Trial of Individualized Lung Tumor Stereotactic Ablative Radiotherapy (iSABR)
Phase: NA
Conditions: Non-small Cell Lung Cancer (NSCLC)
Sponsor: Stanford University

Version: July 21, 2020

 2
Department of Radiation Oncology 
875 Blake Wilbur Drive, MC 5847 
Phone : 650-725-2736 
Email : mbuyyou@stanford.edu 
 
Hokkaido University 
Hiroki Shirato, M.D., Ph.D. 
Department of Radiation Medicine 
Hokkaido University 
Graduate School of Medicine 
Kita 15 jo, Nishi 7 chrome, Kita ku, Sapporo, 
Hokkaido 060-8638 JAPAN 
Tel 81-011-706-5974  Fax 81-011-706-7876 
shirato@med.hokudai.ac.jp 
 
Tetsuya Inoue, M.D., Ph.D 
Department of Radiation Medicine 
Graduate School of Medicine 
North-15, West-7, Kita-ku, Sapporo, Hokkaido, 
060-8638, Japan 
TEL +81(11)-706-5974 
FAX +81(11)-706-7876 
t-inoue@med.hokudai.ac.jp 
 
 
 
 
 
 
 
 
 
Biostatistician: 
Alex McMillan, Ph.D. 
 
 
 
       
 
Department of Health Research and Policy 
       
 
Redwood Bldg, T101E 
 
 
       
 
Stanford, CA 94305-5405       
 
 
 
 
       
 
 
 
 
 
 
 
Study Coordinators: 
Stanford University 
 
Rachel Freiberg, Ph.D. 
       
Department of Radiation Oncology 
 
Cancer Clinical Trials Office 
 
Stanford University Medical Center 
 
800 Welch Road  
 
 
 
       
 
 
      Stanford, CA 94305-5763 
 
 
 
 
 
 
      Tel: 650-725-0438 
      
 
 
 
Hokkaido University 
 
Yuki Sasaki  

 3
 
Research Nurse 
 
Hokkaido University Hospital 
 
Clinical Research & Medical Innovation Center 
 
North-14, West-5, Kita-ku,  
 
Sapporo, Hokkaido, 060-8648, Japan 
 
Phone: +81(11)-706-7600 
 
Email: sasaki-y@med.hokudai.ac.jp 
 
 
Ms. Yuriko Takemura 
 
Research Fellow  
Global Station for Quantum Medical Science 
and Engineering 
 
Hokkaido University 
 
North-15 West-7 Sapporo 
 
JAPAN 
 
Phone: +81-11-706-8513 
 
Email: ytakemura@pop.med.hokukai.ac.jp 
 
Ms. Ran Kavanagh 
Research Project Coordinator 
Hokkaido University                        
Global Station for Quantum Medical Science 
and Engineering 
JAPAN 
 
Tel: +81-11706-8511 
Email: gsq@oia.hokudai.ac.jp 
 
 
 
 
 
 
 
 
 

 4
 
Contents 
1. 
SYNOPSIS .......................................................................................................................... 7 
2. 
SCHEMA .......................................................................................................................... 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................. 11 
4. 
OBJECTIVES .................................................................................................................. 12 
5. 
BACKGROUND AND RATIONALE ........................................................................... 12 
5.1 
Study Disease: Lung Cancer ......................................................................................... 12 
5.2 
Stereotactic Ablative Radiotherapy for Lung Cancer ................................................... 12 
5.3 
Audio-visual Biofeedback ............................................................................................. 13 
5.4 
Rationale for Study ....................................................................................................... 13 
5.5 
Correlative Studies Background ................................................................................... 14 
6. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................... 15 
6.1 
Inclusion Criteria .......................................................................................................... 15 
6.2 
Exclusion Criteria ......................................................................................................... 15 
6.3 
Informed Consent Process ............................................................................................ 15 
7. 
TREATMENT PLAN ...................................................................................................... 15 
7.1 
Study Design/Schedule .................................................................................................. 15 
7.2 
Procedures: SABR Administration and Radiation Treatment Planning....................... 16 
7.2.1 
Pre-SABR Tests, Procedures, and Planning ................................................................. 16 
7.2.2 
Fiducials ....................................................................................................................... 16 
7.2.3 
Simulation ..................................................................................................................... 16 
7.2.4 
Treatment planning ....................................................................................................... 16 
7.2.5 
SABR Treatment Delivery: ............................................................................................ 17 
7.3 
Duration of Follow-Up ................................................................................................. 24 
7.4 
Criteria for Removal from Study................................................................................... 25 

 5
7.5 
Alternatives ................................................................................................................... 25 
7.6 
Compensation ............................................................................................................... 25 
8. 
CORRELATIVE STUDIES ............................................................................................ 25 
8.1 
Analysis of patient plasma for biomarker development. ............................................... 25 
8.2 
Coding of specimens for privacy protection ................................................................. 26 
9. 
STUDY CALENDAR ...................................................................................................... 26 
10. 
MEASUREMENT OF ENDPOINT ............................................................................... 27 
10.1 
Anti-tumor Effect ........................................................................................................... 27 
10.2 
Definitions ..................................................................................................................... 27 
11. 
DATA REPORTING/REGULATORY CONSIDERATIONS .................................... 28 
11.1 
Institutional Review of Protocol ................................................................................... 28 
11.2 
Data and Safety Monitoring Plan ................................................................................. 28 
11.3 
Data Management Plan ................................................................................................ 30 
11.3.1 
Overview of Data Management at Stanford ............................................................. 30 
11.3.2 
Sponsorship of Coordinators at the International Sites ........................................... 31 
11.3.3 
Overview of Data Management for the International Sites ...................................... 31 
11.4 
Evaluation for Adverse Events ...................................................................................... 32 
11.5 
Stopping Rules .............................................................................................................. 34 
11.6 
Confidentiality............................................................................................................... 34 
12. 
STATISTICAL CONSIDERATIONS: TYPE AND NUMBER OF 
EXPERIMENTAL   SUBJECTS ............................................................................................... 34 
12.1 
Primary and Secondary Endpoints ............................................................................... 35 
12.2 
Sample Size ................................................................................................................... 35 
12.3 
Analysis populations ..................................................................................................... 36 
12.4 
Plan of Analysis ............................................................................................................ 36 
13. 
INVESTIGATOR RESOURCES ................................................................................... 36 
13.1 
Qualifications ................................................................................................................ 37 

 6
13.2 
Conflict of interest......................................................................................................... 37 
14. 
References ......................................................................................................................... 37 
APPENDICIES ........................................................................................................................... 40 
Appendix I ................................................................................................................................... 40 
Appendix II .................................................................................................................................. 43 
 
 

 7
 
1. 
SYNOPSIS 
 
Title of Study: Phase II trial of individualized lung tumor stereotactic ablative 
radiotherapy (SABR) 
Study Phase: II 
Study Center(s): Stanford University Hospitals and Clinic 
Indication:  
Stereotactic ablative radiotherapy (SABR) has emerged as an important and effective new 
treatment modality for lung tumors, but optimal dose regimens have not been fully 
established. Significant toxicity can be observed with the most commonly used dose 
regimens, implying that developing treatment regimens that optimize treatment based on 
tumor-specific factors could be of clinical benefit. 
Primary Objective(s):  
a. Evaluate local tumor control with individually optimized lung tumor 
SABR. Tumor control will be assessed by CT, PET-CT, and if 
appropriate, biopsy. The trial will focus on three cohorts: 1) patients with 
limited primary NSCLCs (T1aN0M0, T1bN0M0, T2aN0M0, T2bN0M0, 
or T3N0M0) non-small cell lung cancer; 2) patients with a history of 
NSCLC who have new limited primary NSCLC lesion(s); and 3) patients 
with more advanced lung cancer or lung metastases from a variety of 
different cancers.  
Secondary Objective(s):  
b. Evaluate the toxicity of individually optimized lung tumor SABR. 
Pulmonary, esophageal, chest wall, skin, vascular, cardiac/pericardial, and 
neurologic (brachial plexus/recurrent laryngeal/myelitis) toxicity will be 
scored by the CTCAE 4.0 criteria. 
c. Evaluate the feasibility of anatomically optimized audio-visual 
biofeedback (AVB)-coached breath-hold technique assisted by fast 
delivery using gated RapidArc with flattening free filter mode (FFF) in a 
subset of patients. Feasibility will be assessed based on: 
i. The proportion of patients able to reproduce an anatomically-
optimized breath-hold with AVB-coaching during treatment. 
ii. The reduction in treatment delivery time compared to gated free-
breathing treatment. 
d. Determine progression free, metastasis free, and overall survival in 
patients treated with individually optimized lung tumor SABR. 
e. Examine new biomarkers in lung tumor SABR patients. 
Hypothesis: We hypothesize that the therapeutic ratio of lung tumor SABR can be 
increased by (i) individual dosing based on tumor volume, and (ii) technologies to 
optimize the treatment anatomy by creating the greatest separation between target and 
critical normal organs at the time of treatment delivery.  
Study Design:  

