overall treatment time. The combination of multiple beam angles 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 4 of 26 
 
to achieve sharp dose gradients, high precision localization and a high dose per fraction 
in extracranial locations are referred to as SABR. This approach delivers a high 
biological effective dose (BED) to the target while minimizing the normal tissue 
toxicities, this may translate into improved local control and survival. 
 
Several studies have reported significantly improved local control and survival using 
SABR in patients with stage I lung cancer (10-14). Onishi et al (10) retrospectively 
evaluated results from a Japanese multi-institutional SABR study (18). Patients with 
Stage I NSCLC (n = 245; median age, 76 years; T1N0M0, n = 155; T2N0M0, n = 90) 
were treated with hypofractionated high-dose SABR in 13 institutions. Stereotactic 
three-dimensional treatment was performed using noncoplanar dynamic arcs or multiple 
static ports. A total dose of 18-75 gray (Gy) at the isocenter was administered in 1-22 
fractions. The median calculated biologic effective dose (BED) was 108 Gy (range, 57- 
180 Gy). During follow-up (median, 24 months; range, 7-78 months), pulmonary 
complications of National Cancer Institute-Common Toxicity Criteria Grade > 2 were 
observed in only 6 patients (2.4%). Local progression occurred in 33 patients (14.5%), 
and the local recurrence rate was 8.1% for BED > or = 100 Gy compared with 26.4% for 
< 100 Gy (P < 0.05). The 5-year overall survival rate of medically operable patients was 
88.4% for BED > or = 100 Gy compared with 69.4% for < 100 Gy (P < 0.05). Their data 
showed that hypofractionated high-dose SABR with BED < 150 Gy was feasible and 
beneficial for  curative treatment of patients with Stage I NSCLC. For all treatment 
methods and schedules, local control and survival rates were better with BED > or = 
100 Gy compared with < 100 Gy. Survival rates in medically operable, BED > or = 100 
Gy were comparable to those of surgery. 
 
In the United States, McGarry and Timmerman conducted phase I and phase II clinical 
studies using SABR with 60 Gy in 3 fractions without heterogeneity correction (54 Gy in 
3 fractions heterogeneity correction) with in stage I and selected stage II NSCLC (15, 
16). Based on recent RTOG data analysis, 60 GY without heterogeneity correction is 
equal to 54 GY with heterogeneity correction. They described 10 local failures in 47 
patients treated with stereotactic radioablation; 9 of these local failures occurred at 
doses ≤ 16 Gy X 3 and only one occurred at higher doses While maximum tolerated 
dose (MTD) was not achieved in patients with T1 tumors, in the T2 group with tumors > 
5 cm, 3 of 5 patients treated with 24 Gy X 3 fractions suffered a toxicity ≥ grade 3 (two 
patients with pneumonitis, one with tracheal necrosis). The MTD for this subset was 
therefore defined at 66 Gy (22 Gy X 3 fractions). In their late phase II study (14), they 
found that peripheral lesions can be subjected to higher BEDs, but treatment of centrally 
located lesions can be associated with considerable long-term toxicity. For the latter, 
grade 3-5 long-term toxicity can be as high as 46% due to proximity of critical structures 
such as bronchus, major vessels, heart, spinal cord, esophagus and tracheal compared 
with 17% in peripherally located lesions. The Radiation Therapy Oncology Group 
recently published the final result for SABR in early stage NSCLC (RTOG 0236, chaired 
by Timmerman) in which patients with peripheral non-small cell lung cancers are treated 
with 60 Gy in 3fractions (54 Gy in 3 fractions heterogeneity correction); because of 
concerns regarding tracheal and bronchial stenosis at this dose level, the protocol 
defines a bronchial exclusion zone of 2 cm around major bronchi down to the lobar 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 5 of 26 
 
level; patients with central tumors within this bronchial exclusion zone are not eligible for 
the protocol. They reported 98% local control rate with promising survival and 
acceptable toxicity (12). 
 
SABR is now an accepted treatment for medically inoperable patients with stage I lung 
cancer, and patients with operable stage I lung cancer are entered on clinical protocols. 
Comparable outcomes after SABR and surgery treatments have been reported recently 
by several groups in patients with stage I NSCLC (17-20). Based on promising data 
mentioned above, we believe that it is necessary to conduct a prospective study to 
compare SABR with surgery, the current standard of care for stage I operable NSCLC. 
 
There are several common dose regiments of SABR, one is 40-50 Gy delivered in 4 
consecutive days and another one is the RTOG 0236 study using 54 Gy in 3 fractions 
delivered in 2 weeks. Based on Dr. Onishi’s report, a BED >= 100 GY is associated with 
better local control (91.9% vs 73.6%) and survival (88.4% vs 69.4%) compared with 
BED < 100 GY. However, a very high dose regimen such as RTOG 0236 is associated 
with unacceptable toxicity for centrally located lesions. 
 
At the University of Texas MD Anderson Cancer Center, we have treated more than 
1000 patients with early stage or recurrent NSCLC using 50 Gy in 4 fractions with 
heterogeneity correction in both peripherally and centrally located lesions (14, 21, 22). 
With 26 months median follow up (up to 78 months), the local control rate is higher than 
95% with median survival of 60 months and toxicity is acceptable even in centrally 
located lesions when normal tissue tolerance is respected . There were – a few cases of 
grade III/IV chronic toxicity (skin reaction and brachial plexus neuropathy) at the 
beginning of our program. Dose volume constrains have been modified based on these 
clinical data. Our data indicated that image-guided SABR with respect of critical normal 
tissue dose volume constraints is crucial to achieving optimal tumor control and 
minimizing side effects. 
 
As we know, lung cancer moves during the radiotherapy. Particularly for SABR, tumor 
motion must be taken into consideration due to the high dose per fraction. There are 
several options for motion management. 4-D CT simulation based treatment planning 
and volumetric image guided delivery has significantly improved accuracy of SABR and 
minimized target miss and normal tissue overdosing. Another image-guided SABR 
approach is on-board image tracking. Target position is verified prior to each fraction 
and tracked continually throughout treatment (23, 24). 
 
