Calypso Guided High Precision Stereotactic Ablative Radiosurgery for Lung Tumors Using Real-Time Tumor Tracking & Respiratory Gating: A Seamless Phase I/II Prospective Clinical Trial
Phase: NA
Conditions: Lung Cancer Stage I, Lung Cancer Stage II, Lung Cancer, Nonsmall Cell, Lung Cancer Recurrent, Lung Cancer Stage IV
Sponsor: CancerCare Manitoba

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The GPS Trial 
Calypso Guided High Precision Stereotactic Ablative Radiosurgery for Lung Tumours Using Real-
Time Tumour Tracking & Respiratory Gating: A seamless Phase I/II prospective clinical trial. 
Co-Principal Investigators:  
Dr. Julian Kim, MD, MSc, BEng, FRCPC 
Assistant Professor 
Department of Radiation Oncology 
University of Manitoba and CancerCare Manitoba 
 
Dr. Gordon Buduhan, MD, MSc, FRCSC 
Assistant Professor 
Section of Thoracic Surgery 
University of Manitoba & Health Sciences Center 
 
Co-Investigators: 
Section of Thoracic Surgery, University of Manitoba & Health Sciences Center 
Dr. Biniam Kidane, MD, MSc, FRCSC 
Dr. Sadeesh Srinathan, MD, MSC, FRCSC 
Dr. Larry Tan, MD, FRCSC, FACS 
 
Department of Radiation Oncology, University of Manitoba & CancerCare Manitoba 
Dr. Bashir Bashir, MD, FRCPC 
Dr. Arbind Dubey, MD, FRCPC 
Dr. Rashmi Koul, MD, FRCPC 
Dr. Shrinivas Rathod, MD 
 
Department of Medical Physics, University of Manitoba & CancerCare Manitoba 
Dr. Jeff Bews, PhD 
Dr. Boyd McCurdy, PhD 
Dr. Ryan Rivest, PhD 
Dr. David Sasaki, MSc 
Dr. Sankar Venkataraman, PhD 
 
Department of Pathology, University of Manitoba & Health Sciences Center 
Dr. Gefei Qing, MD, MSc, FRCPC 
 
 
 
 

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Table Of Contents 
1.0 
Study Schema 
2.0 
Background Information and Rationale 
3.0 
Trial Design 
4.0 
Study Population 
5.0 
Eligibility & Exclusion Criteria 
6.0 
Objectives & Hypotheses 
7.0 
Study Endpoints 
8.0 
Pre-Treatment Evaluations 
9.0 
Study Enrollment Procedures 
10.0 
Treatment Plan 
11.0 
Potential Adverse Reactions  
12.0 
Evaluation During and After Protocol Treatment 
13.0 
Statistical Considerations 
14.0 
Biobanking 
15.0 
Ethical Considerations  
16.0 
Protocol Treatment Discontinuation 
17.0 
Serious Adverse Event Reporting 
18.0 
Data Safety & Monitoring Committee 
19.0 
Publication and Authorship 
20.0 
References 
 
APPENDIX I – EORTC QLQ - LC13 Quality of Life Questionnaire (Lung Cancer) 
APPENDIX II – Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 

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1.0 Study Schema 
This trial is a seamless phase I/II prospective, single arm, cohort study.  
 
Phase I of the trial will consist of two patients and will serve to conduct quality assurance assessments 
and to familiarize thoracic surgeons, radiation oncologists, and medical physicists at CancerCare 
Manitoba and Health Sciences Center in the use and work flow of the Health Canada approved 
endobronchial implanted real-time tumor tracking transponder beacons (The Calypso™ beacon).  
Patients in phase I will undergo standard stereotactic ablative radiotherapy (SABR) of a lung tumor with 
prior endobronchial transponder beacon placement. For phase I, the transponder beacons will be used 
for comparative localization analyses and SABR treatment setup procedures will be carried out 
independent of transponder beacon data, however, transponder data will be collected in order to 
conduct, post-treatment, in vivo quality assurance assessments of beacon performance characteristics.  
Otherwise, the SABR treatment for phase I will consist of the currently accepted standard internal target 
volume based and standard image guided SABR.   
 
Phase II of this trial will consist of  26 patients who will undergo a specialized form of SABR radiotherapy 
specifically designed to take full advantage of the real-time tumor tracking ability of the Calypso™ 
transponder beacons.  Specifically, SABR in phase II will consist of smaller radiotherapy treatment 
volumes employing respiratory gating and smaller planning target volume expansion margins given the 
superior tumor location telemetry afforded by the Calypso™ beacons. Comparative dosimetric analyses 
contrasting the traditional ITV/PTV style treatments to those with reduced ITV/PTV margins achieved via  
Calypso guided SABR will be performed.  Patient self-reported quality of life and toxicity assessments 
will be collected with the goal of facilitating power and sample size calculations for the design of a larger 
phase III randomized controlled trial of Calypso guided SABR treatment in the future.  
 
  
Phase I (n=2) 
           Adults ≥ 18 years of age 
T1N0M0 or T2N0M0 (<4cm) NSCLC; or 
A single Metastatic Lung Tumor < 4cm 
ECOG performance status 0 to 2 
Surgically inoperable  
  
Non-Oxygen dependent at baseline 
 
 
Phase II (n=26) 
           Adults ≥ 18 years of age 
T1N0M0 or T2N0M0 (<4cm) NSCLC; or 
A single Metastatic Lung Tumor < 4cm 
ECOG performance status 0 to 2 
Surgically inoperable  
  
Non-Oxygen dependent at baseline 
 
Planned Sample Size:  Phase I (n=2); phase II (n=26) 
“Standard” Stereotactic Ablative Radiotherapy: 
1) Endobronchial Calypso Beacon Placement 
2) 4-Dimensional CT Simulation Scan 
3) ITV based “standard” SABR planning with 5mm PTV    
Expansion margins 
4) Image guided “Standard” SABR (54Gy/3#) 
5) Quality Assurance measurements 
6) Quality of Life and Toxicity Assessments 
Calypso Guided Stereotactic Ablative Radiotherapy: 
1) Endobronchial Calypso Beacon Placement 
2) 4-Dimensional CT Simulation Scan 
3) ITV-free and 2mm PTV margin SABR planning 
4) Respiratory gated Calypso guided SABR (54Gy/3#) 
5) Quality of Life and Toxicity Assessments 
6) Radiotherapy dosimetry planning studies 

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2.0 Background:  
 
Stereotactic Ablative Body Radiotherapy (SABR) 
Stereotactic Ablative Body Radiosurgery (SABR) is a modern radiotherapy technique which consists of 
the delivery of tumoricidal (ablative) doses of radiation to a tumor target inside the body.  In contrast to 
conventional radiotherapy which delivers the total dose to the tumor over six to seven weeks with small 
daily doses of radiotherapy (2 Gy per fraction for 30 to 33 fractions), SABR is delivered using much larger 
ablative doses of radiotherapy per fraction (ranging from 8 to 34 Gy per fraction) allowing for the total 
dose to be delivered in a small number of fractions (1 to 5 fractions).  With larger doses per fraction, and 
delivery of radiotherapy over a shorter period of time, SABR affords a larger biological effective dose of 
radiotherapy when compared to conventional fractionated radiotherapy.  In general, most SABR dose 
regimens have biological effective doses in excess of 100Gy delivered with conventional fractionation.  
 