 8
We hypothesize that therapeutic ratio can be increased by: 
i. Individualized dosing based on tumor volume. Our retrospective 
institutional data indicate that single fraction SABR is effective 
and safe for small volume pulmonary tumors but more intensive 
regimens are required to control larger tumors.  
ii. Technologies to optimize the treatment anatomy by creating the 
greatest separation between target and critical normal organs at the 
time of treatment delivery. We will incorporate anatomically 
optimized AVB-coached breath-hold technique during image-
guided gated RapidArc with FFF mode in a subset of patients, and 
evaluate its dosimetric impact compared to gated treatment during 
normal free-breathing. 
We propose a prospective clinical trial to confirm the improved 
therapeutic ratio of individually optimized lung tumor SABR. 
Primary and Secondary Endpoint(s): 
 Primary Endpoint 
a. Local tumor control of individually optimized lung tumor SABR. This will 
be evaluated separately in the three different patient groups. 
 
Secondary Endpoint 
b. Toxicity of individually optimized lung tumor SABR. 
c. Feasibility of anatomically optimized AVB-coached breath-hold technique 
assisted by fast delivery using gated RapidArc with FFF in a subset of 
patients. Feasibility will be based on the proportion of patients able to 
reproduce an anatomically-optimized breath-hold with AVB-coaching 
during treatment and the reduction in treatment delivery time compared to 
gated free-breathing treatment.   
d. Progression free, metastasis free, and overall survival in patients treated 
with individually optimized lung tumor SABR. 
e. Correlate plasma biomarkers with outcomes of lung tumor SABR patients 
(optional). 
Number of Patients: The target accrual is 246 patients over 4 years (about 260 patients 
will be enrolled in the OnCore database due to study dropouts. NOTE: In a collaborative 
effort, some patients will be accrued at Shantou, CUHK, and Hokkaido Universities in 
China and Japan. We expect no more than 10 patients to be enrolled at each of these sites. 
Accrual at these sites will not increase the total number of patients enrolled. 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria 
- 
Limited primary NSCLCs (T1aN0M0, T1bN0M0, T2aN0M0, T2bN0M0, or 
T3N0M0) or metastatic lung tumors 
- 
Up to 4 lesions may be included. For a single lesion the sum of three 
orthogonal diameters can be no more than 20 cm. For multiple lesions, no 
lesion can have a sum of orthogonal diameters greater than 15 cm. 

 9
- 
Both peripheral and central tumors are accepted for this trial.  
- 
Age > 18 years old  
- 
Both men and women and members of all races and ethnic groups are eligible 
for this trial. 
 
Exclusion Criteria 
- 
Uncontrolled extrathoracic metastases 
- 
Age < 18 years old  
- 
Contraindication to receiving radiotherapy 
- 
Women who are pregnant 
 
 
Study Procedures:  
 
i. Simulation: For a subset of patients, 4-D CT with AVB will be 
acquired with both natural and extreme tidal volume breathing. 
The sorted phase image from either scan demonstrating the 
largest separation between the target(s) and the specified organs 
at risk will be chosen for planning. Plan comparison with the 
natural end-exhale scan will be performed. 
ii. Dose adaptation: Dosing will be based on tumor volume. Doses 
will be calculated using AAA (or Acuros XB when available). 
Conformity and normal tissue dose constraints will be specified 
in detail in the protocol. 
iii. Pre-treatment verification and treatment delivery for AVB-coached 
breath-hold technique subgroup: Fluoroscopy and CBCT will be 
used to verify the ability of the patient to reproduce the targeted 
degree of breath hold with AVB assistance in a subset of 
patients. 
 
Duration of Intervention and Evaluation: The study duration will be approximately 48 
months for accrual, followed by 12 months of data analysis.  
Statistical Methods: 246 patients will be enrolled. NOTE: About 260 patients will be 
enrolled in the OnCore database due to study dropouts. 
 

 10 
2. 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 

 11 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ANC 
Absolute neutrophil count 
AVB 
Audiovisual Biofeedback  
BED 
Biologically Equivalent Dose 
CBC 
Complete Blood Count 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTV 
Clinical Target Volume 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DM 
Distant Metastasis 
DNA 
Deoxyribonucleic acid 
EDTA 
Ethylenediaminetetraacetic acid 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FEV-1 
Forced expiratory volume in 1 second 
FFF 
Flattening Free Filter Mode 
FNA 
Fine needle aspirate 
GTV 
Gross tumor volume 
IDN 
Identification number 
LC 
Local control 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
PFT 
Pulmonary function test 
PTV 
Planning target volume 
QOL 
Quality of life 
RC 
Regional Control 
RPM 
Revolutions per minute 
RTOG 
Radiation Therapy Oncology Group 
SABR 
Stereotactic Ablative Radiotherapy 
SBRT 
Stereotactic body radiation therapy 
XRT 
External beam radiation therapy 
 
 
 
 
 

 
12 of 46 
4. 
OBJECTIVES 
The primary objective is to evaluate the local control of individually optimized lung tumor 
SABR. Secondary objectives include evaluation of toxicity and evaluation of the feasibility of 
anatomically optimized AVB-coached breath-hold technique assisted by fast delivery using 
gated RapidArc with FFF in a subset of patients.  Additional secondary objectives include 
determining progression free, metastasis free, and overall survival in patients treated with 
individually optimized lung tumor SABR. 
 
 
5. 
BACKGROUND AND RATIONALE 
 
5.1 Study Disease: Lung Cancer 
Lung cancer is the leading cause of cancer mortality worldwide, accounting for over 1.3 
million deaths each year, largely because it is most often diagnosed at advanced stages [1]. 
However, early stage non-small cell lung cancer (NSCLC) is often surgically curable with the 
appropriate resection, preferably lobectomy [2]. Unfortunately, a significant fraction of patients 
with early stage NSCLC cannot tolerate surgery owing to medical comorbidities. Similarly, 
while patients with pulmonary oligometastasis from malignancies at other sites may benefit 
from surgical resection [3], many have medical or technical contraindications to pulmonary 
resection [4]. 
 