In the current study, we will use SABR to treat stage Ia NSCLC to a total dose of 50 GY 
with 12.5 GY/fraction (BED: 112.5 GY) for centrally located lesions and 54 Gy in 3 
fractions for peripheral lesions. We anticipate that this regimen will achieve improved 
local control with decreased acute and long term toxicities compared with conventional 
radiotherapy. 
 
Modern treatment planning systems, including PET/CT and 4-D CT, on-board 
volumetric image  or  tumor motion tracking based SABR planning and delivery are 
required to determine appropriate treatment margins. Initially patients were randomized 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 6 of 26 
 
to receive SABR or surgical resection. However, only 39 patients over 5 years were 
enrolled due to failure of treating physicians and patients to accept randomization. The 
study is now revised as a prospective single arm clinical trial of SABR in stage IA non- 
small cell lung cancer patients with the primary objective to evaluate the overall survival 
(OS) for stage I non-small cell lung cancer patients treated with stereotactic body 
radiotherapy (SABR). Overall survival, progression free survival at the primary site, 
disease specific survival, and toxicities will be analyzed and compared between these 
two modalities. 
 
Patient Eligibility: 
 
1. Histological confirmation of non-small cell cancer will be required by either biopsy or 
cytology. The following primary cancer types are eligible: squamous cell carcinoma, 
adenocarcinoma with or without BAC features, large cell carcinoma with or without 
neuroendocrine 
features, 
neuroendocrine 
carcinoma, 
bronchioloalveolar 
cell 
carcinoma, or non-small cell carcinoma not otherwise specified. 
 
2. Eligible patients must have appropriate staging studies identifying them as specific 
subsets of the revised IASLC stage IA based on the following combination of TNM 
staging: 
 
T1a,N0,M0 or T1b,N0,M0 
 
 
 
3. A PET/CT scan is required. Patients with hilar or mediastinal lymph nodes with short 
axis diameter < 1cm and no abnormal hilar or mediastinal uptake on PET will be 
considered N0. Patients with > 1 cm short axis diameter of hilar or mediastinal lymph 
nodes on CT or abnormal PET (including suspicious but non-diagnostic uptake) 
may still be eligible if directed tissue biopsy of all abnormally identified areas are 
negative for cancer. Solitary pulmonary lesions <6mm will not be considered 
significant. 
 
4. The patients must be considered a reasonable candidate for surgical resection of the 
primary tumor. Standard justification for deeming a patient medically operable based 
on   pulmonary function for surgical resection of NSCLC may include any of the 
following: Baseline FEV1 > 40% predicted, post-operative predicted FEV1 > 30% 
predicted, diffusion capacity > 40% predicted, absent baseline hypoxemia and/or 
hypercapnia, exercise oxygen consumption > 50% predicted, absent severe 
pulmonary hypertension, absent severe cerebral, cardiac, or peripheral vascular 
disease, and absent severe chronic heart disease. 
 
5. Patients must be ≥ 18 years of age. 
 
6. The patient’s Zubrod performance status must be Zubrod 0-2. 
 
7. Mandatory staging studies: Must be done within 10 weeks prior to study entry 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 7 of 26 
 
• PET/CT scan to include both lungs, the mediastinum, and adrenal glands; 
Primary tumor dimension will be measured on diagnostic CT and again on 
simulation CT. 
• Mediastinoscopy or endobronchial ultrasound (EBUS) guided biopsy of the 
mediastinal lymph nodes is required for all patients. 
• MRI or  CT  scans of brain if there are symptoms or signs suggesting brain 
metastases, 
• Invasive Mediastinal Staging – All patients with CT and/or PET evidence of hilar 
(level 10) or mediastinal lymph nodes > 1.0 cm in the shortest diameter must be 
staged by either cervical mediastinoscopy, esophageal endoscopic ultrasound 
guided biopsy, or endobronchial ultrasound guided biopsy. For those patients 
with left-sided tumors with enlarged (greater than 1.0 cm in the shortest 
diameter) aortopulmonary window nodes, a lymph node biopsy must be obtained 
of aortopulmonary nodes by either extended mediastinoscopy, Chamberlain 
procedure, VATS approach, or ultrasound guided biopsy to ensure that the 
patient does not have N2 disease. At the time of cervical mediastinoscopy, 
esophageal endoscopic ultrasound guided biopsy, or endobronchial ultrasound 
guided biopsy the following nodal stations must be examined and biopsied, if 
present: ipsilateral nodal station 4, contralateral nodal station level 4 and the 
subcarinal nodes (level 7). Any lymph node in the superior mediastinum or 
anterior mediastinum for left-sided tumors measuring greater than 1.0 cm in the 
shortest axis on CT scan and/or PET positive must be identified and biopsied. 
These nodal stations must be evaluated and nodes from these areas must be 
sampled if they are present, otherwise, the surgeon should note (on the 
Operative Report submitted for this procedure) that these areas were inspected 
and no nodes were present. For patients to be eligible, any positive mediastinal 
or distant sites identified on PET scan must be biopsy negative. 
 
8. Patients must sign a study-specific consent form. 
 
9. Patients (men and women) of child bearing potential should use an effective (for 
them) method of birth control throughout their participation in this study. 
 
Patient Ineligibility: 
 
1. Patients with primary tumors > 3 cm. 
2. Patients with well-differentiated neuroendocrine carcinoma (carcinoid tumor). 
3. Direct evidence of regional or distant metastases after appropriate staging studies, 
or synchronous primary or prior malignancy in the past 3 years other than 
nonmelanomatous skin cancer or in situ cancer. 
4. Previous lung or mediastinal radiotherapy. 
5. Plans for the patient to receive other concomitant local therapy (including standard 
fractionated radiotherapy and surgery) while on this protocol except at disease 
progression. 
6. Pregnant or lactating women, as treatment involves unforeseeable risks to the 
embryo or fetus. 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 8 of 26 
 
7. Cannot achieve acceptable SABR planning to meet minimal requirement of target 
coverage and dose-volume constraints of critical structures (see RT techniques). 
 