To date, SABR has been utilized for the treatment of primary or metastatic tumors of the lung1, 
prostate2, spine3, liver4, and brain5 offering excellent local disease control for patients who are either  
surgically inoperable or for those who refuse surgical management6.  SABR of early stage non-small cell 
lung cancers offers local control rates of the target tumor in the range of 90 to 96% at three years 
following treatment7.  By contrast, the use of conventional 3-dimensional conformal radiotherapy with 
doses as high as 70Gy with standard fraction sizes for early stage lung cancer yields considerably inferior 
results and only provides durable local control in 43% of cases8.  Thus, from a lung tumor control 
standpoint for small lung tumors, SABR has become the most widely accepted choice of radiotherapy 
dose fractionation.    
 
Motion Management Strategies for SABR of Lung Tumors 
SABR treatment of lung tumors is challenging in that lung tumors are constantly in motion in multiple 
axes as a result of respiratory and cardiac motion. This motion creates considerable uncertainty in 
targeting the tumor during SABR treatment.  In some cases, small lung tumors can have a respiratory 
motion path of upwards of 5 centimeters9, especially amongst tumors which are located close to the 
diaphragm in the middle or lower lobes of the lungs10, or for patients with poor pulmonary function with 
irregular breathing patterns.  
 
Lung tumor motion has significant implications for radiotherapy treatment planning especially impacting 
the size of the margin added to the gross tumor volume (GTV) to encompass the moving tumor, and the 
amount of radiation dose delivered to normal thoracic organs at risk (such as the heart, normal lung 
tissue, chest wall, ribs, etc). In general, the more a lung tumor moves, the larger the radiotherapy 
treatment volumes required to encompass the motion and thus the greater the unwanted dose of 
radiotherapy to healthy OARs (Figure 1). 
 
As such, many strategies have been employed to date in order to manage the motion of lung tumors 
undergoing SABR treatment including: respiratory gating, breath hold techniques (either deep 
inspiration, or end-exhalation), abdominal compression plates to force shallow breathing patterns, and 
motion encompassing strategies (4-Dimensional CT scans).  Each of these motion management 
strategies has their distinct advantages and disadvantages in terms of dosimetric sparing of OARs, 
patient tolerability/practicality, and accuracy (see table 1).   
 
Figure 1: The relationship between tumor motion and radiotherapy field sizes11. 

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Respiratory gating consists of the delivery of radiation therapy during a pre-selected portion of the 
respiratory cycle (typically end-exhalation expiration, when the tumor is relatively still) which requires 
continuous monitoring with an external surrogate marker of breathing motion (such as the Varian RPM 
system).  Respiratory gating (Figure 2) can potentially reduce dose to OARs by reducing the ITV and 
therefore the PTV volume, however it requires robust correlation of lung tumor motion to the motion of 
an external surrogate marker. However, this can be difficult for non-compliant patients, or for patients 
with irregular breathing waveforms.  Respiratory gated SABR treatment also takes considerably longer 
to deliver (since radiotherapy is only delivered during 20 to 30% of each respiratory cycle), especially 
when using standard radiotherapy dose rates (600 MU/min) which can result in treatment durations as 
long as 60 minutes per fraction. However, with the advent of rapid radiotherapy dose rates of up to 
2400 MU/min attainable using the latest linear accelerator designs (such as the Varian Edge™ at the 
KIAM) treatment times can be reduced to around 15 to 20 minutes, thus the problem of protracted 
treatment durations have largely been solved.    
 
Figure 2: Respiratory waveform (sinusoidal curve) and gating window during end-exhalation12. 
 
 
Abdominal compression plates13 to induce shallow breathing patterns and breath-held techniques11 have 
the theoretical advantage of reducing dose to OARs by reducing the internal movement of the tumor. 

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Both methods have been studied extensively, but clinical enthusiasm for their use has largely waned due 
to concerns of poor tolerability by patients (especially amongst patients with poor pulmonary function 
and limited respiratory reserve), and the prerequisite of highly compliant and motivated patients. 
 
Figure 3: The end-exhalation breath hold method of lung tumor motion management12. 
 
 
 
 
The most common forms of lung tumor motion management in clinical use today are motion 
encompassing methods. These techniques make use of four-dimensional CT simulation scans (4DCT) to 
provide 3D patient anatomy sampled at regular time points throughout the respiratory cycle. A 4DCT is a 
specialized radiotherapy CT simulation scan whereby the patient is scanned when comfortably free-
breathing while their respiratory motion is continuously quantified using an external surrogate marker 
system (which consists of an infrared marker box placed on the abdominal surface of the supine patient, 
and its position is monitored continuously).  
 
Both the CT data and the surrogate respiratory motion data are acquired simultaneously during the 
4DCT scan which takes approximately 90 seconds to capture14. Specialized computer software is used to 
“bin” the scan’s data into ten distinct respiratory-phase correlated CT datasets which represent the 
different phases of the respiratory cycle.  Radiotherapy treatment planning software allows a radiation 
oncologist to delineate the gross tumor volume (GTV) on each of the ten phases of the respiratory cycle.  
These 10 GTVs are summed together (using a “merge structure” function) and the resultant structure, 
termed the the internal target volume (ITV) 15 represents all the regions of the lung in which the lung 
tumor could be at any given moment during the respiratory cycle.  The advantage of the ITV based 
method is that it produces an “individualized” representation of the GTV to account for its internal 
movement in the body and therefore reduces the possibility of a geographic “miss” of the tumor during 
SABR.  The disadvantage of this method of tumor delineation is that it can make for very large treatment 
volumes and lead to higher radiation doses to OARs.  As a result of the ITV method, a generous portion 
of a patient’s healthy lung tissues are ablated during SABR and so patients are subject to potential 
adverse effects due to radiation dose delivered to healthy organs at risk (OAR) nearby to the tumor 
(summarized in table 2).   
 

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Table 1: Overview of Current Lung Tumor Motion Management Strategies 
 
Management Strategy 
Advantages 
Disadvantages 
Respiratory Gating 
-Potential to reduce OAR dose 
-No need for traditional ITV 
-Potential to reduce PTV volume 
when compared to ITV based 
approaches   
 
-Protracted Treatment Durations (if using 
“slow” dose rates) due to low duty cycle 
(note: this is not an issue with the Varian 
Edge linear accelerator) 
-Dependent on external surrogate marker 
for tumor motion signal  
-Some patients are unable to breathe 
with a regular rhythm (anxiety) 
Abdominal 
Compression plate 
-Reduction in tumor motion due 
to forced shallow breathing 
-Reduced internal margin 
-Potential to reduce PTV volumes 
when compared to non-
compression treatments 
-Not well tolerated by patients due to 
discomfort 
-Difficult for patients with limited 
functional lung volumes to tolerate 
-Time consuming daily treatment setup 
Motion Encompassing 
methods (4DCT scans) 
-Well tolerated by patients 
-Can be employed for patients 
with poor pulmonary function 
 