5.2 Stereotactic Ablative Radiotherapy for Lung Cancer  
In such patients, stereotactic ablative radiotherapy (SABR), also called stereotactic body 
radiation therapy (SBRT), has recently emerged as an important treatment option [5, 6].  A 
landmark prospective phase II clinical trial conducted by the Radiation Therapy Oncology 
Group, RTOG 0236, found that SABR resulted in outstanding local control (LC) and overall 
survival (OS) rates of 98% and 56% at 3 years in a cohort of strictly medically inoperable 
patients with peripherally located stage I NSCLC [7]. While treatment was well tolerated 
overall there was nevertheless a moderate incidence of significant (grade 3-4) toxicities. A 
prospective multi-institutional phase I/II trial of SABR for patients with 1-3 pulmonary 
metastases demonstrated similarly excellent 2-year LC of 96% [8]. 
Analyses of the dose-response relationships in SABR for both primary and metastatic lung 
tumors have demonstrated the importance of dose intensity [9-11], identifying a biologically 
effective dose (BED) of ≥100 Gy as a factor for achieving high rates of LC. In general these 
dose-response analyses have not been stratified by tumor volume. An earlier report from our 
institution of the initial results of a phase I dose escalation study using single fraction SABR 
for primary and metastatic lung tumor demonstrated 1 year LC of 91% using doses of >20 Gy 
[12]. A subsequent expanded analysis revealed that the critical factor for LC was tumor 
volume, such that in the dose range of 15-30 Gy in a single fraction, 11 month LC was 93-
100% for tumors up to 12 mL but only 47% for tumors >12 mL [13]. Based on these 
observations we adopted a volume-adapted dosing strategy for lung tumor SABR in which 
patients with small tumors (<12 mL) were treated with single fraction regimens with BED 
<100 Gy while larger tumors (≥12 mL) were treated with more dose-intensive multi-fraction 

 
13 of 46 
regimens with BED ≥100 Gy. The goal of this approach was to maintain equivalent LC while 
potentially reducing toxicities and improving convenience for patients with smaller tumors.  
We have recently retrospectively analyzed lung tumor patients treated with the volume-adapted 
strategy. Median follow-up in this study was 13.5 months. LC at 12 months for smaller tumors 
treated with lower dose, single fraction regimens was 91.4% and for larger tumors treated with 
multi-fraction, higher dose regimens 92.5% (p=0.24). For primary lung tumors only (excluding 
metastases), LC was 92.6% and 91.7%, respectively (p=0.58). RC, freedom from DM and OS 
did not differ significantly between the groups. Rates of radiation pneumonitis, chest wall 
toxicity, and esophagitis were low in both groups, but all grade 3 toxicities developed in Group 
2 (p=0.02). 
Based on this experience, we propose a prospective phase 2 clinical trial of tumor volume 
adapted dosing for SABR of pulmonary tumors. The primary endpoints will be LC and 
toxicity. Our hypothesis is that an individualized regimen will result in high local tumor control 
across strata of tumor volumes, while toxicity can be minimized by avoiding the need for the 
most dose intensive regimens in most patients. 
We will include three cohorts for analysis, each with 82 patients. The first cohort (1A) will 
consist of patients with Stage I non-small cell lung cancer. The second cohort (1B) will consist 
of patients with multiple primary non-small cell lung cancer. The third cohort (II) will consist 
of patients with lung metastases from a variety of different cancers.  
 
5.3 Audio-visual Biofeedback   
In addition, unique technological features of the Varian TrueBeam STX system for SABR, 
particularly the very rapid treatments afforded by RapidArc using the flattening filter free 
(FFF) mode, make possible novel treatment approaches. While margins can be reduced by the 
use of respiratory gating, the long treatment delivery times using conventional dose rates and 
field arrangements necessitate treating during natural free breathing. However, fast treatments 
could in theory be completed in a small number of breath holds, which would then not be 
restricted to the natural breathing range but could be at extremes of tidal volume. It would then 
be possible to select a degree of breath hold that is anatomically-optimized, creating the 
greatest separation between the target and critical organs at risk. Of note, at 1400 MU/min in 
6X FFF mode, a 25 Gy fraction could be delivered in less than 3.5 minutes of beam-on time, or 
~15 breath holds even in a patient with compromised pulmonary function. 
We propose in this trial to use audio-visual biofeedback to enable patients to reproduce 
anatomically-optimized breath-holds to achieve plans producing the highest possible separation 
between the tumor and the organs at risk. We will evaluate the feasibility of this approach, as 
assessed by the proportion of patients able to reliably reproduce the anatomically-optimized 
breath-holds with AVB-coaching, and the reduction in treatment delivery time compared to 
treatment during free-breathing. We will also evaluate the dosimetric impact of the 
anatomically-optimized approach compared to conventional free-breathing treatment gated at 
natural end-exhale. 
 
5.4 Rationale for Study 
 

 
14 of 46 
Stereotactic ablative radiotherapy (SABR) has emerged as an important and effective new 
treatment modality for lung tumors, but currently many different dose regimens are used and 
optimal regimens remain to be established. Significant toxicity can occur with the most 
effective published regimens, indicating that the therapeutic ratio could be further improved. 
 
We hypothesize that therapeutic ratio can be increased by: 
 
i. 
Individualized dosing based on tumor volume. Our institutional data indicate that 
single fraction SABR is effective and safe for small volume pulmonary tumors but 
more intensive regimens are required to control larger tumors.  
ii. 
Technologies to optimize the treatment anatomy by creating the greatest separation 
between target and critical normal organs at the time of treatment delivery. We will 
incorporate anatomically optimized AVB-coached breath-hold technique during 
image-guided gated RapidArc with FFF mode, and evaluate its dosimetric impact 
compared to gated treatment during normal free-breathing. 
 
We propose a prospective clinical trial to confirm the improved therapeutic ratio of 
individually optimized lung tumor SABR. At our institution about 70 patients per year with 
lung tumors are treated with SABR, and essentially all would benefit from the knowledge 
gained from this study. Thousands of patients per year worldwide stand to benefit as well. Our 
approach would allow individualization of therapy for the maximum efficacy with the least 
toxicity. 
 
 
5.5 Correlative Studies Background  
 
Blood-based biomarkers hold great promise as diagnostic markers indicative of disease state 
and predictors outcomes in lung tumor patients. A variety of biomarkers have been 
investigated in patients with lung tumors, including protein, DNA, and miRNA biomarkers. 
Cell-free DNA (cfDNA) is a particularly intriguing biomarker in this patient population [14].  
Tumors continually release DNA into the circulation through incompletely understood 
mechanisms that appear to involve both apoptosis and necrosis [15].  Previous studies have 
indicated that NSCLC patients have statistically significantly higher levels of cfDNA in the 
circulation than unaffected controls [16]. Furthermore, cfDNA levels have been shown to 
decrease after effective treatment in a variety of tumors, indicating that they can be used to 
assess dynamics of treatment response [15]. 
 
We plan to measure plasma levels of cfDNA in patients prior to initiating treatment and at each 
follow-up visit. We hypothesize that changes in cfDNA concentration will be predictive of 
outcome in this group of patients. 
 
Additional biomarkers may also be assessed. 
 
 
 

 
15 of 46 
6. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
6.1 Inclusion Criteria 
 
- 
Limited primary NSCLCs (T1aN0M0, T1bN0M0, T2aN0M0, T2bN0M0, or T3N0M0) 
or metastatic lung tumors with no evidence of uncontrolled extrathoracic metastases. 
- 
Up to 4 lesions may be included. For a single lesion the sum of three orthogonal 
diameters can be no more than 20 cm. For multiple lesions, no lesion can have a sum of 
orthogonal diameters greater than 15 cm. 
- 
Both peripheral and central tumors are accepted for this trial.  
- 
Age > = 18 years old  
- 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
- 
Note: Patients may be enrolled more than once (eg, for a new tumor) 
 
6.2 Exclusion Criteria 
 
- 
Evidence of uncontrolled extrathoracic metastases 
- 
Contraindication to receiving radiotherapy 
- 
Age < 18 years old. Children are excluded because lung malignancies rarely occur in this 
age group.  Furthermore, treatment requires a great deal of patient cooperation including 
the ability to lie still for several hours in an isolated room. 
- 
Pregnant and breastfeeding women are excluded; as well as women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth control 
(hormonal or barrier method of birth control; abstinence) to avoid pregnancy for the 
duration of the study.  Male subjects must also agree to use effective contraception for the 
same period as above.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician immediately. 
- 
Prior radiation therapy is allowed but there should not be overlap with the prior high dose 
regions unless approved by the protocol directors. 
 