Linear Accelerator (Linac) based SABR: 
 
Immobilization and simulation: 
 
Patients will be evaluated for regularity of breathing, responsiveness to feedback 
guidance, breath-hold capability. Based on this evaluation, one of the following 
acceptable treatment delivery techniques will be selected according to the treating 
physician’s discretion: 
 
1. breath-hold with feedback guidance 
 
2. gated treatment 
 
3. ITV based free-breathing 
 
A CT study taken using the same method of respiratory management as treatment will 
be required for treatment planning purposes. This includes 4DCT for free-breathing, 
gated or abdominal compression techniques or repeated breath-hold CTs for breath- 
hold techniques. Feedback guidance, visual and/or audio, will be used for all patients 
who would both benefit from and respond to training with the feedback devices. 
 
Four-dimensional CT is method of acquiring a collection of 3DCTs each representing a 
different portion of the patients breathing cycle. 4DCT acquires data for all locations in 
the treatment area over a time equal to or greater than a full respiratory cycle while 
simultaneously monitoring respiration. This is commercially available from several 
vendors using either a CINE or Helical acquisition technique. For free breathing 
treatment techniques radiotherapy will be designed based on the path of tumor motion 
during the whole breathing cycle, or a subset for gated techniques. For breath-hold 
treatment techniques the target shall be determined from a series of breath-hold CTs 
acquired at the time of simulation. 
 
1. All simulations are strongly recommended to be done on CT scanners capable of 
acquiring 4DCT image data sets. Intravenous contrast is encouraged to help 
distinguish centrally located tumor from adjacent hilar vessels as appropriate. 
 
2. Each patient will be immobilized in the treatment position on a flat table 
according to institutional practice and imaged in the treatment position. 
 
3. The imaging session should consist of acquisition of a 4DCT covering both lungs 
entirely as well as the entire treatment volume plus at least 5 cm. 
 
4. If the tumor is observed to move more than 1 cm on the 4DCT (edge to edge at 
motion extremes) or if critical normal tissue sparing is of concern, respiratory gated 
treatment, either free breathing or breath hold, should be considered. 

Protocol 2007-0870 
Revised Oct 28,2020 
Page 9 of 26 
 
5. An extended range free breathing scan may be acquired at the same time to 
serve as an anatomical reference. 
 
Target delineation for SABR: 
 
Four-dimensional (4D) CT images are strongly recommended in all cases. A 5-mm 
margin was added to iGTV to account for set-up errors, thereby creating the PTV. 
 
Gross Tumor Volume (GTV): PET-CT scans should be used for the staging purposes 
and a guide. The GTV should be delineated using a 4-D CT taken in treatment position. 
Gross tumor volumes (GTVs) were delineated by using maximum intensity projection of 
4D CT and modified by visual verification at different breathing phases. The path of 
movement of the GTV during the respiratory cycle was the internal gross tumor volume 
(iGTV). Pulmonary extent of lung tumors should be delineated on lung windows 
settings. However, soft tissue windows with contrast may be used to avoid inclusion of 
adjacent vessels, atelectasis, or mediastinal or chest wall structures within the GTV. 
The target lesion will be outlined by an appropriately trained physician. 
 
Clinical Target Volume (CTV): CTV margin is set to zero. 
 
Planning Target Volume 1 (PTV): iGTV plus 5 mm isotropic margin to take residual 
motion, set up, uncertainty into consideration. No additional margins were used 
between the PTV and the block edge. 
 
Contouring of Normal Tissue Structures 
 
Spinal Cord The spinal cord will be contoured based on the bony limits of the spinal 
canal. The spinal cord should be contoured starting at least 10 cm above the superior 
extent of the PTV and continuing on every CT slice to at least 10 cm below the inferior 
extent of the PTV. 
 
Esophagus The esophagus will be contoured using mediastinal windowing settings on 
CT to correspond to the mucosal, submucosa, and all muscular layers out to the fatty 
adventitia. The esophagus should be contoured starting at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 cm below the 
inferior extent of the PTV. 
 
Brachial Plexus 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 2nd rib. This contour is 
only required when the lesion is located in the upper lobe. 

Protocol  2007-0870 
Revised March 7, 2017 
Page 10 of 26 
 
 
 
Heart The heart will be contoured along with the pericardial sac. The superior aspect (or 
base) for purposes of contouring will begin at the level of the inferior aspect of the aortic 
arch (aorto-pulmonary window) and extend inferiorly to the apex of the heart. 
 
Trachea and Proximal Bronchial Tree The trachea and proximal bronchial tree will be 
contoured as two separate structures using mediastinal windows on CT to correspond 
to the mucosal, submucosa and cartilage rings and airway channels associated with 
these structures. For this purpose, the trachea will be divided into two sections: the 
proximal trachea and the distal 2 cm of trachea. The proximal trachea will be contoured 
as one structure, and the distal 2 cm of trachea will be included in the structure 
identified as the proximal bronchial tree. 
 
Proximal Trachea Contouring of the proximal trachea should begin at least 10 cm 
superior to the extent of the PTV or 5 cm superior to the carina (whichever is more 
superior) and continue inferiorly to the superior aspect of the proximal bronchial tree. 
 
Proximal Bronchial Tree The proximal bronchial tree will include the most inferior 2 cm 
of distal trachea and the proximal airways on both sides as indicated in the diagram. 
The following airways will be included according to standard anatomical relationships: 
the distal 2 cm of trachea, the carina, the right and left mainstem bronchi, the right and 
left upper lobe bronchi, the bronchus intermedius, the right middle lobe bronchus, the 
lingular bronchus, and the right and left lower lobe bronchi. Contouring of the lobar 
bronchi will end immediately at the site of a segmental bifurcation. 
 
Whole Lung Both the right and left lungs should be contoured as one structure. 
Contouring should be carried out using pulmonary windows. All inflated and collapsed 
lung should be contoured; however, gross tumor (GTV) and trachea/ipsilateral bronchus 
as defined above should not be included in this structure. 
 
Chest wall/Skin: The skin and the chest wall outside lung will be contoured. 
 
