A Phase I/II Trial of Stereotactic Body Radiation Therapy (SBRT) Dose Escalation in the Treatment of Patients With Inoperable Stage I/II Non-Small Cell Lung Cancer Arising Within the Zone of the Proximal Bronchial Tree
Phase: PHASE1
Conditions: Inoperable Stage I/II Non-small Cell Lung Cancer
Sponsor: Washington University School of Medicine

 
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A Phase I/II Trial of Stereotactic Body Radiation Therapy (SBRT) Dose 
Escalation in the Treatment of Patients with Inoperable Stage I/II Non-Small 
Cell Lung Cancer Arising within the Zone of the Proximal Bronchial Tree 
 
HRPO #: 06-0691 / 201012832 
Version date: 04/19/19 
 
Principal Investigator 
Clifford G. Robinson, M.D. 
Department of Radiation Oncology 
4921 Parkview Place 
Campus Box 8224 
Saint Louis, MO 63110 
Telephone: 314-362-4633 
Fax: 314-747-9557 
crobinson@radonc.wustl.edu 
 
Sub-Investigators 
Jeffrey D. Bradley, M.D. 
Department of Radiation Oncology 
4921 Parkview Place 
Campus Box 8224 
Saint Louis, MO 63110 
Telephone: 314-362-4633 
Fax: 314-747-9557 
jbradley@radonc.wustl.edu 
 
 
Statistician 
Feng Gao, M.D., Ph.D. 
Department of Surgery 
600 S. Taylor Ave. 
Campus Box 8100 
Saint Louis, MO 63110 
Telephone:  314-362-3682 
feng@wustl.edu 
 
SCHEMA 
 
 
Phase I 
 
 

 
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Phase II 
Deliver maximum tolerated dose from Phase I portion to 43 patients with the 
objective of determining local control rate (primary objective) and patterns of 
recurrence disease-free and overall survival rates (secondary objectives) at two 
years. 
 
* Biological equivalent dose (BED) levels: A – 85.5 Gy; B- 100 Gy; C- 115.5 Gy; 
D- 132 Gy.  BED = nd(1+d/ /) where n =number of fractions , d =daily dose, 
and / = 10 for tumors. 
 
 
Patient Population: (See Section 3.0 for eligibility) 
Patients with T1, T2 (≤ 7 cm), or T3 (≤ 7 cm), N0, M0 (stage I or II) medically 
inoperable non-small cell lung cancer involving the central chest. Patients with 
tumors ≤ 7 cm that are invading or abutting the mediastinal pleura or parietal 
pericardium, including those tumors located within the zone of the proximal 
bronchial tree are eligible. (See Figure 1) 
 
 
R 
E 
G 
I 
S 
T 
E 
R 
Stereotactic Body Radiation Therapy 
(SBRT), 5 fractions over 2-3 weeks 
Dose Level A – 9 Gy x 5* 
 