6.3 Informed Consent Process 
 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any study 
specific procedure. The participant must receive a copy of the signed and dated consent 
document.  The original signed copy of the consent document must be retained in the medical 
record or research file. 
 
7. 
TREATMENT PLAN 
 
7.1 Study Design/Schedule 
 
• This is a prospective phase II study.  
• Patients with primary lung cancer or metastasis to the lung with no evidence of 
uncontrolled extrathoracic metastasis will be enrolled on this study. 

 
16 of 46 
 
7.2 Procedures: SABR Administration and Radiation Treatment Planning  
 
7.2.1 Pre-SABR Tests, Procedures, and Planning 
 
The following will be completed prior to SABR: 
 
a)   Medical history and clinical examination. 
b) CBC (optional).  Additionally, up to 50 ml of blood may be drawn for research in Dr. 
Diehn’s laboratory; blood may also be collected at post-treatment follow-up visits.  
At most, the lesser of 50 ml or 3 ml per kg will be collected for research purposes in 
an 8 week period. For specific information regarding collection and processing, see 
Section 8 Correlative Studies.   
c) Pathologic confirmation of malignancy whenever possible.  (This will generally be 
accomplished using CT-guided or bronchoscopic biopsies.)  If consent is provided by 
the patient, tumor tissue for research may be obtained. If pathologic confirmation is 
not possible, a target lesion must be a non-calcified pulmonary nodule or lymph node 
that is present on at least 3 imaging studies (can include simulation scan). The nodule 
must have increased in size or proportion of solid component on CT and/or show 
increased FDG uptake on PET over at least 2 imaging studies. 
d)   FDG-PET/CT and thoracic CT scan with contrast (recommended). 
 
e)   Signed informed consent document. 
f) Permission from patient for future postmortem examination (optional). 
 
 
7.2.2 Fiducials 
 
We will implant peri-tumoral metallic fiducial markers for image-guided tumor localization 
as needed, generally for lower lobe locations where the magnitude of tumor motion tends to 
be greatest. The fiducials will be used as surrogates for targeting the daily tumor position 
during treatment.  The fiducials will be placed directly into the tumor and/or periphery 
under CT guidance.  Fiducials may be implanted prior to enrollment as this is an acceptable 
standard of care procedure for any patient receiving SABR for lung tumors. 
 
 
7.2.3 Simulation 
 
During radiotherapy simulation, customized immobilization devices will be formed for 
each patient, and 4-dimensional CT (4-D CT) and PET-CT will be acquired in the 
treatment position.  
 
 
7.2.4 Treatment planning 
 
The treating physicians will contour the gross tumor volume (GTV) on axial CT slices 
using lung windows for visualizing tumor/lung interfaces and mediastinal windows for 
tumor/soft tissue interfaces, with the aid of fused PET. No explicit expansion for 

 
17 of 46 
microscopic extension will be added to form the clinical target volume (CTV), i.e., 
CTV=GTV. Breathing-induced tumor motion will be assessed using the 4-D CT data and 
managed by respiratory gating, dynamic tumor tracking, or motion-inclusive technique, and 
the internal target volume (ITV) will be designed accordingly. A 0.5 cm setup margin will 
be added to the ITV to form the final planning target volume (PTV).  
 
Treatment will be delivered using any suitable linear accelerator with 
image-guidance capabilities. Dose calculations should be heterogeneity 
corrected using an accurate algorithm (pencil beam not acceptable). 
7.2.5  SABR Treatment Delivery: 
Presciption doses for peripheral tumors (except colorectal cancer metastases): 
Peripheral tumors are tumors that do not meet the definition for central tumors described 
below.  Volume-adapted dose prescriptions for peripheral tumors will be as follows: 
 
Tumor volume 
Peripheral dose 
(covering 95% of 
PTV) 
Maximum dose 
(centered in GTV) 
of at least: 
<=10 
25 Gy / 1 fraction 
30 Gy /1 fraction 
>10 and <=30 
50 Gy / 4 fractions 
60 Gy / 4 fractions 
>30 
54 Gy / 3 fractions 
64.8 Gy / 3 fractions 
 
Prescription doses for peripheral colorectal cancer metastases: 
Retrospective analyses of our own data as well as published results from other institutions 
indicated that colorectal cancers appear to be relatively radioresistant. Particularly, we 
noted high rates of local failure in colorectal cancer metastases to the lung in tumor that 
received 25 Gy in one fraction. Therefore, volume-adapted dose prescriptions for 
peripheral colorectal cancer tumors will be as follows: 
 
Tumor volume 
Peripheral dose 
(covering 95% of 
PTV) 
Maximum dose 
(centered in GTV) 
of at least: 
<=10 
50 Gy / 4 fraction 
60 Gy /4 fraction 
>10 and <=30 
50 Gy / 4 fractions 
60 Gy / 4 fractions 
>30 
54 Gy / 3 fractions 
64.8 Gy / 3 fractions 
 
Central tumors: 
Central tumors are defined as having their GTV within or touching the zone of the 
proximal bronchial tree or near critical central structures. The zone of the proximal 
bronchial tree is defined as a volume 2 cm 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 below] For the purposes of this protocol central tumors include those within 2 

 
18 of 46 
cm of the zone of the proximal bronchial tree. Alternatively, tumors whose PTV overlaps 
major vessels (aorta or superior vena cava), esophagus, heart, trachea, pericardium, or 
brachial plexus will also be considered central. 
 
Prescription doses for central tumors (except colorectal cancer metastases): 
Volume-adapted dose prescriptions for central tumors will be as follows: 
Tumor volume 
(mL) 
Peripheral dose 
(covering 95% of 
PTV) 
Maximum dose 
(centered in GTV) of 
at least: 
<=10 
40 Gy / 4 fractions 
48 Gy / 4 fractions 
>10 and <=30 
50 Gy / 4 fractions 
60 Gy / 4 fractions 
>30 
60 Gy / 8 fractions 
72 Gy / 8 fractions 
 
 
Prescription doses for central colorectal cancer metastases: 
Volume-adapted dose prescriptions for central colorectal cancer tumors will be as 
follows: 
Tumor volume 
(mL) 
Peripheral dose 
(covering 95% of 
PTV) 
Maximum dose 
(centered in GTV) 
of at least: 
<=10 
50 Gy / 4 fractions 
60 Gy / 4 fractions 
>10 and <=30 
50 Gy / 4 fractions 
60 Gy / 4 fractions 
>30 
60 Gy / 8 fractions 
72 Gy / 8 fractions 
 
 
Prescription Dose Constraints and Conformality 

 
19 of 46 
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 V95%RX = 100%).  The global maximum dose point should be 
within the PTV and ideally within the GTV.  The maximum dose within the GTV should 
be at least 120% of the prescription dose (as indicated in tables above). The minimum dose 
to the GTV should be at least 100% of the prescription dose (specifically, no more than 
0.035 mL of the GTV should receive less than 100% of the prescription dose, with a 
tolerance of 2.5%). 
Conformality parameters: Treatment plans should be as conformal as possible.  For tumors 
located far from critical structures, a very conformal distribution should be obtained.  For 
tumors very close to critical structures, dose distributions may be somewhat asymmetric, 
with a sharper fall-off on the side(s) of the tumor that are closest to the critical structure(s) 
at risk. The following conformality criteria must be met: 
 
GTV volume 
(mL) 
Ratio of Prescription Isodose 
Volume to the PTV Volume 
Maximum Dose @ 2 cm from 
PTV (in % of dose prescribed) 
 
Ideal 
Required 
Ideal 
Required 
<=10 
<1.2 
<1.5 
<55 
<65 
>10 and <=30 
<1.2 
<1.5 
<64 
<82 
>30 
<1.2 
<1.5 
<72 
<90 
 
Critical organ dose constraints 
The following tables list dose constraints to critical structures based on the number of 
fractions prescribed. Exceeding these dose limits by more than 5% constitutes an 
unacceptable protocol deviation. 
Single fraction treatment: 
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 (1 fraction) 
Maximum Point 
dose limit (<0.035 
mL) 
 