 
Treatment planning: 
 
Three-dimensional conformal SABR or intensity-modulated radiotherapy (IMRT) or 
volumetric modulated radiotherapy (VMAT) plan should be optimized using 6 to 12 
coplanar or non-coplanar 6-MV photon beams or two arcs. SABR will be prescribed to a 
dose of 50 Gy to the PTV between the 75% and 90% isodose lines, which are created 
via AAA, Pinnacle calculation algorithms with heterogeneity correction. Typically, the 
lower prescription isodose line is chosen when the proximity of critical normal structures 
mandated a compromise to the PTV, and therefore a higher dose to the tumor center 
and sharper dose gradients are required. Normal tissue dose-volume constraints are 
based on BED calculations and our previous clinical findings of the toxicity of SABR and 
are shown in Table 1. It is required that the prescribed isodose line cover 100% of the 
IGTV in all cases. Typically, when the tumor was close to a critical structure, a 
compromise in PTV coverage is considered acceptable. In any situation, however, the 
iGTV plus a margin of 5 mm was required to receive at least 95% of the prescribed 

 
Protocol 2007-0870 
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Page 11 of 26 
 
dose and at least 95% of the iGTV plus a margin of 5 mm should receive at least the 
prescribed dose. Patients with lesions very close/ abutting to critical structures and 
whose normal tissue dose volume constraints, except for preferred dose volume 
constraints, can’t be achieved should be removed from protocol. 
 
Treatment Delivery 
 
Daily imaging using in-room CT or linac-based cone beam CT (CBCT) will be required 
before each fraction. Adjustment of patient position is needed if target coverage is not 
adequate and/or critical normal tissues toxicity is a concern. Particularly, if the 
relationship between the GTV and the nearby boney anatomy moves beyond the PTV, 
the position is required to be re-adjusted and confirmed by repeated on-board CT. 
 
a. The patient is initially set up based on simulation skin marks. The patient is then 
shifted to be approximately at the final isocenter in the longitudinal (sup-inf) and 
vertical (AP) direction, the lateral position is left at zero to facilitate CT imaging. 
 
b. CT images are acquired either free breathing or breath-hold and these are used 
to determine a couch shift to cover the GTV. 
 
c. The couch is shifted to the determined coordinates daily (for 4 fraction 
treatments) and orthogonal projection images are taken and shifts are verified based 
on bony anatomy as compared with DRRs (shifts away from boney anatomy to cover 
the GTV are factored into this evaluation). If any disagreement is identified the CT 
acquisition shall be repeated. 
 
SABR Dose Specification: 
Peripheral lesion: 
Patients with peripherally located lesions, defined as located more than 2 cm away 
using the CT lung window level in all directions around the proximal bronchial tree 
(carina, right and left main bronchi, right and left upper lobe bronchi, intermedius 
bronchus, right middle lobe bronchus, lingular bronchus, right and left lower lobe bronchi 
(See figure 2), major vessels, esophagus, heart, tracheal, vertebral body, pericardium, 
mediastinal pleural and brachial plexus, 

 
Protocol 2007-0870 
Revised March 7, 2017 
Page 12 of 26 
 
 
 
 
will  receive  SABR  for  a  total  dose  of  54  GY  calculated  using  the  Monte  Carlo 
comparable  algorithm and CT heterogeneity correction with 18 Gy/fraction for a total of 
3 fractions of radiation. The SABR dose is prescribed to the highest isodose line which 
is required to cover 100% of the GTV and more than 95% of the PTV (GTV + 5 mm). 
100% of the PTV volume coverage by at least prescribed GY is encouraged. Higher 
isodoses (hotspots) must be manipulated to occur within the target and not in adjacent 
normal tissue. Treatment is recommended to be delivered on consecutive days. To 
consider some unanticipated issues such as holidays, machine down time, patient 
hospitalizations, and travel difficulty, treatment interruption will be allowed, but it should 
be completed within 12 days. It will be considered a minor deviation if treatment is 
delivered within 14days and a violation if longer than 14days. 
 
It is crucial that all critical organ dose-volume limits are evaluated and respected. 
 
 
Organ 
Volume 
Dose (cGy) 
Spinal Cord 
Any point 
18 Gy(6 Gy per fraction) 
Esophagus 
Any point 
27 Gy (9 Gy per fraction) 
Ipsilateral Brachial Plexus 
Any point 
24 Gy (8 Gy per fraction) 
Heart/Pericardium 
Any point 
30 Gy (10 Gy per fraction) 
Trachea and Ipsilateral 
Bronchus 
Any point 
30 Gy (10 Gy per fraction) 

 
Protocol 2007-0870 
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Page 13 of 26 
 
 
Whole Lung (Right & Left, 
subtracting GTV) 
Mean Lung Dose (MLD) 
V20 Gy V10 Gy 
V5 Gy 
<= 5 Gy (preferred) 
<10%(of volume,preferred) 
<15% (preferred) 
<20% (preferred) 
Skin 
Chest wall 
<= 1 cc 
<= 50 cc(<=30cc preferred) 
35 Gy (11.7 Gy/fx) 
35 Gy (11.7 Gy/fx) 
Table 1: Critical Organ Dose-Volume Limits for peripheral lesions 
 
The table 1 lists maximum dose limits to a point or volume within several critical organs. 
These are absolute limits except for preferred dose volume constraints, and 
treatment delivery that exceeds these limits will constitute a major protocol 
violation. The dose is listed as total over 3 fractions and per fraction. If dose volume 
constraints of critical structures conflicts with required dose coverage of target volume, 
priority should be given to keep these dose volume constraints. However, 100% of the 
GTV volume must receive at least the prescribed dose (hot spots within GTV are 
allowed), ≥95% of the PTV volume must receive at least the prescribed dose, otherwise, 
it will constitute a major protocol violation. If these conditions cannot be met, the patient 
should be excluded from this protocol. 
 
Central lesion: 
 
Patients with a centrally located lesion, defined as located within 2 cm but more than 0.5 
cm away using the CT lung window level of the bronchial tree (carina, right and left main 
bronchi, right and left upper lobe bronchi, bronchus intermedius , right middle lobe 
bronchus, lingular bronchus, right and left lower lobe bronchi), major vessels, 
esophagus, heart, tracheal, pericardium, mediastinal pleural and brachial plexus and 1 
cm away from the spinal canal, will receive SABR for a total dose of 50 GY calculated 
with Monte Carlo comparable algorithm and CT based heterogeneity correction with 
12.5 GY/fractions for a total of 4 fractions. This dose is prescribed to the highest 
isodose line which is required to cover 100% of the GTV and more than 95% of the PTV 
(GTV + 5 mm). 100% of the PTV coverage by at least the prescription dose is 
encouraged. 
 