Dose Level B – 10 Gy x 5* 
 
Dose Level C – 11 Gy x 5* 
 
Dose Level D – 12 Gy x 5* 

 
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TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 1 
1.0 
INTRODUCTION ................................................................................................................ 4 
1.1 
Stage I Non-small Cell Lung Cancer .............................................................................. 4 
1.2 
Stereotactic Body Radiation Therapy ............................................................................ 5 
1.3 
Rationale for Proposed SBRT Dose Schema ................................................................ 8 
1.4 
Summary of Phase I Results for this trial ..................................................................... 11 
2.0 
OBJECTIVES ................................................................................................................... 12 
3.0 
ELIGIBILITY...................................................................................................................... 12 
4.0 
REGISTRATION ............................................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ................................................................................. 14 
4.2 
Patient Registration in the Siteman Cancer Center Database ..................................... 14 
4.3 
Assignment of UPN ...................................................................................................... 14 
5.0 
RADIATION THERAPY .................................................................................................... 14 
5.1 
Dose Specifications ...................................................................................................... 14 
5.2 
Technical Factors ......................................................................................................... 16 
5.3 
Localization, Simulation, and Immobilization ............................................................... 16 
5.4 
Treatment Planning/Target Volumes ........................................................................... 17 
6.0 
CRITICAL STRUCTURES ................................................................................................ 20 
6.1 
Critical Organ Dose-Volume Limits .............................................................................. 20 
6.2 
Contouring of Normal Tissue Structures ...................................................................... 21 
7.0 
DOCUMENTATION REQUIREMENTS ............................................................................ 22 
7.1 
Treatment Breaks ......................................................................................................... 22 
8.0 
COMPLIANCE CRITERIA ................................................................................................ 22 
8.1 
Dosimetry Compliance ................................................................................................. 22 
8.2 
Treatment Delivery Compliance ................................................................................... 22 
9.0 
RADIATION TOXICITY .................................................................................................... 23 
9.1 
Radiation Pneumonitis ................................................................................................. 23 
9.2 
Bronchial Injury ............................................................................................................ 23 
9.3 
Other Significant Toxicity ............................................................................................. 24 
10.0 
STUDY CALENDAR ......................................................................................................... 24 
11.0 
DATA SUBMISSION SCHEDULE .................................................................................... 25 
12.0 
CRITERIA FOR EVALUATION ........................................................................................ 25 
12.1 
Baseline documentation of “Target” and “Non-Target” Lesions ................................... 25 
12.2 
Criteria for Removal from Protocol Treatment ............................................................. 26 
13.0 
ADVERSE EVENT REPORTING ..................................................................................... 27 
13.1 
Adverse Events (AEs) .................................................................................................. 27 
13.2 
Unanticipated Problems ............................................................................................... 27 
13.3 
Noncompliance ............................................................................................................ 27 
13.4 
Serious Noncompliance ............................................................................................... 28 
13.5 
Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC): ............................................ 28 
13.6 
Reporting of AE Information Following Study Completion ........................................... 28 
13.7 
SBRT Adverse Event Reporting .................................................................................. 28 
13.8 
Life-Threatening, Grade 4, and Grade 5 Events .......................................................... 30 
14.0 
DATA AND SAFETY MONITORING ................................................................................ 30 
15.0 
STATISTICAL CONSIDERATIONS ................................................................................. 31 
15.1 
Statistical Methods for Phase I Portion ........................................................................ 31 
15.2 
Statistical Methods for Phase II Portion ....................................................................... 33 
15.3 
Monitoring the Study for Early Stopping Due to Unacceptable Toxicity ...................... 34 
15.4 
Accrual ......................................................................................................................... 34 
15.5 
Interim Analysis ............................................................................................................ 34 
16.0 
REFERENCES ................................................................................................................. 35 
 
 

 
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1.0 
INTRODUCTION 
 
1.1 
Stage I Non-small Cell Lung Cancer 
 
Lung cancer is the most frequent cause of cancer death in both men and 
women in North America, accounting for approximately 13% of all cancers 
diagnosed and 28% of all cancer deaths.  There will be an estimated 
173,770 new lung cancer cases in the United States in the year 2004 with 
an estimated 160,440 deaths due to lung cancer.1 Seventy-five percent of 
patients with bronchogenic carcinoma will be diagnosed with non-small 
cell lung cancer (NSCLC).  The number of patients with early or localized 
disease (currently an estimated 15-20% of NSCLC patients)2 is expected 
to rise over the next several years due to widespread screening with CT 
scanning. 
 
The treatment of choice for stage I (T1-T2N0) NSCLC is surgical resection 
which results in 5-year survival rates of approximately 60 to 70%.3-5 
Occasionally, however, there are patients with early-stage NSCLC that are 
unable to tolerate surgical resection or the postoperative recovery period 
due to various comorbidities. 
 
While conventionally fractionated radiation therapy has been utilized as 
nonsurgical therapy for these medically inoperable patients, close 
observation with no specific cancer therapy has also been advocated in 
highly selected cases.  McGarry, et. al., reviewed outcomes in 75 patients 
who had received no specific cancer therapy for stage I NSCLC, and the 
cause of death was progressive cancer in 53% of cases with a median 
survival time of 14.2 ± 2.4 months.6 
 
Definitive conventionally fractionated RT for early-stage NSCLC is 
considered reasonable non-surgical therapy but yields poor 5-year survival 
rates ranging from 10 to 30%.7-11 Several studies have suggested a dose-
response relationship reporting a benefit to dose escalation above the 
standard conventionally fractionated 4,500 to 6,600 cGy. This benefit was 
evident in both survival and local control in these patients.10-14 Sibley, et. 
al., reviewed 156 medically inoperable patients with stage I NSCLC 
treated with primary RT at Duke University between 1980 and 1995. They 
reported a 5-year, cause-specific survival rate of 32%. There was a trend 
toward improved survival in those patients achieving local control which 
approached significance for higher RT doses (p = 0.07).13 At this 
institution, we have published a series treating 56 patients with medically 
inoperable NSCLC with a median dose of 70 Gy using conformal 
radiotherapy techniques.15 Actuarial local control rates were 69% and 63% 
at two- and three years of follow up, respectively.  These data serve as the 
estimate for statistical power calculations for this trial. 
 