-Requires use of ITV, which increases 
treatment volumes (especially for tumors 
with large motion amplitude).  
-Dependent on external correlative 
surrogate for tumor motion 
Breath hold technique 
- Reduced internal margin 
-No need for ITV 
-Potential to reduce PTV volumes 
when compared to non-breath 
hold techniques 
-Potential to reduce OAR Dose  
-Requires highly compliant patients 
- Difficult for patients with limited 
functional lung volumes to tolerate 
- Dependent on external correlative 
surrogate for tumor motion 
  
 
Table 2: Common Complications to Thoracic Organs At Risk following Standard SABR treatments 
 
Organ at Risk 
Potential Complication 
Risk 
Lung 
Pneumonitis (≥Grade 2) 
10-20%16-19 
Ribs 
Rib Fracture 
35%20 
Chest Wall 
Chest Wall Pain (≥Grade 2) 
39%21 
    
Real-time tracking of a lung tumor’s location during SABR treatment would obviate the need to use a 
standard ITV-based approach for treatment planning and would serve to simultaneously improve the 
accuracy and precision of SABR while reducing the volume of healthy lung treated to an ablative dose of 
radiotherapy.  Real-time tumor location telemetry data would allow the SABR radiation treatment beam 
to be automatically activated when the tumor is positioned within the desired target location in the 
thorax, and deactivated when the tumor moves outside of the chosen target location.  This method of 
radiation treatment delivery is known as respiratory-gated12 radiotherapy and it carries the potential 
benefit of reducing the planning target volume of the radiotherapy22.  The dosimetric benefits of 
respiratory-gated radiotherapy depend mainly on the size of the target tumor (larger tumors benefit 

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more than smaller tumors) and the extent of the motion of the tumor (tumors with large amplitudes 
benefit the most and tumors with amplitudes <1cm do not seem to benefit in a meaningful way from 
respiratory gated therapy10,23).   Since most patients undergoing SABR treatments are almost always 
surgically inoperable due to the presence of one or more respiratory comorbidities (emphysema, 
bronchiectasis, etc) with poor pulmonary function, minimizing the volume of functional normal lung 
tissue ablated along with the tumor is of critical importance.    
 
SABR Treatment of Lung Tumors using Calypso Tracking Beacons 
In 2016, a Varian Edge™ radiotherapy treatment machine (linear accelerator) was installed and 
commissioned at the Kleysen Institute for Advanced Medicine (KIAM) at the Health Sciences Center 
(HSC) in Winnipeg, Canada.  This state of the art linear accelerator was specifically designed to deliver 
SABR treatments and is specially equipped with the Calypso™ lung tracking beacon system.   
 
The anchored Calypso™ lung tracking beacon is a grain-of-rice sized transponder beacon (Figure 4) 
which is placed immediately adjacent to a lung tumor using a flexible bronchoscope.  Typically three 
beacons are placed in the small airways of the lung (2 to 2.5 mm diameter airways) adjacent to the 
target tumor (within 3 cm of the tumor)24. The Calypso beacon can be used as either a traditional 
radiopaque fiducial marker (which can be identified using standard kilovoltage x-rays, fluoroscopy, or CT 
scans) or as a passive electromagnetic beacon transponder.  Each beacon measures 2 mm in diameter 
and 8 mm in length (14mm including the anchoring legs) and consists of a miniature electrical circuit 
that is encapsulated in a sealed biocompatible glass capsule. In order to prevent the beacon from 
migrating within the airways, the beacon has an affixed five-legged anchoring system which expands to 
5mm in diameter once deployed from the Calypso lung catheter. The Calypso transponder beacon is 
placed endobronchially using the working channel of a bronchoscope and the Calypso lung catheter 
(Figure 5). Navigational bronchoscopy can be used to pre-plan the optimal location for each beacon to 
be placed within the airways by using a pre-bronchoscopy CT scan.   
 
FIGURE 4: The Calypso™ Anchored Transponder Beacon with legs completely constrained (left), and 
deployed (right). 
 
 
 
 
 

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Figure 5: The single use Calypso Lung Catheter (for use in the working channel of a bronchoscope) 
 
 
The transponder’s electrical circuit is passive and the beacon does not contain an internal energy source.  
The transponder only emits a radiofrequency (RF) signal when it is excited by a harmless, non-ionizing RF 
field generated by the Calypso array (Figure 6).  After RF excitation, each transponder briefly emits a 
response signal at a unique frequency that is specific to each beacon. This signal is detected by the 
sensor array with a refresh rate of 25 times per second (25 Hz). The Calypso system uses this 
information from all of the beacons to continuously determine the three dimensional location of the 
tumor isocenter relative to the linear accelerator’s isocenter.  This allows for real time monitoring of a 
lung tumor’s motion during radiation treatment delivery. 
 
Figure 6: Calypso system components 
 
 

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The Calypso lung beacon was recently granted Health Canada approval for routine endobronchial 
implantation in human patients following a phase I human study of the Calypso transponder beacon for 
patients with early stage lung cancer24 which demonstrated excellent tolerability and safety.   
 
In lay terms, the Calypso beacons function similarly to a GPS navigation device, only instead of locating 
the position of a person on a map, they locate the position of the tumor within the lung in real time at 
the time of SABR treatment. This real-time tumor position information permits very high accuracy SABR 
delivery to lung tumors with the potential for significantly smaller treatment volumes and therefore less 
acute or late SABR related toxicity.  
 
Calypso beacons have been employed in other radiotherapeutic settings including prostate cancer 25 and 
liver cancer.  In the case of prostate cancer patients treated with Calypso-guided radiotherapy, the 
improved accuracy and real-time tumor tracking allowed treatment PTV margins to be reduced to as 
small as 3mm, which in turn resulted in smaller PTV volumes, less toxicity to nearby organs at risk, and 
improved quality of life25.  It is therefore expected that Calypso-guided radiotherapy could produce 
analogous beneficial results for patients undergoing SABR treatments for their lung tumors. To this end, 
we therefore propose this seamless phase I/II prospective clinical trial for patients with mobile tumors 
of the lungs undergoing SABR which will utilize the Calypso tracking beacon to enable end-exhalation 
gated,ITV-free radiotherapy treatment planning with minimal PTV margins. The integration of these 
treatment planning and SABR delivery features is anticipated to reduce radiotherapy treatment 
volumes, dose to OARs, with excellent tolerability and quality of life.  
 
3.0 Trial Design 
This is a prospective, single arm, seamless phase I/II cohort study (investigator initiated trial) with a 
planned total accrual of 28 patients. 
 
4.0 Study Population: 
Potentially eligible patients are adults with surgically inoperable, biopsy proven or suspected single 
T1N0 or T2N0 Non-small cell lung cancer tumor or patients with a single pulmonary metastasis (<4 cm 
maximal tumor dimension) from a known primary malignancy of any histology (either metastatic failure 
to a single pulmonary site after primary radical treatment, or metastatic progression to a single lung 
metastasis following palliative chemotherapy with no other sites of uncontrolled disease). Tumors 
should be located either in the lower lobe, lingula, or right middle lobe of the lung however, patients 
with upper lobe tumors are eligible as long as the tumors have a respiratory amplitude of ≥1cm. Tumors 
should be located at least 2 cm from the proximal bronchial tree (non-central tumors). 
 