Higher isodoses (hotspots) must be manipulated to occur within the target and not in 
adjacent normal tissue. Treatment is recommended to be delivered on consecutive 
days. To consider some unanticipated issues such as holidays, machine down time, 
patient hospitalizations, and travel difficulty, treatment interruption will be allowed but it 
should be completed within 5 days. It will be considered a minor deviation if treatment is 
delivered within 12 days and a violation if longer than 14 days. 
 
The dose delivered to all important organs should be kept in the dose volume 
constraints as showed below: 
 
Critical organ dose-volume constraints for central lesions: 
It is required that spinal cord must be at least 5 mm away from 35 Gy isodose line. 

 
Protocol 2007-0870 
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Page 14 of 26 
 
 
Volume 
Dose (cGy) 
Esophagus 
Dmax 
<= 1 cc 
35 Gy (8.8 Gy/fx) 
30 Gy (7.5 Gy/fx) 
Brachial Plexus 
Any point 
<= 0.2cc 
<35 Gy 
30 Gy (7.5 Gy/fx) 
Trachea 
<= 1 cc 
35 Gy (8.8 Gy/fx) 
Main bronchus and bronchial 
tree 
<= 1 cc 
35 Gy (8.8 Gy/fx) 
Heart 
Dmax 
<= 1 cc 
<= 5 cc 
45 Gy (11.25 Gy/fx) 
40 Gy (8.8 Gy/fx) 
20 Gy (5 Gy/fx, preferred) 
Whole Lung (Right & Left, 
subtracting GTV) 
MLD 
V20 GY 
V10 GY 
V5 GY 
<= 5 Gy (preferred) 
<10% (of volume,preferred) 
<15% (preferred) 
<20% (preferred) 
Major vessels 
Dmax 
<= 1 cc 
<=56 Gy 
40 Gy (10 Gy/fx) 
Skin Chest wall Spinal cord 
<= 1 cc <= 50 cc (<=30 cc 
preferred) 
Dmax 
35 Gy (8.8 Gy/fx) 35 Gy (8.8 
Gy/fx) 
<25 Gy (6.25 Gy/fx) 
Table 2: Critical Organ Dose-Volume Limits for central lesions. The table is 
modified based  on our previous publications (22,23) 
 
These are absolute limits except for preferred dose volume constraints, and 
treatment delivery that exceeds these limits will constitute a major protocol 
violation. The dose is listed as total over 4 fractions and per fraction. If dose volume 
constraints of critical structures conflicts with required dose coverage of target volume, 
priority should be given to keeping these dose volume constraints. However, 100% of 
the GTV volume must receive at least the prescribed dose (hot spots within GTV are 
allowed), ≥95% of the PTV volume must receive at least the prescribed dose, otherwise, 
it will constitute a major protocol violation. If these conditions cannot be met, the patient 
should be excluded from this protocol. 
 
Chemotherapy after SABR: 
 
Adjuvant Chemotherapy after SABR is not permitted for clinical stage IA patients. 
 
Salvage surgery after SABR: 
 
For a patient who has persistent or recurrent local disease after SABR as demonstrated 
by CT and/or PET and confirmed by biopsy after SABR, salvage surgical resection 
should be considered if the patient still can tolerate it. We will consider post-operation 
radiotherapy and chemotherapy for a positive margin or pathological N1 and N2. 

 
Protocol 2007-0870 
Revised March 7, 2017 
Page 15 of 26 
 
Pre-treatment evaluation: 
 
A complete history and physical to include performance status and concurrent non-
malignant disease and its therapy must be recorded. 
 
Laboratory studies will include a CBC with differential, platelet count, LFTs, electrolytes, 
creatinine. 
 
Chest X-ray (optional), MRI or CT scans of brain should be performed if signs or 
symptoms of brain metastases are noted. A PET/CT scan within 10 weeks prior to 
study entry is required. All patients must have the mediastinum stage by EBUS or 
mediastinoscopy. 
 
PFTs including FEV1, DLCO, TVC, FEV should be obtained within 10 weeks prior to 
study entry. A xenon study is recommended to evaluate the patient’s tolerance for 
surgical resection. 
 
Prescription Dose 
Monte Carlo comparable 
Algorithm 
Peripheral Lesions 
54 Gy in 3 fractions 
Central Lesions 
50 Gy in 4 fractions 
Table 3: Summary of prescription doses 
 
Treatment evaluation: 
 
Acute radiation reactions including esophagitis, pneumonitis and other adverse events 
will be evaluated during the period of treatment. The adverse events will be graded 
according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC, V3). Only 
grade III and above toxicity will be recorded and analyzed. 
 
Post-treatment evaluation: 
6 months 
12 months 
18 
months 
2 years 
3 years 
4 years 
5 years 
H & P 
X 
X 
X 
X 
X 
X 
X 
PET-CT 
X 
(Recommended but not 
required) 
CT 
X 
(only if PET/CT 
not done) 
X 
X 
X 
X 
X 
X 
PFT 
 
X 
(Recommended 
but not 
required) 
 
 
 
 
 
All timepoints are defined as +/- 1 month 
 
 
 

 
Protocol 2007-0870 
Revised March 7, 2017 
Page 16 of 26 
 
Patients will be followed according to the table above following treatment. The first point 
of follow up will be at 6 months after treatment consisting of a history and physical 
exam and CXR if clinically indicated. PET-CT scanning is recommended but not 
required at the 6-12 month follow up period. All patients will undergo a CT scan at the 6 
month follow up. If PET-CT is not performed at the 6-12 month follow up period, then a 
CT scan of the chest is required. PFTs are also recommended but not required 
during the 12 month follow up period. CT scans are required at the 12 month, 18 month, 
24 month, 3 year, 4 year and 5 year follow-up encounters. All CT scans should be 
performed with IV contrast if possible. Interpretation of imaging studies for each 
patient by a single radiologist is strongly encouraged. It is strongly recommended that 
a single radiologist be appointed to coordinate the interpretation of all imaging studies for 
this protocol. Each of the above follow up points should be accompanied by a history 
and physical exam. For all follow up points except the 4-6 week following period, 
timing of +/- 1 month from the stated time period will be accepted. 
 