 
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Radiation fields have historically encompassed the primary tumor as well 
as the regional lymphatics in the ipsilateral hilum and mediastinum. This 
elective treatment was based on the identified risk of occult lymph node 
involvement ranging up to 20% in some surgical series.16 In recent years, 
elimination of elective nodal irradiation, which is potentially poorly 
tolerated in this population,17 has been validated by several retrospective 
studies permitting treatment of the primary tumor alone with limited 
fields.18-21 Slotman, et. al., in a study from the Netherlands, reported the 
use of limited "postage-stamp" fields to treat early stage lung cancer 
patients using hypofractionated RT (i.e., 4,800 cGy in 400-cGy fractions). 
Reported 3-year overall and disease-specific survival rates were 42% and 
76%, respectively.20 
 
Most of the aforementioned retrospective studies utilized radiotherapy 
equipment from the era of 1-D and 2-D treatment planning. Several 
limitations are evident from these older techniques, including target 
visualization, selection of beam directions, and computational algorithms 
describing deposited dose. Recent improvements in software, hardware, 
and computer processing speed have revolutionized the delivery of 
radiation doses appropriate for tumor cell killing. 
 
In this new era of three-dimensional treatment planning, more precise 
delivery methods are available allowing for dose escalation to the target 
volume without excessive dose being deposited in normal tissues. The 
RTOG 
has 
completed 
an extensive 
dose 
escalation 
study 
of 
conventionally fractionated three-dimensional conformal radiotherapy (3D-
CRT) for NSCLC for stages I, II, and III disease as long as all detectable 
tumor can be encompassed by the radiation therapy fields including both 
primary tumor and regional lymph nodes.22 No mechanism for minimizing 
lung and tumor movements was utilized.  One hundred and seventy-nine 
patients were treated with radiation doses escalated to as high as 90.3 
Gy.  Patients were stratified within each dose level according to the 
percentage of the total lung volume that received >20 Gy with the 
treatment plan (V20). For patients receiving radiation alone or radiation 
following induction chemotherapy, data from RTOG 9311 established that 
the radiation dose could be safely escalated using 3D-CRT techniques to 
83.8 Gy for patients with V20 values of <25% and to 77.4 Gy for patients 
with V20 values between 25% and 36%, using fraction sizes of 2.15 Gy. 
Excess mortality was observed at 90.3 Gy with two dose-related deaths. 
The incidence of grade 3 or higher acute toxicity is less than 10%; 
however, grade 3 or higher late toxicity was approximately 15%. 
 
1.2 
Stereotactic Body Radiation Therapy 
 
Stereotactic body radiation therapy (SBRT) is the delivery of high 
precision, biologically potent doses of radiation to tumors of the chest, 

 
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abdomen, and pelvis. Implementing elements of 3D-CRT with stereotactic 
targeting, SBRT permits delivery of 3-4 high dose fractions totaling 48-60 
Gy with good local control and low toxicity. 
 
Blomgren, et. al., from the Karolinska Hospital in Stockholm, Sweden 
reported the results of over 100 patients treated in the extracranial 
stereotactic frame (developed by researchers at the Karolinska Hospital) 
for metastases in the chest and abdomen beginning in 1992.23, 24 More 
recently, Blomgren, et. al., reported the treatment of 17 patients with 
extracranial stereotactic radiotherapy for lung metastases.25 Tumors 
ranged from 1.8 cm to 7.2 cm in size.  Margin doses ranged from 20 Gy in 
a single fraction to 45 Gy in three fractions. Follow-up ranged from 3.5 to 
25 months. Repeat CT scans to assess response to treatment 
demonstrated disappearance in 35%, reduction in 41%, stabilization in 
18%, and progression in only one patient (the largest tumor treated in the 
report).  Because of concern for acute inflammatory effects, all patients 
were pre-medicated with corticosteroids prior to treatment.  Side effects 
were, however, limited and primarily consisted of fatigue and fever for a 
few days after the treatments.  One patient experienced typical radiation 
pneumonitis two months after treatment, with subsequent fibrosis, and 
another developed a chronic cough.  There was no severe late pulmonary 
toxicity or treatment-related deaths. 
 