5.0 Eligibility Criteria: 
1) Adult ≥ 18 years of age who is surgically inoperable, or refusing surgical management. 
2) Tumor criteria (a patient must satisfy one of “a”, “b” below to be eligible): 
a. AJCC 7th edition clinical T1aN0M0, T1bN0M0, or T2aN0M0 (<4cm) Non-small cell lung cancer 
(adenocarcinoma, squamous cell carcinoma, or NSCLC Not Otherwise Specified) of the 
middle or lower lobes of the lung*;  
b. A single pulmonary metastasis (<4cm) of a known primary malignancy of any histology 
involving the middle or lower lobes of the lung* (either metastatic failure to a single 
pulmonary site after primary radical treatment, metastatic progression to a single lung 

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metastasis following palliative chemotherapy, or a single pulmonary metastatic lesion of 
newly diagnosed stage IV malignancy).  
*upper lobe tumors are eligible for trial participation if the tumor has a demonstrated tumor motion of 
≥1 cm in any axis (as assessed by fluoroscopy at the time of bronchoscopy).  
3) Confirmation of malignancy (a patient must satisfy one of “a”, “b” below to be eligible): 
a. Tumors accessible by bronchoscopy, image-guided percutaneous biopsy, or other invasive 
staging methods require biopsy confirmation of malignancy. 
b. If a tumor is not amenable to a diagnostic biopsy, evidence of growth of the target tumor on 
serial imaging scans is necessary prior to enrollment.  An increase in SUV of the target tumor 
on serial PET scans is also acceptable. 
4) ECOG performance status of 0 to 2. 
5) Minimum life expectancy of 6 months. 
6) Deemed fit to undergo bronchoscopy by their participating thoracic surgeon 
7) Deemed fit to undergo SABR by their participating Radiation Oncologist. 
8) Respiratory function (a patient must satisfy both “a” and “b” below): 
a. Minimum FEV1 of 0.8 liters 
b. Minimum DLCO of 35% predicted. 
9) Able to provide written informed consent and understand verbal instructions necessary for 
radiotherapy treatments. 
 
Exclusion Criteria: 
1) Tumors located < 1cm from the chest wall based on CT imaging. 
2) Tumors located ≤ 2 cm from the proximal bronchial tree (see figure 7) 
3) Patients who require supplemental oxygen at rest. 
4) Patients who are unable to lie flat or still for a minimum of 30 minutes. 
5) ECOG performance status 3 or 4. 
6) Evidence of uncontrolled extra-thoracic metastatic disease (based on imaging or clinical findings). 
7) Proven or suspected intrathoracic lymph node involvement. 
8) Prior SABR to the target tumor. 
9) Prior history of idiopathic pulmonary fibrosis, interstitial lung disease, or active collagen vascular 
disease (systemic lupus erythematosus, Rheumatoid arthritis, or Scleroderma)  
10) Pregnancy. 
11) Active pulmonary infection 
12) Known hypersensitivity to nickel titanium (Nitinol) 
13) Known Bronchiectasis of the small airways nearest to the tumor 
 
 
 
 
 
 
 
 
 
 
 

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Figure 7: The proximal bronchial tree (tumous within this region are ineligible for trial participation). 
 
 
6.0 Study Objectives:  
Phase I:  
1) To allow for members of the interdisciplinary care team (Thoracic surgeons, Radiation Oncology, 
Radiation Therapists, and Medical Physicists) to familiarize themselves with the clinical use of 
implanted endobronchial tumor tracking beacons and carry out quality assurance assessments in 
preparation for the subsequent phase II component of the study. 
2) To quantify the presence (if any) of beacon migration (inter-beacon distance) at different time 
points in a patient’s care path (time of implantation, CT simulation scan, and days of SABR 
treatment). 
3) To assess the quality of life of patients having Calypso placement (EORTC QLQ - LC13 questionnaire) 
4) To assess acute toxicity of beacon implantation using the Common Terminology for Criteria for 
Adverse Events (CTCAE version 4.0) 
5) To quantify the potential benefit of continuous monitoring of tumor location using Calypso by 
comparing it to traditional imaging-based setup.  
 
Phase II:  
1) To quantitatively assess the differences in irradiated treatment volumes and radiotherapy dose 
volume metrics for the PTV and healthy thoracic organs at risk between Calypso™ guided respiratory 
gated SABR and the traditional ITV based radiotherapy. 
2) To serially quantify the acute and late toxicity of patients undergoing Calypso™ guided SABR using 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
3) To serially quantify the self-reported quality of life of patients undergoing Calypso Guided SABR 
using the EORTC QLQ - LC13 questionnaire 
4) To serially biobank blood and urine samples for patients undergoing radical SABR of lung tumors to 
allow for the future development of novel prognostic and predictive biomarkers for patients 
undergoing SABR. 
5) To serially quantify changes to pulmonary function following SABR treatment 

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6) To demonstrate the benefit of Calypso treatments in reducing patient-specific component of PTV 
margins 
 
Study Hypotheses:  
Phase I: Calypso beacon placement will be safe and well tolerated and will function within their specified 
tolerances with minimal (sub-millimeter) inter-beacon migration. 
 
Phase II: The Median Planning Target Volume (PTV) of Calypso guided respiratory gated SABR will be 
40% smaller than the median PTV volume of standard ITV based SABR treatment with standard PTV 
margins.  Furthermore, thoracic organs at risk will receive significantly less radiotherapy dose when 
compared to the standard SABR treatment. 
 
7.0 Study Endpoints:  
 
Primary Endpoints 
Phase I:  Mean difference in inter-beacon distance (in millimeters) (at time of 4DCT simulation compared 
to fractions 1,2, and 3 of SABR) 
 
Phase 2: Mean within patient difference in PTV volumes of standard ITV-based SABR compared to gated 
SABR utilizing Calypso based PTV margins (expressed as a percentage difference). 
 
Secondary Endpoints: 
1) Patient self-reported quality of life (EORTC QLQ - LC13 questionnaire) 
2) Acute and late toxicity - Common Terminology for Criteria for Adverse Events (CTCAE version 4.0) 
3) Median within patient difference in radiotherapy doses to thoracic Organs at risk 
4) Median change in FEV1, DLCO, and 6 minute walking distance on room air at baseline compared to 
follow-up time points. 
5) Local tumor control (using the RECIST version 1.1 Criteria26) 
6) Progression Free Survival 
7) Cancer Specific Survival 
8) Overall Survival 
 
8.0 Pre-treatment Investigations: 
All staging investigations shall be completed within 12 weeks prior to study enrollment.  
1) History and Physical Exam  
2) CT scan or MRI of brain 
3) PET scan 
4) CT chest and abdomen 
5) Pulmonary function testing (including spirometry, diffusion capacity, and 6 minute walk test) 
6) CBC, electrolytes, BUN, Creatinine 
7) Quantitative beta-HCG (Only if the participant is a premenopausal female). 
 
9.0 Study Enrollment Procedures 
Participating investigators are responsible for confirming the eligibility/ineligibility status of a potential 
study participant prior to enrollment.  Since this trial requires the active participation of both thoracic 

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surgeons and radiation oncologists, a patient should be assessed by both specialists prior to being 
offered participation in the trial. 
 