Progression free survival at the primary site will be evaluated by the serial CT scanning 
as described in the follow up table above. Two years PFS will be calculated. PET 
information will be considered for calculation of PFS for distant metastasis and local 
recurrence. 
 
Disease specific survival will be evaluated. Grade 3 and above acute and chronic 
toxicities by Common Toxicity Criteria will be analyzed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol 2007-0870 
Revised March 7, 2017 
Page 17 of 26 
 
RESPONSE 
CT MASS SIZE 
(RECIST) 
CT MASS 
QUALITY 
PET* 
COMPLETE 
(Two of the 
following) 
Lesion 
disappearance 
(scar) or less than 
25% of original 
size 
Cyst cavity 
formation 
Low density 
SUV<2.5 
PARTIAL 
(One of the 
following) 
More than 30% 
decrease in the 
sum LD of target 
lesions 
Mass central 
necrosis or 
central cavity 
with liquid 
density 
Decreased SUV or 
area of FDG uptake 
STABLE 
LESION 
(One of the 
following) 
Less than 30% 
decrease in the 
sum LD of target 
lesions 
Mass solid 
appearance, no 
central necrosis 
or cavity 
Unchanged SUV or 
area of FDG uptake 
PROGRESSION 
Increase of more 
Solid mass, 
Higher SUV (>5) or 
(Two of the 
than 25% in sum 
invasion 
larger area of FDG 
following) 
LD of target 
adjacent 
uptake more than 6 
lesions 
structures 
months after SABR 
should promote 
biopsy (24) 
 
Response assessment and calculation of PFS at the primary site: 
 
Modified from the RECIST criteria (20, 21) *. (Target lesions= tumors treated; Sum LD= 
sum of the largest diameter (LD) of target lesion; SUV= standard uptake value of 18- 
FDG in PET scan). 

 
Protocol 2007-0870 
Revised March 7, 2017 
Page 18 of 26 
 
 
Evaluation of Non-Target Lesions 
Marginal Failure 
(MF) 
Refers to a measurable tumor located in the same lobe after 
SRT and within 2.0 cm of the treated PTV that has been 
confirmed with PET with uptake of a similar intensity as the pre- 
treatment staging PET, or confirmed by biopsy. 
Regional Failure 
(RF) 
Refers  to  a  measurable  tumor  within  lymph  nodes  along  the 
natural lymphatic drainage typical for the location of the treated 
primary disease with dimension of at least >1.0 cm in the short 
axis on imaging studies (preferably CT scans) within the lung, 
bronchial hilum, or the mediastinum. Equivocally appearing 
enlarged lymph nodes should be positive on PET imaging or 
biopsied to confirm involvement with carcinoma. 
Metastatic 
Dissemination 
(MD) 
Refers  to  the  appearance  after  protocol  therapy  of  cancer 
deposits characteristic of metastatic dissemination from non- 
small cell lung cancer. Appropriate evaluations for making this 
determination include physical examination and imaging studies. 
PET scan or biopsy to confirm MD is encouraged but not 
required. 
 
 
 
Criteria for Removal from Protocol Treatment 
 
All reasons for discontinuation of treatment must be documented. All patients will be 
followed until death or 3 years post-treatment (whichever time point comes first) even 
though they are removed from protocol treatment. 
 
1. Disease progression at any time during therapy or the follow up period; the patient 
should be re-staged and sites of recurrence and/or progression documented. Re- 
biopsy is strongly encouraged. 
2. Development of unpredictable, irreversible, or persistent non-hematological grade 4 
toxicity. 
3. The patient may elect to withdraw from study treatment at any time for any reason. 
4. Development of intercurrent, non-cancer related illnesses  that prevent  either 
continuation of therapy or regular follow up. 

Protocol 2007-0870 
  Revised March 7, 2017 
Page 19 of 26 
 
 
STATISTICAL CONSIDERATIONS 
 
Sample Size Justification 
 
The primary endpoint is overall survival. From the historical data of 229 patients treated 
with surgery, the 3-year OS rate was 85.5% (median OS time of 13.27 years). We expect 
that treatment of SABR will achieve similar therapeutic results. We will treat 80 patients 
with an anticipated accrual rate of 2 patients per month. Originally 20 patients entered in 
the first STARS randomized trial were to be included. However, these 20 patients were 
included in a combined randomized clinical trial analysis recently published in Lancet 
Oncology (Chang et al. Stereotactic ablative radiotherapy versus lobectomy for operable 
stage I non-small-cell lung cancer: a pooled analysis of two randomized trials, Lancet 
Oncology, 2015). Twenty additional patients will be entered in the study as the original 20 
patients include many from other institutions where it will be difficult to obtain current 
follow-up and to avoid publishing results from the same patients in more than one paper. 
To achieve the sample size of 80 treated patients, we would want to inflate the maximum 
sample size to 90 to account for the potential patients who are enrolled but not treated for 
ineligibility reasons.   
 
All patients will be followed for a minimum of 3 years or until death. The final analysis 
will be performed when the last patient accrued in the trial is followed for 3 years, even if 
the total number of patients on the SABR arm is less than 80 patients. With 80 
patients in the trial, a two-sided 95% confidence interval (CI) for the 3-year OS rate 
will extend ±7.7% from the observed rate for an expected rate of 85.5% 
(nQuery7.0). The final conclusion will be based on a 95% CI of the adjusted 
hazard ratio of OS computed from a Cox proportional hazards regression model 
including the potential confounding covariates given the study is not a randomized 
trial(27,28). Non- inferiority is claimed if the 3-year OS rate is not lower than the 
historical arm by more than 12%. The corresponding hazard ratio between the 
SBRT arm and the historical arm for the 3-year OS rate of 73.5% vs. 85.5% is 
1.965. The upper bound of the observed 95% CI for HR less than 1.965 would lead 
to a conclusion of non- inferiority of SBRT to surgery. On the other hand, we will not 
claim that SBRT is non- inferior to surgery if the upper bound of the observed 95% 
CI for HR is greater than 1.965. 
 