Dose 
Volume 
Dose 
Spinal cord 
10 Gy 
7 Gy 
<0.35 mL 
<1.2 mL 
14 Gy 
Brachial plexus 
14 Gy 
<3 mL 
17.5 Gy 
Skin 
23 Gy 
<10 mL 
26 Gy 
Lungs-GTV 
7.4 Gy 
7 Gy 
<1000 mL 
<1500 mL 
NA 

 
20 of 46 
20 Gy 
<10% (require 
<15%) 
Stomach 
11.2 Gy 
<10 mL 
12.4 Gy 
Small bowel* 
11.2 Gy 
9 Gy 
<5 cc 
<10 cc 
12.4 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  
(1 fraction) 
Maximum point dose limit 
(<0.035 mL) 
 
Dose 
Volume 
Recommended 
Required 
Esophagus* 
11.9 Gy 
<5 mL 
15.4 Gy 
105% of PTV 
prescription 
dose 
Heart/pericardium 
16 Gy 
<15 mL 
22 Gy 
105% of PTV 
prescription 
dose 
Great vessels* 
25 Gy 
<10 mL 
25 Gy 
105% of PTV 
prescription 
dose 
Trachea and 
ipsilateral 
bronchus* 
10.5 Gy 
<4 mL 
20.2 Gy 
105% of PTV 
prescription 
dose 
Chest wall# 
18 Gy 
<10cc (<30cc 
required) 
NA 
105% of PTV 
prescription 
dose 
Liver 
9.1 Gy 
<700 mL 
NA 
105% of PTV 
prescription 
dose 
* Avoid circumferential radiation 
# Chest wall limits may be exceeded for an otherwise excellent plan. This will not be 
considered a violation. 
 
Three fraction treatment: 
Critical structures with absolute volume and absolute point dose limits: Exceeding any 
of these limits constitutes a major protocol violation. 

 
21 of 46 
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-GTV 
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 

 
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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 limits may be exceeded for an otherwise excellent plan. This will not be 
considered a violation. 
 
Four fraction treatment: 
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 (4 fractions) 
Maximum Point 
dose limit (<0.035 
mL) 
 
Dose 
Volume 
Dose 
Spinal cord 
20.8 Gy 
13.6 Gy 
<0.35 mL 
<1.2 mL 
26 Gy 
Brachial plexus 
23.6 Gy 
<3 mL 
27.2 Gy 
Skin 
33.2 Gy 
<10 mL 
36 Gy 
Lungs-GTV 
12.4 Gy 
11.6 Gy 
20 Gy 
<1000 mL 
<1500 mL 
<10% (require 
<15%) 
NA 
Stomach 
17.6 Gy 
<10 mL 
27.2 Gy 
Small bowel* 
17.6 Gy 
12 Gy 
<5 cc 
<10 cc 
27.2 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 
(4 fractions) 
Maximum point dose limit 
(<0.035 mL) 
 
Dose 
Volume 
Recommended 
Required 

 
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Esophagus* 
18.8 Gy 
<5 mL 
30 Gy 
105% of PTV 
prescription 
dose 
Heart/pericardium 
28 Gy 
<15 mL 
30 Gy 
105% of PTV 
prescription 
dose 
Great vessels* 
43 Gy 
<10 mL 
49 Gy 
105% of PTV 
prescription 
dose 
Trachea and 
ipsilateral 
bronchus* 
15.6 Gy 
<4 mL 
34.8 Gy 
105% of PTV 
prescription 
dose 
Chest wall# 
33.6 Gy 
<10cc (<30cc 
required) 
NA 
105% of PTV 
prescription 
dose 
Liver 
19.2 Gy 
<700 mL 
NA 
105% of PTV 
prescription 
dose 
* Avoid circumferential radiation 
# Chest wall limits may be exceeded for an otherwise excellent plan. This will not be 
considered a violation. 
 
Eight fraction treatment: 
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 (8 fractions) 
Maximum Point 
dose limit 
(<0.035 mL) 
 
Dose 
Volume 
Dose 
Spinal cord 
27.2 Gy 
16.8 Gy 
<0.35 mL 
<1.2 mL 
36 Gy 
Brachial plexus 
32.8 Gy 
<3 mL 
36.8 Gy 
Skin 
40.8 Gy 
<10 mL 
44.8 Gy 
Lungs-GTV 
14.4 Gy 
13.6 Gy 
20 Gy 
<1000 mL 
<1500 mL 
<10% (require 
<15%) 
NA 
Stomach 
20 Gy 
<10 mL 
36.8 Gy 

 
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Small bowel* 
20 Gy 
13.6 Gy 
<5 cc 
<10 cc 
36.8 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 
(8 fractions) 
Maximum point dose limit 
(<0.035 mL) 
 
Dose 
Volume 
Recommended 
Required 
Esophagus* 
21.6 Gy 
<5 mL 
40 Gy 
105% of PTV 
prescription 
dose 
Heart/pericardium 
36.9 Gy 
<15 mL 
39.7 Gy 
105% of PTV 
prescription 
dose 
Great vessels* 
57.7 Gy 
<10 mL 
65 Gy 
105% of PTV 
prescription 
dose 
Trachea and 
ipsilateral 
bronchus* 
19.8 Gy 
<4 mL 
46.4 Gy 
105% of PTV 
prescription 
dose 
Chest wall# 
43.4 Gy 
<10cc (<30cc 
required) 
NA 
105% of PTV 
prescription 
dose 
Liver 
23.2 Gy 
<700 mL 
NA 
105% of PTV 
prescription 
dose 
* Avoid circumferential radiation 
# Chest wall limits may be exceeded for an otherwise excellent plan. This will not be 
considered a violation. 
 
7.3 Duration of Follow-Up 
 
Upon completion of SABR, study follow up will include serial imaging (CT scans and/or 
PET/CT if possible and as deemed necessary), detailed medical history, physical examination 
and quality of life assessment every 3 months for 1 year (+/- 4 weeks).  Thereafter all patients 
are considered to be off study treatment and will be followed for progression and survival 
outcomes collected during standard of care visits.  Typically this includes imaging studies, 

 
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history and physical examinations every 6 months for 2 years, then annually. Follow up 
intervals may also be more frequent as indicated clinically.  A complete blood count (CBC) 
(optional), tumor marker studies (optional), history/physical, CT and/or PET/CT (optional) will 
be performed at each follow-up interval until death. PFTs (optional) with DLCO and FEV-1 
will be obtained 6 and 12 months post-SABR then once annually. Separate samples of blood 
may be drawn at the time of follow-up visits, studies, and/or laboratory draws and retained for 
research efforts to develop novel blood biomarkers. 
 
Patients will remain enrolled on this protocol until there is evidence that their disease has 
progressed either locally or distantly. Patients whose disease has progressed either locally or 
distantly and get treated for the progression during the 1-year of active follow-up will be taken 
off the study. We will continue to obtain follow up information for 3 years after RT.  
 
7.4 Criteria for Removal from Study 
 
Patients may be removed at any time from the study at their request.  Additionally, patients 
who are unable to cooperate with obtaining the protocol studies will be withdrawn.  Patients in 
whom usable imaging studies are not attainable or who can’t be reproducibly positioned at the 
time of treatment will also be withdrawn.  Withdrawals will be replaced to achieve the target 
accrual. 
 
7.5 Alternatives 
 
This study is optional, so the only alternative is to not participate in this study. 
 
7.6 Compensation 
 
Patients will not be paid. Costs of protocol studies will be paid through protocol funding, and 
patients will not incur additional costs due to their participation. 
 
 
8. 
CORRELATIVE STUDIES 
 
8.1 Analysis of patient plasma for biomarker development.  
 
Collection of Specimen(s) (optional):  
 
Patients will elect whether they want to participate in this portion of the study on the consent 
form.  
 