Potentially eligible patients will be offered voluntary participation in this trial by their participating 
physician.  Patients will be given an informed consent form to review and will be contacted at a later 
date by trial personnel to answer any questions which may arise and to obtain written informed 
consent. 
 
Patients who have consented to trial participation will then undergo all required pre-treatment 
investigations (if not already done) in a timely manner. 
 
10.0 Treatment 
 
Calypso Beacon Placement: 
Calypso beacon placement will be performed using flexible bronchoscopy under general anesthesia or 
conscious sedation.  The site of implantation will be localized using a combination of direct visualization, 
fluoroscopy, ultrasound and electromagnetic navigation bronchoscopy.  Drs. Buduhan and Tan have 
received formal course training on the use of SuperDimension Navigational Bronchoscopy System for 
localization of lung nodules and directed bronchoscopic placement of implant devices.  This will greatly 
facilitate accurate beacon placement.  The bronchoscope will be advanced under direct vision into the 
targeted implantation site.  Using navigational bronchoscopy and fluoroscopy the target implant sites 
will be identified and guide sheath placed through the bronchoscopy working channel.  Through the 
guide sheath, the catheter with anchored beacon transponder will be directed to the implantation sites 
under bronchoscopic and fluoroscopic direction.  The beacon transponders will be deployed until 
properly anchored in the appropriate peri-tumoral implantation sites.  Satisfactory beacon placement 
will be verified using fluoroscopy.   The anchored transponders are implanted in a triangle around the 
tumor target and are at least 1 cm but no more than 7.5 cm from each other.  Although navigational 
bronchoscopy is recommended for beacon placement, conventional bronchoscopy with fluoroscopic 
guidance is also acceptable for beacon placement at the discretion of the attending thoracic surgeon in 
the event that navigational bronchoscopy is unavailable on the day of the beacon placement procedure. 
 
Radiotherapy: 
4-Dimensional CT simulation Scan: Patients will be simulated in the supine position and immobilized 
using a Vac-lok bag with arms raised above their heads and with legs on a knee rest for comfort.  
Patients will be free breathing with a relaxed tidal breathing pattern. The CT simulation scan will be 
performed using the Varian RPM system in order to produce 10-respiratory phase correlated CT data 
sets (4-DCT scan). Intravenous contrast is not required. 
 
Co-registration of PET scan: For purposes of contouring the primary tumor, PET scan fusion is 
recommended but not mandatory. 
 
Organ at Risk Delineation: The following organs at risk will be contoured on the CTaverage dataset: 
1) Normal Lung; 
2) Esophagus; 
3) Chest wall (within 5 cm of the PTV); 

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4) Ribs (within 5 cm of the PTV); 
5) Heart; 
6) Kidneys (if the tumor is a lower lobe tumor); 
7) Ipsilateral brachial plexus (if located within 5 cm of the PTV); 
8) Spinal Cord; 
9) Proximal Trachea; 
10) Proximal bronchial tree; 
11) Aorta (if left sided tumor); 
12) Vena Cava (if right sided tumor); 
13) Liver (if tumor is located in the right lower lobe) 
14) Nearest vertebral body, and the vertebral body above and below the nearest vertebral body. 
 
For organ at risk contouring guidelines, radiation oncologists are encouraged to reference the RTOG 
0236 trial protocol. 
 
Target Volume Delineation:  
The Gross Tumor Volume (GTV) will be delineated on all 10 respiratory-phase correlated CT datasets 
with the CT Hounsfield unit window level set to the “lung window” preset.  Participating radiation 
oncologists are encouraged to cross-reference the pre-treatment investigations (Infused CT chest, PET 
scan, etc) in order to aid with the delineation of the GTV. 
 
Internal Target Volume: Using the average CT dataset, the ITV will be generated using the Eclipse™ 
“accumulate structure” function incorporating the GTVs created on all 10 phase-correlated datasets. 
 
Gating Window Internal Target Volume (ITVGW): The ITVGW will consist of a accumulated structure 
composed of the GTVs contoured on the end-exhalation phases of the breathing cycle.  The end-
exhalation phases will typically include the GTVs from the CT50, CT40, and CT60 phases of the 4DCT 
scan.  Depending on the individual patient’s breathing pattern, the ITVGW could also include the GTVs 
from CT30 and CT70 if necessary (this decision to include CT30 and CT70 needs to be approved by the 
study PI on a case-by-case basis). 
 
Planning Target Volume expansion margins: 
For Phase I of the study - 5 mm isotropic expansion of the ITV 
For Phase II of the study - 3mm isotropic expansion of the ITVGW.   
 
Note: For patients treated in phase II of the study, If setup errors noted during the first fraction of 
treatment are greater than 3mm in size for more than 10% of the overall treatment time, then a larger, 
case-specific PTV margin will be applied for the remaining 2 fractions of the radiotherapy.  Any 
enlargements to the PTV will be applied with the prior approval of the study PI. 
 
Radiotherapy Dose Prescription: 54 Gy to 95% of PTV in 3 fractions. 
 
Radiotherapy Dose Coverage: 99% of the PTV receives at least 90% of prescription dose 
 
Timing of Fractions: A minimum of 40 hours should separate each fraction. 
 

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Radiotherapy treatment planning: SABR treatment plans will be calculated using the Varian Acuros 
dosimetric algorithm with inhomogeneity correction.  Two co-planar, two-hundred and forty degree arcs 
of volumetric modulated arc therapy (VMAT) will be the default beam arrangement. 
 
SABR Delivery: SABR will be delivered using the Varian Edge linear accelerator at the KIAM using 10MV 
flattening filter free photon beams using a dose rate of 2400 MU/min. 
 
Gating Window: The end-exhalation phase (CT50) plus one phase directly preceding (CT40) and 
following (CT60) will used as the gating window. CT30 and CT70 may also be included in the gating 
window. 
 
Chemotherapy: Chemotherapy, immunotherapy, or mutation targeted therapies should be held at least 
24 hours prior to the first fraction, and can be restarted 24 hours after the delivery of the last fraction. 
 
Cone Beam CT-based (CBCT) Image Guidance: In phase I of the trial, cone beam CT scans will be 
performed daily in order to allow for initial image guidance of treatment setup using bony landmarks 
(vertebral bodies) and soft tissue (tumour).  Calypso beacon data will be collected during phase I 
including inter-transponder geometry. 
 
Calypso Guidance: In Phase II of the trial, calypso beacon data will be used toe tine initial patient 
positioning and treatment delivery. The location data from the Calypso beacons will be captured by the 
Calypso array in order to assess inter-transponder beacon distance, as well as beacon geometric center 
location relative to the linear accelerator's isocenter. This position is used as the reference for Calypso 
to provide continuous monitoring. Calypso data will then be used for respiratory gating of the SABR 
treatment.  CBCT imaging may also be performed to verify the soft tissue-beacon correspondence. CBCT 
images will be evaluated and may be used for patient repositioning if necessary. 
 
Respiratory gating (phase I): For phase I of the trial, the respiratory gating signal will not be used to 
control the radiation beam delivery, however, Calypso transponder beacons will be used to provide 
location telemetry for quality assurance and data analysis purposes only.     
 
Respiratory Gating (Phase II): The SABR radiation beam delivery will be gated using the Calypso 
transponder location data for phase II of the study. 
 