Trial Monitoring for OS 
 
We will monitor the primary endpoint, OS, in the trial. The first of two interim analyses 
will occur when a total of 40 patients have accrued. The second interim analysis will 
occur when the 60th patient accrues. Interim analysis will be deferred if insufficient 
events have occurred. At both interim analyses trial accrual will stop for predicted non-
inferiority if there is at least 99% predictive probability of non- inferiority assuming the 
currently accrued patients are followed for an additional three years. Similarly, 
accrual will stop for futility if this predictive probability is less than 1%. These 
conservative boundaries have negligible effects on the trial’s operating characteristics. 
 
 
 
 
 

Protocol 2007-0870 
  Revised March 7, 2017 
Page 20 of 26 
 
 
 
 
Analysis Plans 
 
The primary efficacy endpoint is overall survival. The secondary endpoints include local 
recurrence free survival and time to local recurrence. OS will be measured from the  
start of treatment until death. LRFS will be measured from the start of treatment until the 
first date that local recurrence is objectively documented or death due to any cause, and 
patients without local recurrence or death will be censored at the last date when 
recurrence status is checked. TTLR will be measured from the start of treatment until 
the first date the local recurrence is objectively documented, and patients without local 
recurrence will be censored at the last date when recurrence status is checked.  The 
Kaplan-Meier method will be used to estimate OS and LRFS(25). The method of 
Gooley, et al. will be used to estimate TTLR with death as a competing event(26). 
Complete response rate and overall response rate will be estimated with their 95% 
confidence intervals. Complete response rate and overall response rate will be 
estimated with their 95% confidence intervals. 
 
We will conduct a risk-factor matched comparison study of the outcome  (overall survival, 
progression-free survival,  pattern of failure,  grade 3 and above toxicities) between the current 
protocol and our institutional database using modern video-assisted thoracoscopic surgery 
(VATS) for stage I NSCLC (Stephens et al: Europe Journal of Cardio-Thoracic Surgery, 1-7, 
2014, doi:10.1093.).  We realize that selection bias between the current single arm trial and the 
VATS group will inherently present in this analysis.  Besides the regular analysis we may also 
perform the propensity score matched (PSM) analysis to reduce the impact of the selection bias 
on the estimation of the primary endpoint, overall survival (OS), between the two groups. We 
will first decide on the set of potential confounding variables such as age, tumor size, etc., to be 
used for the matching. We will then identify patients from the two groups at a ratio of 1:1 or 1:2 
using a 5 to 1 digit greedy match algorithm.  We will use Fisher’s exact test or Chi-square test to 
evaluate the association between categorical variables.  We will use t-test or Wilcoxon rank sum 
test to evaluate the difference in a continuous variable between patient groups.  Kaplan-Meier 
method will used for time-to-event outcome (including OS, LRFS, etc.) analysis, and log-rank 
test will be used to assess the difference in time-to-event outcome between patient 
groups.  Multivariable Cox proportional hazards models will be used for multicovariate analysis 
to include important and significant covariates.  To quantify the risk of developing progression 
event, we will use the cumulative incidence function counting death without progression (local 
recurrence, regional recurrence, or distant mets) as competing risk. To compare cumulative 
incidence functions, we will use Gray’s test. The multivariable proportional hazards models of 
Fine and Gray may be used. 
 
Safety: 
 
Primary endpoint: 
 
The primary safety endpoint is the occurrence of acute and late treatment-related grade 
3 or 4 toxicity (per CTCAE, v.3.0) related to specific symptoms, including: 
 
• Gastrointestinal: dysphagia, esophagitis, esophageal stricture, esophageal 
ulceration 
• Cardiac: pericarditis, pericardial effusion, cardiomyopathy, ventricular dysfunction 
• Neurologic: myelitis, neuropathy - cranial and motor 
• Hemorrhage: pulmonary or upper respiratory 

Protocol 2007-0870 
  Revised March 7, 2017 
Page 21 of 26 
 
• Pulmonary: decline in pulmonary function as measured by pulmonary function 
tests, pneumonitis, pulmonary fibrosis, hypoxemia, pleural effusion or any grade 
4 or 5 toxicity attributed to the therapy. 
 
Secondary endpoint: 
 
Toxicity frequency will be tabulated by most severe occurrence. 
 
 
 
ADVERSE EVENT REPORTING 
 
Adverse events will be reported in accordance with all applicable FDA, or regional/local 
governmental laws, ICH, and IRB rules, regulations, and guidelines including the 
International Standards Organization (ISO) 14155 and the Medical Devices (MEDDEV) 
guidelines. All adverse events regardless of toxicity grade and assigned treatment will 
be recorded in the appropriate online databases. Adverse event data will be analyzed 
and submitted to appropriate regulatory agencies per local regulations. 

Protocol 2007-0870 
  Revised March 7, 2017 
Page 22 of 26 
 
 
References: 
 
1. Mountain CF. A new international staging system for lung cancer. Chest. 89:225-233, 
1986. 
2. Naruke T, et al. Prognosis and survival in resected lung carcinoma based on the new 
international staging system. J Thorac Cardiovasc Surg. 96: 440-447, 1988. 
3. Kaskowitz L, et al. Radiation therapy alone for stage I non-small cell lung cancer. Int 
J Radiat Oncol Biol Phys. 27: 517, 1993. 
4. Dosoretz DE, Katin MJ, Blitzer PH, Rubenstein JH, Galmarini DH, Garton GR, 
Salenius SA. Medically inoperable lung carcinoma: The role of radiation therapy. Sem 
Radiat Oncol. 6(2):98-104, 1996. 
5. Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone 
for medically inoperable stage I non-small cell lung cancer: The Duke experience. Int 
J Radiat Oncol Biol Phys. 40(1): 149-54, 1998. 
6. Fang L, Komaki R, Allen P, et al. Comparison of outcomes for patients with medically 
inoperable Stage I non-small-cell lung cancer treated with two-dimensional vs. three- 
dimensional radiotherapy. Int J Radiat Oncol Biol Phys 2006, 66, 108-116. 
7. Dosoretz D, et al. Radiation therapy in the management of medically inoperable 
carcinoma of the lung: Results and implications for future treatment strategies. Int J 
Radiat Oncol Biol Phys. 24:3, 1992. 
8. Dosoretz DE, Galmarini D, Rubenstein JH, et al. Local control in medically inoperable 
lung cancer: An analysis of its importance in outcome and factors determining the 
probability of tumor eradication. Int J Radiat Oncol Biol Phys. 27(3): 507-16, 1993. 
9. Chang JY, Roth JA. Stereotactic body radiation therapy for stage I NSCLC. Thoracic 
Surgery Clinics 17:251-259, 2007. 
10. Onishi H, Araki T, Shirato H, et al: Stereotactic hypofractionated high-dose 
irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects 
in a Japanese multiinstitutional study. Cancer. 2004 Oct 1;101(7):1623-31. 
11. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 
48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a 
stereotactic body frame. Int J Radiat Oncol Biol Phys. 63(5):1427-31, 2005. 
12. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for 
inoperable early stage lung cancer. JAMA. 2010; 303:1070–1076. 
13. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of 
medically inoperable stage I non small-cell lung cancer patients treated with 
stereotactic body radiotherapy. J Clin Oncol. 2009; 27:3290–3296. 
14. Chang JY, Liu H, Balter P, et al. Clinical outcome and predictors of survival and 
pneumonitis after stereotactic ablative radiotherapy for stage I non-small cell lung 
cancer. Radiat Oncol. 2012; 7:152. 
15. McGarry RC et al. Stereotactic body radiation therapy of early-stage non–small-cell 
lung carcinoma: phase I study. Int. J. Radiation Oncology Biol. Phys. 63(4): 1010– 
1015, 2005 
16. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive Toxicity When Treating 
Central Tumors in a Phase II Study of Stereotactic Body Radiation Therapy for 
Medically Inoperable Early-Stage Lung Cancer. J Clin Oncol 24(30):4833-4839, 2006. 
 