Blood Samples 
 
a)  Blood (EDTA preserved) for research purposes may be drawn prior to radiation treatment 
and at follow-up visits, studies, or blood draws.  For each collection, up to 50 ml will be drawn 
(purple/violet tubes). 
 

 
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b)  Immediately, after collection, blood will be centrifuged at 3000 RPM for 10 minutes at 4°C 
and plasma collected. The supernatant will be aliquoted for storage at -80°C.  The pellet 
containing (white and red blood cells) will also be stored in a separate tube at -80°C. 
 
Tumor Biopsy Tissue Samples 
 
a) Consent for obtaining tumor samples:  All patients with a presumed diagnosis of malignancy 
within the lung can give consent or decline consent to obtain an additional tumor tissue for 
research purposes.  In this situation, the research biopsy should be obtained only after a final 
diagnosis (preliminary if determined by the pathologist during the diagnostic biopsy) of 
malignancy has been reached by the pathologist.  Once a preliminary/final diagnosis has been 
obtained, fiducials can be placed into the tumor for tumor tracking.  In the event the patient 
already has a confirmed pathologic diagnosis of cancer in the lung, a repeat biopsy procedure 
(usually CT-guided) may be performed to obtain tissue with/or without simultaneous 
placement of fiducials. 
 
b)  Tumor sample processing:  Fine needle aspirations (FNA) and core biopsies (if possible) of 
tumor tissue will be immediately placed into small twist tubes that can be stored at -80°C.  
Sample tubes are immediately immersed into a canister of liquid nitrogen with forceps/tube 
holder until completely frozen.  Samples are then transferred into a -80°C freezer for storage. 
 
c) Consent for use of left over diagnostic specimens: All patients with a presumed diagnosis of 
malignancy within the lung can give consent or decline consent to allow left over biological 
materials from diagnostic procedures (e.g. paraffin-embedded tissues, DNA, frozen tissues) to 
be used for research purposes. 
 
 
8.2 Coding of specimens for privacy protection  
 
At the time of enrollment each patient will be given a specific confidential identification 
number (IDN). Specimens will be stored under the patient’s IDN. The information can be 
shared with other investigators listed on this protocol. Study data will be maintained in 
password protected computer files (protected online database). Only research personnel will 
have access to this information. 
 
 
 
9. STUDY CALENDAR 
   
Pre-
Registration 
Timeframes are 
in weeks prior 
to registration 
Pre-
Treatment 
Timeframes 
are in 
weeks prior 
to treatment 
Follow-Up (Post SABR): Every 3 mos. 
for 1 year (+/- 4 weeks); then follow-up 
for progression and survival outcomes  
 
Histologic confirmation (strongly 
encouraged but not required when 
clinical suspicion of malignancy is 
 
X 
 
 

 
27 of 46 
high) # 
History/physical 
 
Within 12 
weeks 
 
X 
Performance Status and Weight # 
 
Within 8 
 weeks 
X 
CT scan of thorax with or without 
contrast (with contrast is preferable)* 
 
Within 8 weeks 
 
X 
FDG PET* 
Within 8 weeks 
 
Optional but encouraged.  
PFTs, including DLCO, FEV1, and 
FVC #^ 
 
 
Within  
12 weeks 
6,12 months post-SABR then yearly 
 
CBC w/ diff & ANC #^ 
 
 
Within 4 
weeks 
X 
 
Urine or Serum pregnancy test (if 
applicable) 
 
 
Within 3 
days 
 
 
Tumor response evaluation 
 
 
 
X 
 
Adverse event evaluation 
 
 
 
X 
Tissue for banking and blood for 
translational research (if patient 
consents) # 
 
X 
 
QOLs # 
 
X 
                          X 
# Encouraged but not required 
^ PFTs and CBC are used as baseline measures. Ideally, they should be obtained prior to treatment, 
but at the latest they can be obtained by the completion of treatment.  
* CT and PET/CT scans obtained at the time of simulation are acceptable. PET is not required if 
tumor is known to be PET negative from prior scans, or for oligometastatic tumors of non-lung 
primary. 
 
10. 
MEASUREMENT OF ENDPOINT 
 
10.1 Anti-tumor Effect 
 
Patients will be evaluated for anti-tumor effect by follow-up imaging (lung protocol CT and/or 
PET-CT imaging) as outlined above. Lung protocol CT scans (biphasic imaging, 1.25 mm 
cuts) and/or FDG PET-CT scans will be obtained at all follow-up intervals as described in the 
treatment calendar. All subsequent scans (post-treatment) will be compared to the same 
pretreatment CT or PET/CT that was used in conjunction with radiation treatment planning.  
 
 
 
 
10.2 Definitions 
 

 
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Patients will be evaluable for toxicity and evaluable for objective response at the follow-up 
intervals specified above. 
 
Local Failure refers to either primary tumor failure or involved lobe failure or both. Failure 
will be documented by biopsy when possible and otherwise will be defined as radiographic 
progression on CT and/or PET/CT that leads to a change in management, including institution 
of chemotherapy, re-irradiation, etc. The criteria for time to progression and progression-free 
survival (PFS) will be the duration from SABR treatment to documented local/regional or 
distant progression or death.  Local PFS will be the duration from SABR treatment to local 
progression or death from any cause.  
 
 
 
 
 
11. 
DATA REPORTING/REGULATORY CONSIDERATIONS 
 
11.1 Institutional Review of Protocol 
 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by 
the Stanford IRB and Stanford Cancer Center Scientific Review Committee (SRC).  Any 
changes made to the protocol will be submitted as a modification and will be approved by the 
IRB prior to implementation.  The Protocol Director will disseminate the protocol amendment 
information to all participating investigators. 
 
11.2 Data and Safety Monitoring Plan 
 
The Stanford Cancer Center Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to 
the IRB and the appropriate regulatory authorities at the time of continuing review, or in an 
expedited fashion, as needed. 
 
11.2.1  Data Monitoring Plan for International Sites 
 
The data monitoring plan for the iSABR international sites has six components: 
 
11.2.1.1 Local GCP and human subjects protection training 
 
The coordinators at each site will undergo training in Good Clinical Practice and human 
subjects protection and will email their completion certificates to the Stanford coordinator. 
 
11.2.1.2 Local delegation logs 
 

 
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The Stanford coordinator will send a delegation log to each site, to be filled out with the 
names, signatures, and roles of all personnel working on the iSABR international study. 
Once complete, the delegation logs will be emailed back to the Stanford coordinator.  
 
11.2.1.3 Initial OnCore and Redcap training session via BlueJeans 
 
The Stanford coordinator will create a BlueJeans training session on how to register 
patients in OnCore and fill out case report forms (CRFs) in Redcap. The BlueJeans training 
session will be held before each site starts enrolling patients on the study. All sites will fill 
out the forms in English. Important: When the local coordinator is working in OnCore or 
Redcap, he or she will only be able to see local data, not Stanford data or data from the 
other international sites. 
 
11.2.1.4 Regular training on protocol amendments 
 
Any time an amendment is made to the iSABR protocol, the Stanford coordinator will 
communicate the change to all sites via email or a BlueJeans session if needed. The sites 
will then have the amended protocol approved by the local IRB. 
 
11.2.1.5 Remote monitoring during the study  
 
As described earlier in this document, all data recording and storage will be in English. 
However, at Shantou medical documentation is in Chinese and at Hokkaido it is in 
Japanese. At CUHK, some medical documentation may be in English. Coordinators at all 
three sites will attach source documents in Redcap so that the Stanford coordinator can 
monitor and verify that patients have been screened correctly for eligibility and that the 
data is correct and complete. At Shantou and CUHK, the source documents will be 
translated into English first before they are sent to Stanford. The cost of the 
translations will be absorbed by Shantou and CUHK as described in their statement 
of work (SOW). Conversely, Hokkaido will send us their source documents first and 
they will be translated by Interpreter Services here at Stanford Hospital. We will bill 
Hokkaido for the actual cost of the translations. Interpreter Services has given the 
Stanford coordinator a rough quote: 40 pages of Japanese source documentation will 
be translated for $1500, and 80 pages of Chinese source documentation will be 
translated for $3800.  
 