OAR Tolerances (as derived from the RTOG 0618 protocol by Timmerman et. al.): 
 
Organ 
Volume 
Dose Constraint (Gy) 
Spinal Canal 
Point Dose 
<0.35cc 
<1.2cc 
19 Gy 
18 Gy 
10 Gy 
Esophagus 
Point Dose 
<5cc 
28 Gy 
15 Gy 
Ipsilateral Brachial Plexus 
Point Dose 
<3cc 
24 Gy 
22 Gy 
Heart 
Point Dose 
<15cc 
30 Gy 
24 Gy 

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Proximal Bronchial Tree 
Point Dose 
<4cc 
30 Gy 
14 Gy 
Skin 
Point Dose 
<10cc 
24 Gy 
22 Gy 
Ribs 
Point Dose 
< 1cc 
30 Gy 
24 Gy 
Chest Wall 
Point Dose 
< 30 cc 
30 Gy 
20 Gy 
Great Vessels 
Point Dose 
<10cc 
35 Gy 
30 Gy 
Stomach 
Point Dose 
<10 cc 
22Gy 
15 Gy 
Liver 
>700cc 
15 Gy 
Bilateral Normal Lung 
See section below 
See section below 
Bilateral Normal Lung 
V20Gy 
<10% 
 
Dose Spillage and conformality: 
 
High dose spillage: Any dose > 105% of the prescription dose should occur primarily within the PTV itself 
and not within normal tissues outside of the PTV. The cumulative volume of all tissues outside of the 
PTV receiving a dose of > 105% of the prescription dose should be no more than 15% of the PTV volume. 
 
The falloff gradient beyond the PTV extending into normal tissue structures (especially the lungs) must 
be rapid in all directions and meet the following criteria which are dependent on the PTV volume as 
outlined in the table below: 1) The ratio of the volume of the 54 Gy isodose surgace to the PTV volume 
should be less than 1.2 (see column two of the table below); 2) The ratio of the volume of the 30Gy 
isodose volume to the volume of the PTV must be no greater than the “R30Gy”(see column three in the 
table below); 3) the maximum point dose at least 2 cm outside the PTTV edge in any direction must be 
less than “D2cm” (see column four in table below); and 4) the percentage of total lung volume receiving 
20Gy or more (V20) should be less than 10% (see column five in table below).  
 
 
 
11.0 Potential Adverse Reactions:  

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The adverse effects associated with the use of the Calypso transponder beacons are similar in profile to 
other bronchoscopic procedures such as bronchoscopic biopsies or the implantation of inert gold seed 
fiducial markers.   
 
Pneumothorax: The most commonly encountered adverse effect of fiducial marker placement is 
pneumothorax which has a risk of between 2 to 5 percent27,28 with the majority of these treated either 
conservatively or with a pigtail catheter for a day or two24 after the procedure.   
 
COPD Exacerbations: Exacerbations of emphysema or chronic obstructive pulmonary disorder (COPD) 
have been reported with a risk of up to 11 percent 29 in one small case series of 9 patients who had non-
calypso beacons implanted. However, several much larger case series reported no COPD 
exacerbations24,27,28 whatsoever.   
 
Beacon Migration: Beacon migration has been reported at a rate of 1%24 using anchored calypso 
beacons which can lead to the expectoration of the migrated beacon.  
 
Infection: There is a 1% risk of pulmonary infection in the tissue in close proximity to an anchored 
Calypso beacon24.   
 
Minor Bleeding: There is a small risk of minor local bleeding in the airway implanted with the 
transponder beacon with a risk similar to other bronchoscopic based procedures, however no 
pulmonary hemorrhages were reported in the case series using the anchored Calypso lung beacon24. 
 
MRI compatibility: Anchored Calypso beacons can be safely scanned using MRI with either a 1.5 or 3.0 
Tesla static magnetic field with or a magnetic field gradient of up to 9.3 Tesla/meter without inducing 
any clinically significant displacement force or torque.  An MRI image artifact may extend up to 2 cm 
from the anchored transponder, which is of no clinical significance for patients on this trial since, outside 
of research studies, MRI is not used in the routine diagnosis of intrapulmonary lesions.  
 
Retrieval of Calypso Beacons: 
If an unanticipated adverse effect occurs with a Calypso beacon and removal of the beacon is required, 
then the anchored beacons can be retrieved using a flexible bronchoscope and forceps similar to other 
endobronchial foreign body retrievals.   
 
12. 0 Evaluation During and After Protocol Treatment 
 
 
Baseline 
4DCT 
Sim* 
Each SABR 
Fractionᵠ 
2 
mo# 
6 
mo 
12 
mo 
18 
mo 
2 yr 
3 yr 
History & 
Physical Exam 
x 
 
 
x 
x 
x 
x 
x 
x 
CT or MRI Brain 
x 
 
 
 
 
 
 
 
 
CT Chest & 
Abdomen 
x 
 
 
 
x 
x 
x 
x 
x 
PET Scan 
x 
 
 
 
 
 
 
 
 
Chest X-ray 
 
 
 
x 
 
 
 
 
 
Pulmonary 
x 
 
 
 
x 
 
x 
 
x 

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Function 
Testing 
6 min walking 
test 
x 
 
 
 
x 
 
x 
 
x 
Medication 
Profile 
x 
 
 
x 
x 
x 
x 
x 
x 
CBC, Lytes, 
Bun, Cr 
x 
 
 
 
 
 
 
 
 
EORTC QLQ - 
LC13 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Toxicity Profile 
(CTCAE V 4.0) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inter-beacon 
distance 
 
x 
x 
 
 
 
 
 
 
Notes:  
* 4DCT is to be performed no later than 4 calendar weeks after the date of beacon implantation  
ᵠ The first fraction of SABR is to start no later than 14 calendar days after the 4DCT simulation scan 
# the timing of all follow up evaluations are relative to the date of the last fraction of SABR. 
 
13.0 Statistical Considerations: 
 
Descriptive characteristics: 
Baseline patient, tumor, and treatment characteristics will be summarized using standard descriptive 
statistics as summarized in the table below. 
 
Patient Factors 
 
Age 
Mean & Standard Deviation 
Gender 
Percentage 
Comorbidity (Charlson Index) 
Mean & Standard Deviation 
Smoking History Category (Current smoker, 
previous smoker, never smoker) 
Percentage 
Smoking Pack-Year History 
Mean & Standard Deviation 
FEV1 (Liters) 
Mean & Standard Deviation 
Diffusion Capacity (%) 
Mean & Standard Deviation 
6 Minute Walk Test (% of expected distance) 
Mean & Standard Deviation 
Tumor Factors 
 
T-stage (T1, T2) 
Percentage 
Tumor size (cm3) 
Mean & Standard Deviation 
Tumor location (by lobe) 
Percentage 
Tumor Histology  
Percentage 
Treatment Factors 
 
GTV (cm3) 
Mean & Standard Deviation 
PTV (cm3) 
Mean & Standard Deviation 
Maximal observer tumor motion (cm) 
Mean & Standard Deviation 
Radiotherapy Dose Prescription (cGy) 
Percentage 
Radiotherapy Delivery Time Per Fraction 
Mean & Standard Deviation 

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Study Power: 
Power calculations were conducted using the STATA 12.0 statistical software package (College station, 
Texas).  Zhao et al.22 carried out dosimetric analyses of lung tumors undergoing SABR lung treatments 
with similar characteristics (T1-T2N0 NSCLC) to those which would be eligible for this study and found a 
median PTV volume of 62.9 cm3 (sd 43.6 cm3).  Presuming similar sized tumor volumes as Zhao et al., A 
sample size of 28 patients would yield a power of 0.92 to detect a 40% reduction in the mean PTV 
volume between standard ITV based SABR treatment as compared to gated calypso guided SABR, with 
an alpha value of 0.05 and using a 1-sided test for statistical significance. 
 