 
 
 

Protocol 2007-0870 
  Revised March 7, 2017 
Page 23 of 26 
 
17. Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SABR) for 
operable stage I non-small-cell lung cancer: can SABR be comparable to surgery? 
Int J Radiat Oncol Biol Phys. 2011; 81:1352-8. 
18. Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung 
radiotherapy or wedge resection for stage I non small-cell lung cancer. J Clin Oncol. 
2010; 28:928–935. 
19. Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy 
versus surgical resection for stage I non small cell lung cancer. J Thorac Cardiovasc 
Surg. 2010; 140:377–386. 
20. Shirvani SM, Jiang J, Chang JY, et al. Comparative effectiveness of 5 treatment 
strategies for early-stage non-small cell lung cancer in the elderly. Int J Radiat 
Oncol Biol Phys. 2012; 84:1060-1070. 
21. Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally 
and superiorly located Stage I or isolated recurrent non-small-cell lung cancer. Int J 
Radiat Oncol Biol Phys. 2008; 72:967–971. 
22. Chang JY, Liu H, Balter P, Komaki R, Liao Z, Welsh J, Mehran RJ, Roth JA and 
Swisher SG. Clinical outcome and predictors of survival and pneumonitis after 
stereotactic ablative radiotherapy for stage I non-small cell lung cancer. Radiation 
Oncology 7(1):152, 2012. e-Pub 9/2012. 
23: Chang JY, Xu, Q, Li Q et al: Stereotactic ablative radiotherapy for centrally located 
early stage or isolated parenchymal recurrences of NSCLC: How to fly in a “no fly 
zone”. J Thoracic Oncology, in press. 
24. Zhang X, Liu H, Balter P, et al. Positron emission tomography for assessing local 
failure after stereotactic body radiotherapy for non-small cell lung cancer. Int J 
Radiat Oncol Biol Phys. 2012; 85(5):1558-1565. 
25. Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. 
Journal of the American Statistical Association, 53:457-481, 1958. 
26. Gooley TA, Leisenring W, Crowley J, and Storer BE. Estimation of failure 
probabilities in the presence of competing risks: new representations of old 
estimators. Statistics in Medicine, 18:695-706, 1999. 
27. Rothmann M, Li N, Chen G, Chi GYH, Temple R, and Tsou HH. Design and 
analysis of non-inferiority mortality trials in oncology. Statistics in Medicine, 2003; 
22:239-264. 
28. Cox DR. Regression models and life tables (with discussion). Journal of the Royal 
Statistical Society B 1972; 34:187-220. 

Protocol 2007-0870 
Revised March 7, 2017 
Page 24  of 26 
 
 
 
APPENDIX A – Performance Scales 
 
 
KARNOFSKY PERFORMANCE SCALE: 
 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most 
personal needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death 
not imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 
 
 
ZUBROD PERFORMANCE SCALE: 
 
0 
Fully active, able to carry on all predisease activities without 
restriction (Karnofsky 90-100). 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out 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 any self-care. Totally confined 
to bed or chair (Karnofsky 10-20). 
5 
Death (Karnofsky 0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 2007-0870 
Revised March 7, 2017 
Page 25  of 26 
 
 
 
APPENDIX B - Revised Lung Cancer Staging IASLC Lung Cancer Staging Project 
 
Regional Lymph Nodes 
 
Direct extension of the primary tumour into lymph nodes is classified as lymph node 
metastasis. 
 
Distant Metastasis 
 
The categories M1 and pM1 may be further specified according to the following 
notation: 
 
Pulmonary PUL 
Bone marrow MAR 
 
Osseous OSS 
Pleura PLE 
 
Hepatic HEP 
Peritoneum PER 
 
Brain BRA 
Adrenals ADR 
 
Lymph nodes LYM 
Skin 
SKI Others OTH 
 
 
R Classification 
 
The absence or presence of residual tumour after treatment is described by the symbol 
R. The definitions of the R classification are: 
 
RX Presence of residual tumour cannot be 
assessed R0 No residual tumour 
R1 Microscopic residual tumour 
R2 Macroscopic residual tumour 
 
Lung 
(ICD-O C34) 
Rules for Classification 
The classification applies only to carcinomas. There should be histological confirmation 
of the disease and division of cases by histological type. 
The following are the procedures for assessing T, N, and M categories: 
T categories Physical examination, imaging, endoscopy, and/or surgical exploration 
N categories Physical examination, imaging, endoscopy, and/or surgical exploration 
M categories Physical examination, imaging, and/or surgical exploration 
 
 

Protocol 2007-0870 
Revised March 7, 2017 
Page 26  of 26 
 
 
 

Protocol 2007-0870 
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Page 27  of 26