11.2.1.6 SAE Reporting 
 
Serious adverse events (SAEs) will be reported by the international sites to (a) the local 
IRBs and (b) the Stanford coordinator. The Stanford coordinator will provide the 
international sites with SAE reporting paperwork. Once SAE paperwork has been delivered 

 
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to Stanford, the Stanford coordinator will submit it to the Cancer Clinical Trials Office 
(CCTO) to be recorded in OnCore.  
 
11.3 Data Management Plan 
 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.   Case report forms 
will be developed using paper documents. CRFs will be kept in a locked cabinet, only 
accessible to the research team. 
 
11.3.1 Overview of Data Management at Stanford 
Data on the iSABR study at Stanford is managed via three components: 
 
a. OnCore 
Patients are registered and reported to the NCI through OnCore, a web-based 
database application. Patients are registered in OnCore within 5 days after signing 
the consent form. Patients are numbered consecutively. 
 
b. Redcap 
Case report forms (CRFs) are filled and stored electronically in Redcap, a web-
based database application. Patients are numbered consecutively using the same 
numbers as in OnCore. The CRFs include a Baseline Evaluation Form, 
Registration Form, Treatment Summary Form, and Follow-Up Form. One 
Follow-Up Form is filled out for each patient follow-up visit, so several Follow-
Up Forms are filled out for each patient over the course of the study. The Follow-
Up Form records local, regional, and distant control provided by the iSABR 
treatment. It also records any adverse events experienced by the patient. Common 
adverse events such as esophagitis and pneumonitis are recorded using radio 
buttons. Other adverse events can be typed into a Comments box.   
 
c. Document binders 
Key documents are stored as hardcopy in patient binders. Key documents include: 
A. The signed informed consent form 
B. The eligibility checklist and source documents required to prove eligibility 
(history and physical, pathology, and CT or PET/CT scan) as well as 
documentation of optional tests used as baseline measures (pulmonary 
function tests, complete blood count) 
C. The Treatment Summary written by the treating physician  
D. Follow-up visit notes written by the treating physician 
E. Documentation of any serious adverse events (SAEs) 
 

 
31 of 46 
There is some redundancy between Redcap and the document binders. 
Specifically, the Redcap Registration Form mirrors the eligibility checklist, the 
Treatment Summary Form captures key information from the physician’s 
Treatment Summary, and the Follow-Up Forms capture key information from the 
follow-up visit notes.  
 
11.3.2 Sponsorship of Coordinators at the International Sites 
 
The Stanford PI will sponsor the coordinators at the three international sites to obtain 
limited SUNet IDs (no email account included) so they can use OnCore and Redcap. In 
order to access OnCore using their SUNet ID, the coordinators will also need to set up (1) 
Virtual Private Network (VPN) access and (2) dual-step authentication. The instructions 
for setting these up are in a separate document. 
 
11.3.3 Overview of Data Management for the International Sites 
 
When the iSABR study expands to the three international sites (Shantou, CUHK, and 
Hokkaido), the same three components of data management will be used as described 
above.  
 
a. OnCore 
The NCI requires multi-site patients to be reported in OnCore: even though they 
are not Stanford patients, they are involved in Stanford’s research activities. The 
Stanford clinical research coordinator (CRC) will provide training in OnCore to 
the research teams as described in the data monitoring plan, above. Patients will 
be registered in OnCore at the international sites within 5 days of signing the 
consent form, as they are at Stanford. The numbering scheme will be as follows 
for the three sites: 
 
• SHAN-001, SHAN-002, SHAN-003…. for Shantou University patients 
• CUHK-001, CUHK-002, CUHK-003…. for Chinese University at Hong 
Kong patients 
• HOKK-001, HOKK-002, HOKK-003…. for Hokkaido University patients 
 
b. Redcap 
Redcap has a Data Access Groups (DAGs) feature that allows separate teams to 
share a database without viewing each other’s data. The Stanford coordinator will 
provide training in Redcap to the PIs and coordinators as described in the data 
monitoring plan, above. The numbering scheme will be the same as in OnCore:  
 
• SHAN-001, SHAN-002, SHAN-003…. for Shantou University patients 
• CUHK-001, CUHK-002, CUHK-003…. for Chinese University at Hong 
Kong patients 

 
32 of 46 
• HOKK-001, HOKK-002, HOKK-003…. for Hokkaido University patients 
 
Note that in Redcap it will be necessary to manually enter the international ID in 
the “International ID” field at the top of the Baseline Evaluation Form. The ID 
number that is auto-generated by Redcap will not be used.  
 
NOTE: Coordinators at the international sites will upload source documents 
into Redcap so that these documents can be translated at Stanford to monitor 
whether information has been recorded correctly in the Redcap database. 
See “Remote monitoring during the study,” above.  
 
c. Document binders 
Document binders will be kept at the international sites for international patients 
enrolled on the iSABR study. Whenever a new patient is enrolled at a subsite, a 
document binder will be created for that patient just as it is at Stanford. The 
Stanford coordinator will instruct the international research teams on how to 
create a patient binder. 
 
 
11.4 Evaluation for Adverse Events 
 
Toxicity will be scored according to the NCI CTCAE v4.0 (Appendix II).  
 
Serious adverse events (SAE’s) will be reported to the Stanford PI and to the IRB, and DSMC as per the 
Cancer Clinical Trials Office Standard Operating Procedure for SAE reporting. All SAEs will be 
reported while on study and will be monitored for up to one year after the last dose of the study 
treatment is given.  
 
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 

 
33 of 46 
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) 

 
34 of 46 
 
• 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 
 
11.5 Stopping Rules 
 
All outcome data (toxicity and efficacy) will be reviewed every 6 months by the Principal 
Investigators and key Co-Investigators.  This study will be monitored by the DSMC.  All 
potential adverse events will be reported to the thoracic disease management group and 
the DSMC.  The study will terminate when the target accrual is met and all data are 
analyzed.  
 
11.6 Confidentiality 
 
Study data will be maintained in protected patient binders.  Only research personnel listed 
on this protocol will have access to this information.  Only the patients unique IDN will 
be used.  Specimens will be stored under the patient’s IDN.   
 
12. 
STATISTICAL CONSIDERATIONS: TYPE AND NUMBER OF EXPERIMENTAL   
SUBJECTS 
 

 
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12.1 Primary and Secondary Endpoints 
 
Primary Endpoints:  
Local tumor control of individually optimized lung  
  
tumor SABR.  
 
 Secondary Endpoints:  
Toxicity of individually optimized lung tumor SABR 
12.1.1 Feasibility of anatomically optimized AVB-coached breath-hold technique assisted by 
fast delivery using gated RapidArc with FFF in a subset of patients. Feasibility will be 
assessed based on: 
(1) The proportion of patients able to reproduce an anatomically-
optimized breath-hold with AVB-coaching during treatment. 
(2) The reduction in treatment delivery time compared to gated free-
breathing treatment. 
12.1.2  Metastasis free and overall survival in patients treated with SABR.  
 
 
12.2 Sample Size 
 
12.2.1 Accrual Estimates 
 
In 2009, 80 lung SABR procedures were performed at Stanford Hospital. We estimate 
based on the number of lung SABR procedures done a year that approximately 5-6 
patients can reasonably expect to accrue per month with primary lung cancer or cancer 
metastatic to lung. 
 
Accrual will occur over 48 months, at the rate of approximately 5-6 per month. 
 