Endpoints: 
 
Percentage Change in PTV:  For each participating patient, the PTV volumes will be calculated on the 
same 4DCT for standard ITV-based SABR treatment as well as the Calypso guided SABR treatment.  The 
comparison of the PTV volumes will be calculated as follows: 
 
 
% change in PTV = (PTVstandard SABR - PTVCalypso Guided SABR)/ (PTVstandard SABR) x 100 
 
 
This metric will be reported as a mean for the cohort with SD 
 
Quality of Life Data: The mean EORTC QLQ – LC13 plus standard deviation will be tabulated in 
descriptive format for each evaluation time point. 
 
Acute and Late Toxicity: The maximum grade of observed toxicity during treatment and follow-up will be 
tabulated in a descriptive format by adverse effect. 
 
Percentage Change in Organ at Risk Dose Volume Metrics: For each organ at risk, percentage change in 
the dose-volume histogram metric of interest will be calculated as per the following example: 
 
 
 
% Change in Lung V20 = (V20standard SABR – V20Calypso Guided SABR)/ V20standard SABR x 100 
 
Pulmonary Function Test Results: Percentage change in pulmonary function test results (FEV1, DLCO, 
and 6 minute walk distance) will be calculated as per the following example at each follow-up time 
point: 
 
 
% Change FEV1 = (FEV1baseline – FEVfollow-up)/FEV1baseline x 100% 
 
Local Control: The RECIST30 version 1.1 criteria will be used to assess the effect of SABR treatment on the 
local control of the tumor as per the following definitions: 
 
RECIST Outcome 
Description 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions taking as 
reference the smallest sum LD recorded since the treatment started or 

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the appearance of one or more new lesions 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
7) Survival: Progression-Free Survival (PFS), Cancer-Specific Survival (CSS), and Overall Survival (OS) will 
be estimated using the Kaplan-Meier method. For all three survival estimates, the survival period 
will be defined as the time from tissue diagnosis to progression event (for PFS), Cancer related death 
(CSS), death from any cause (OS) or time of censoring (due to loss to follow-up, or end of study). 
 
14. 0 Biobanking of Serum & Urine 
In parallel to this study, patients will be offered voluntary participation in the Manitoba Tumor Bank 
(operating under auspices of the Manitoba Tumor Bank’s Informed Consent Form).  Blood and urine 
specimens from consenting volunteers will be collected at baseline, on the last day of SABR, at 6 
months, and 1 year of follow up.  This will allow for correlative biomarker studies to be performed in the 
future. 
15.0 Ethical Considerations 
This study will be carried out with the written approval of the biomedical research ethics board of the 
University of Manitoba. All patient care for this study will be in accordance with the principles of human 
medical research outline in the Declaration of Helsinki as adopted by the World Medical Association. 
 
This study will be conducted in accordance with the International Conference on Harmonization (ICH) 
for Good Clinical Practice (GCP) and the appropriate regulatory requirements. The investigators will be 
familiar with the appropriate study treatments as described in the protocol. Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data collected. 
 
16.0 Protocol Treatment Discontinuation 
Patients may discontinue protocol treatment in the following circumstances:  
1) Unacceptable toxicity (defined as any grade 3 or higher NCI CTCAE 4.0 acute toxicity relating to 
either the radiotherapy or the study drug); or  
2) The development of an intercurrent illness that would preclude the continuation of the study 
treatment; or 
3) Development of an intercurrent illness that would preclude further clinical assessments; or; 
4) Request by the patient; or  
5) Completion of study therapy and follow-up as per section 12; or 
6) Cancer Cancer recurrence or progression (based on any combination of imaging, biochemical or 
clinical findings).  
 
Patient management following stoppage of protocol treatment is to be reviewed by the Principal 
Investigators of the study (Dr. Julian Kim and Dr. Gordon Buduhan). This will allow the Principal 
Investigators to provide recommendations on the schedule and duration of additional follow-up, 
depending on the value of additional follow-up, patient convenience, trial safety, etc. 
 
17.0 Serious Adverse Event Reporting 

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A serious adverse event (SAE) is any adverse event, regardless of causality that: 
 Results in death. 
 Is life-threatening. (When a patient is at immediate risk of death from a reaction as it occurred, i.e., it 
does not include a reaction which hypothetically might have caused death had it occurred in a more 
severe form. 
 Requires in-patient hospitalisation or prolongation of existing hospitalisation.  Hospitalisation 
admissions and/or surgical operations scheduled to occur during the study period, but planned prior to 
study entry are not considered AEs if the illness or disease existed before the patient was enrolled in the 
trial, provided that it did not deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned). 
 Results in persistent or significant disability/incapacity.  Disability is defined as a substantial 
disruption of a persons’ ability to conduct normal life functions. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event.  An important medical event is an event that may not result in death, 
be life-threatening, or require hospitalization but may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.   
 
Clarification should be made between the terms “serious” and “severe” since they are not synonymous.  
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as a severe headache).  This is not the same as “serious” which is based on 
patient/event outcome or action criteria described above and are usually associated with events that 
pose a threat to a patient’s life or functioning.  A severe adverse event does not necessarily need to be 
considered serious.  For example, persistent nausea of several hours duration may be considered severe 
nausea but not an SAE.  On the other hand, a stroke resulting in only a minor degree of disability may be 
considered mild, but would be defined as an SAE based on the above noted criteria.  
 
Serious Adverse Event requires reporting with completion of the SAE report. Fax the SAE report within 
24 hours of the investigator knowledge or designee knowledge of the event to the attention of: Dr. 
Julian Kim and Dr. Gordon Buduhan to (204) 786-0194 (fax). Accrual may be stopped immediately as 
indicated upon review and confirmation of the SAE by the co-PIs in liaison with the investigator/ 
Research Ethics Board. This trial will conform to the monitoring requirements of Biomedical Research 
Ethics Board of the University of Manitoba. 
 
18.0 Data Safety & Monitoring Committee 
A committee consisting of non-trial related University of Manitoba affiliated personnel will serve as the 
Data Safety & Monitoring Committee.  The committee will be chaired by a radiation oncologist (Dr. 
Andrew Cooke).  Committee members will include a medical physicist (Dr. Anita Berndt), and a thoracic 
surgeon (Dr. Helmut Unruh). The DSMC will be convened after the fourteenth patient completes their 
first follow up visit after completion of their protocol mandated SABR treatments.  Primary and 
secondary endpoints will be assessed.  Should evidence of statistically significant detrimental effects of 

Protocol Version 1.4 (8 Sept 2017) 
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the study intervention become apparent for the study's primary endpoints then futility will be declared 
and the trial will be closed.  
 