12.2.2 Sample Size Justification 
 
This protocol targets three cohorts of patients: 1) patients with an initial diagnosis of 
limited primary NSCLCs (T1aN0M0, T1bN0M0, T2aN0M0, T2bN0M0, or T3N0M0) 
(i.e. no prior history of non-small cell lung cancer); 2) patients with a prior history of 
non-small cell lung cancer who have new limited primary NSCLC lesion(s); and 3) 
patients with more advanced lung cancer or lung metastases from a variety of different 
cancers. The three cohorts will be analyzed separately. A sample of size 82 for cohorts 1 
and 3 was chosen in order to have 80% power to reject a rate of local control of 80%, if 
the true rate is 90%.  Once cohorts 1 and 3 have enrolled 82 informative patients, the trial 
will be closed. Cohort 2 will likely have fewer than 82 patients and will have a larger 
margin of error.  Approximately 86 subjects in cohorts 1 and 3 will be enrolled to allow 
for a 5% drop-out rate.  Cohort 2 has been slower to accrue and we wish to conclude this 
phase of the study without waiting for full enrollment. 
 
Specifically, proportions estimated on the basis of 82 subjects in each of cohorts 1 and 3 
carry a margin of error (90% confidence interval) of 10 percentage points. If we observe 
a rate of local control of 90%, we will be able to exclude, with 95% confidence, a true 

 
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rate less than 82%. Likewise, if the observed rate of grade 2+ toxicity is 30%, we will be 
able to exclude, with 95% confidence, a true rate of 39%; if we observe a rate of 15% 
grade 3+ toxicity (12/82), we will be able to exclude, with 95% confidence, a true rate of 
23%.  Precision for cohort 2 will be reduced. 
 
In a collaborative effort, some patients will be accrued at Shantou, CUHK, and Hokkaido 
Universities in China and Japan. We expect no more than 10 patients to be enrolled at 
each of these sites. Accrual at these sites will not increase the total number of patients 
enrolled and will not change the statistical analysis. 
 
 
 
 
12.3 Analysis populations 
 
Analysis will be carried out in all patients who complete protocol procedures. 
 
 
12.4  Plan of Analysis 
 
Local control at 12 months will be estimated along with a one-sided lower 95% confidence 
bound to allow an informal assessment of the null hypothesis that the proportion is larger than 
80%.  Patients with distant progression before local failure will be censored one day after the 
last imaging study; patients who die before local control will be censored at the time of death.  
These definitions are used for comparability.  Cumulative incidence estimates for local failure 
and other failure type will also be presented. 
 
Time to event data (local control, PFS, time to progression) will be evaluated using Kaplan-
Meier estimates with 95% confidence intervals at multiples of 12 months based on 
Greenwood’s formula with a log transform.  Confidence intervals for median times to event, if 
relevant, will be constructed using the method of Brookmeyer and Crowley.  
 
Biomarkers (e.g. cfDNA) will be summarized using medians and interquartile ranges; changes 
in biomarkers will be assessed using the Wilcoxon signed rank test.  Correlation of biomarkers 
with local control and progression will be evaluated informally using a Wilcoxon rank sum test 
on patients with and without the event of interest. If feasible, these analyses will be 
supplemented by more formal analyses with the Cox model. 
 
Proportions (e.g. proportion of patients with grade 4 or higher toxicity) will be estimated along 
with 95% exact confidence intervals.  Patient clinical and demographic characteristics will be 
reported with the appropriate summary statistic (mean, range, proportion etc.). Adverse events 
will be tabulated by organ system and severity. 
 
 
13. 
INVESTIGATOR RESOURCES 
 

 
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13.1 Qualifications 
 
The study staff will include, but is not limited to, the Principal Investigators, Co-Investigators, 
research coordinators, research nurses, and any residents or fellows working with the 
physicians.  Also, laboratory personnel in the Principal Investigators’ laboratory will be 
involved in analyzing the plasma and tumor specimens collected from patients. 
 
All study staff have completed the required training specific for their responsibilities in this 
study.  Furthermore, each member of the research team from each institution will be given a 
thorough explanation of the protocol and their responsibilities, including helping with 
scheduling, procedures, follow-up, data entry, or analysis.  All research investigators will be 
required to complete proper training through their institutional review boards.  
 
NOTE: The study staff at Shantou, CUHK, and Hokkaido must receive approval from their 
own IRBs to conduct the research in this protocol. They will also receive training from the 
Principal Investigators and Co-Investigators. The data collected at these sites will be sent to 
Stanford for review and quality assurance. We will also be doing remote data review. 
 
 
 
13.2 Conflict of interest 
 
Dr. Billy Loo received speaking honoraria from Varian and GE Medical Systems. 
 
 
 
14. 
References 
 
 
1. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277-300. 
2. 
Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 
non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995; 60: 615-622; discussion 
622-613. 
3. 
Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The 
International Registry of Lung Metastases. J Thorac Cardiovasc Surg 1997; 113: 37-49. 
4. 
Timmerman RD, Bizekis CS, Pass HI et al. Local surgical, ablative, and radiation treatment of 
metastases. CA Cancer J Clin 2009; 59: 145-170. 
5. 
Hadziahmetovic M, Loo BW, Timmerman RD et al. Stereotactic body radiation therapy 
(stereotactic ablative radiotherapy) for stage I non-small cell lung cancer--updates of radiobiology, 
techniques, and clinical outcomes. Discov Med 2010; 9: 411-417. 

 
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6. 
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. 
7. 
Timmerman R, Paulus R, Galvin J et al. Stereotactic body radiation therapy for inoperable early 
stage lung cancer. JAMA 2010; 303: 1070-1076. 
8. 
Rusthoven KE, Kavanagh BD, Burri SH et al. Multi-institutional phase I/II trial of stereotactic 
body radiation therapy for lung metastases. J Clin Oncol 2009; 27: 1579-1584. 
9. 
Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. 
Radiother Oncol 2005; 77: 83-87. 
10. 
Onishi H, Shirato H, Nagata Y et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) 
for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional 
study. J Thorac Oncol 2007; 2: S94-100. 
11. 
Timmerman RD, Park C, Kavanagh BD. The North American experience with stereotactic body 
radiation therapy in non-small cell lung cancer. J Thorac Oncol 2007; 2: S101-112. 
12. 
Le QT, Loo BW, Ho A et al. Results of a phase I dose-escalation study using single-fraction 
stereotactic radiotherapy for lung tumors. J Thorac Oncol 2006; 1: 802-809. 
13. 
Brown JM, Diehn M, Loo BW, Jr. Stereotactic ablative radiotherapy should be combined with a 
hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys 2010; 78: 323-327. 
14. 
Xue X, Zhu YM, Woll PJ. Circulating DNA and lung cancer. Ann N Y Acad Sci 2006; 1075: 
154-164. 
15. 
Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. 
Nat Rev Cancer 2011; 11: 426-437. 
16. 
Sozzi G, Conte D, Leon M et al. Quantification of free circulating DNA as a diagnostic marker 
in lung cancer. J Clin Oncol 2003; 21: 3902-3908. 
 
 
 
 
 
 
 
 

 
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APPENDICIES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix I 
Eligibility Checklist 
 
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration. The completed, signed, and dated checklist must be retained in the patient’s study file 
and the study’s Regulator Binder.  
 
Study Name: Phase II trial of individualized lung tumor stereotactic ablative radiotherapy (SABR) 
 
Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
Study Information:  SRC Approved 
 IRB Approved 
 Contract signed 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation 
1. Limited primary lung tumors or 
metastatic lung tumors. Limited 
primary tumors are early-stage 
NSCLCs (T1aN0M0, T1bN0M0, 
 
 
14.1.1.1 
      

 
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*CT and PET scans obtained at the time of simulation are acceptable. PET is not required if tumor is 
known to be  
PET negative from prior scans, or for oligometastatic tumors of non-lung primary. 
# All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation  
can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and 
medical  
record review.     
 
 
 
 
 
 
 
 
 
 
 
Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for participation in 
the study.  
This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford IRB, and 
has finalized financial and contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
 
 
 
 

 
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Appendix II 
 
 
EORTC QLQ-C30 and  
 
EORTC QLQ-PAN26 

 
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