19.0 Publication & Authorship 
The results of this study will be prepared for publication in relevant peer-reviewed journals of radiation 
oncology/medical physics/thoracic oncology.  It is anticipated that more than one publication will arise 
from this study.  For clinical papers, the Co-Principal Investigators (JK, GB) will alternate first and senior 
authorship.  All remaining co-investigators will be listed in descending order of their contributions to the 
overall success of the trial.  Contributions to the success of the trial include but are not limited to: 
protocol design, drafting of grant applications, calypso physics commissioning/quality assurance, accrual 
of patients to the study, analysis of study results, and writing/editing of the manuscript.  For physics 
based papers, a medical physicist will serve as a first author and a radiation oncologist (JK) will serve as 
the senior author. Co-investigators will 30 days from the receipt of manuscript drafts to return revisions 
or comments prior to submission for publication.  
 
 
 
19.0 References 
1. Maquilan G, Timmerman R. Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer. Cancer J 
2016;22: 274-279. 
2. Lischalk JW, Kaplan ID, Collins SP. Stereotactic Body Radiation Therapy for Localized Prostate Cancer. 
Cancer J 2016;22: 307-313. 
3. Jabbari S, Gerszten PC, Ruschin M, et al. Stereotactic Body Radiotherapy for Spinal Metastases: 
Practice Guidelines, Outcomes, and Risks. Cancer J 2016;22: 280-289. 
4. McPartlin AJ, Dawson LA. Stereotactic Body Radiotherapy for Hepatocellular Carcinoma. Cancer J 
2016;22: 296-301. 
5. Minniti G, Scaringi C, Paolini S, et al. Single-Fraction Versus Multifraction (3 x 9 Gy) Stereotactic 
Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of 
Radiation-Induced Brain Necrosis. Int J Radiat Oncol Biol Phys 2016;95: 1142-1148. 

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6. Kosmidis S, Katsochi D. Advanced Radiation Techniques: Stereotactic Body Radiation Therapy (SBRT) 
in Early Stage Inoperable Lung Cancer Disease. Pract Radiat Oncol 2013;3: S16. 
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. Lagerwaard FJ, Senan S, van Meerbeeck JP, et al. Has 3-D conformal radiotherapy (3D CRT) improved 
the local tumour control for stage I non-small cell lung cancer? Radiother Oncol 2002;63: 151-157. 
9. Chen QS, Weinhous MS, Deibel FC, et al. Fluoroscopic study of tumor motion due to breathing: 
facilitating precise radiation therapy for lung cancer patients. Med Phys 2001;28: 1850-1856. 
10. Rao M, Wu J, Cao D, et al. Dosimetric impact of breathing motion in lung stereotactic body 
radiotherapy treatment using intensity modulated radiotherapy and volumetric modulated arc therapy 
[corrected. Int J Radiat Oncol Biol Phys 2012;83: e251-6. 
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: S101-12. 
12. Berson AM, Emery R, Rodriguez L, et al. Clinical experience using respiratory gated radiation therapy: 
comparison of free-breathing and breath-hold techniques. Int J Radiat Oncol Biol Phys 2004;60: 419-426. 
13. Heinzerling JH, Anderson JF, Papiez L, et al. Four-dimensional computed tomography scan analysis of 
tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of 
lung and liver. Int J Radiat Oncol Biol Phys 2008;70: 1571-1578. 

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14. Slotman BJ, Lagerwaard FJ, Senan S. 4D imaging for target definition in stereotactic radiotherapy for 
lung cancer. Acta Oncol 2006;45: 966-972. 
15. Underberg RW, Lagerwaard FJ, Cuijpers JP, et al. Four-dimensional CT scans for treatment planning 
in stereotactic radiotherapy for stage I lung cancer. International Journal of Radiation Oncology* 
Biology* Physics 2004;60: 1283-1290. 
16. Yamashita H, Takahashi W, Haga A, et al. Radiation pneumonitis after stereotactic radiation therapy 
for lung cancer. World J Radiol 2014;6: 708-715. 
17. Barriger RB, Forquer JA, Brabham JG, et al. A dose-volume analysis of radiation pneumonitis in non-
small cell lung cancer patients treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol 
Phys 2012;82: 457-462. 
18. Koto M, Takai Y, Ogawa Y, et al. A phase II study on stereotactic body radiotherapy for stage I non-
small cell lung cancer. Radiother Oncol 2007;85: 429-434. 
19. Inoue T, Katoh N, Onimaru R, et al. Stereotactic body radiotherapy using gated radiotherapy with 
real-time tumor-tracking for stage I non-small cell lung cancer. Radiation Oncology 2013;8: 69. 
20. Voroney JP, Hope A, Dahele MR, et al. Chest wall pain and rib fracture after stereotactic 
radiotherapy for peripheral non-small cell lung cancer. J Thorac Oncol 2009;4: 1035-1037. 
21. Mutter RW, Liu F, Abreu A, et al. Dose-volume parameters predict for the development of chest wall 
pain after stereotactic body radiation for lung cancer. Int J Radiat Oncol Biol Phys 2012;82: 1783-1790. 

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22. Zhao B, Yang Y, Li T, et al. Image‐guided respiratory‐gated lung stereotactic body radiotherapy: 
Which target definition is optimal? Med Phys 2009;36: 2248-2257. 
23. Kim J, Wu Q, Zhao B, et al. To gate or not to gate - dosimetric evaluation comparing Gated vs. ITV-
based methodologies in stereotactic ablative body radiotherapy (SABR) treatment of lung cancer. Radiat 
Oncol 2016;11: 125. 
24. Nader D. Safety of endobronchial implantation of electromagnetic fiducials for real-time tracking of 
lung tumours during radiothreapy. J Thorac Oncol 2013;8: S171. 
25. Sandler HM, Liu P, Dunn RL, et al. Reduction in patient-reported acute morbidity in prostate cancer 
patients treated with 81-Gy Intensity-modulated radiotherapy using reduced planning target volume 
margins and electromagnetic tracking: assessing the impact of margin reduction study. Urology 2010;75: 
1004-1008. 
26. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45: 228-247. 
27. Harley DP, Krimsky WS, Sarkar S, et al. Fiducial marker placement using endobronchial ultrasound 
and navigational bronchoscopy for stereotactic radiosurgery: an alternative strategy. Ann Thorac Surg 
2010;89: 368-374. 
28. Schroeder C, Hejal R, Linden PA. Coil spring fiducial markers placed safely using navigation 
bronchoscopy in inoperable patients allows accurate delivery of CyberKnife stereotactic radiosurgery. J 
Thorac Cardiovasc Surg 2010;140: 1137-1142. 

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29. Anantham D, Feller-Kopman D, Shanmugham LN, et al. Electromagnetic navigation bronchoscopy-
guided fiducial placement for robotic stereotactic radiosurgery of lung tumors: a feasibility study. CHEST 
Journal 2007;132: 930-935. 
30. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45: 228-247. 
 

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APPENDIX I – EORTC QLQ - LC13  Quality of Life Questionnaire (Lung Cancer) 
 
 

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APPENDIX II – Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 - Respiratory Disorders 
 
 
 
 

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