A phase I dose escalation trial has been completed at Indiana University 
for treatment of medically inoperable patients with stage I NSCLC.26, 27 
SBRT was administered with large doses per fraction in an extracranial 
stereotactic body frame, which includes a system for decreasing breathing 
motion. The starting dose was 8 Gy times 3 (24 Gy total), and fraction 
dose was escalated by 2 Gy per fraction for each cohort.  The target 
lesion was outlined by a physician and designated as the gross tumor 
volume (GTV).  An additional 0.5 cm in the axial plane and 1.0 cm in the 
longitudinal plane was added to the GTV to constitute the PTV based on 
validation measurements for this commercially available system.23, 28, 29 
Typically, 7 to 10 non-coplanar beams were used to encompass the PTV.  
Dose was prescribed to the 80% isodose line. However, higher isodoses 
occurred within the center of the target mimicking the heterogeneous dose 
profile common to intracranial stereotactic radiosurgery.  The treatment 
isocenter was identified with 3-D coordinates defined stereotactically and 
localized on verniers attached to the frame. No skin or bony landmarks 
were used to set the treatment isocenter; however, orthogonal port films 
were used on a daily basis for isocenter verification.30 Separate dose 
escalations were carried out independently for patients with T1 versus T2 
small (≤ 5 cm) versus T2 large (5-7 cm) tumors at diagnosis. 
 
According to the Indiana University protocol guidelines, dose-limiting 
toxicity (DLT) was any grade 3 cardiac or pulmonary toxicity or any grade 

 
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4 toxicity attributed to the therapy. Thirty-seven patients were treated 
using a standard dose escalation protocol with 3 patient cohorts with 
minimum 1 month between dose levels to assess toxicity. Patients were 
categorized into separate independent dose escalations according to 
tumor volume, T1 vs. T2 (≤ 5 cm) vs. T2 (> 5 to ≤ 7 cm). Grade 3 
pneumonitis was seen at a dose of 14 x 3 = 42 Gy total in one T2 patient 
with a 7-cm tumor and transient grade 3 hypoxia was seen at 16 x 3 = 48 
Gy total in one patient.  Additional patients were treated at each of these 
levels without further toxicity observed. Twenty-one patients had mild to 
moderate fibrosis distal to the treated lesion appear on chest x-ray after 
treatment. Nine of these patients had a decline of an element of their 
pulmonary function tests (FEV1, FVC, DLCO, or PO2) by 10-20% of 
predicted which returned back to baseline values with follow-up in all but 
two. The timing of onset of this toxicity was generally acute to subacute (< 
1 month in most cases).  The maximum tolerated dose (MTD) was not 
reached on this trial for patients with T1 tumors and smaller T2 tumors (≤ 
5 cm).  Dose-limiting pneumonitis or pericarditis occurred in 2/5 patients 
with larger T2 tumors (>5 to ≤ 7 cm) at a dose of 24 x 3 = 72 Gy defining 
the MTD for this subgroup at 22 x 3 = 66 Gy.  Patients treated at a dose of 
22 Gy per fraction times three fractions had follow up of over 24 months 
without late toxicity for all T-stage tumor categories.  Treatment failure 
within the PTV has been observed in 8 of 26 patients treated at doses of 
up to 20 x 3 = 60 Gy.  However, all but one of these local failures occurred 
at doses of 16 x 3 = 48 Gy or lower.31 
 
Onishi, et. al., showed that patients treated with biologically effective 
doses (BED) of 100 Gy [using BED = nd(1 +d//), where n = number of 
fractions, d =  dose per fraction, and / = 10 for acute-reacting tissue] 
had better local control and survival compared to those receiving BED 
<100 Gy. Local recurrence rates were significantly lower for tumors 
treated with BED 100 Gy (8.1% vs. 26.4%, p < 0.01). The 3-year overall 
survival rate of medically operable patients was 88.4% for BED 100 Gy 
compared with 69.4% for BED <100 Gy. Though not all agree, these data 
are consistent with other reports in the literature supporting the use of 
BED values greater than 100 Gy for optimal local control of lung tumors 
with SBRT.32, 33 
 
The above data demonstrate that solitary lung lesions including early 
stage NSCLC are better controlled with SBRT when compared to 
conventional radiation. In addition, reduced volume treatments are 
attractive in these patients with medically inoperable stage I NSCLC who 
may have an increased risk of radiation pneumonitis associated with 
conventional large volume radiation fields.  SBRT permits dose escalation 
by significantly reducing the high-dose treatment volume.  
 
The RTOG opened in May 2004 a phase II trial of SBRT in the treatment 

 
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of medically inoperable patients with stage I/II non-small cell lung cancer 
in an effort to determine if SBRT could achieve acceptable local control as 
seen in retrospective series.24, 26, 32-38 A secondary objective is to 
determine if this technique achieves acceptable treatment-related toxicity. 
In this trial, patients with T1, T2 (≤ 5 cm), or T3 (≤ 5 cm), N0, M0 medically 
inoperable non-small cell lung cancer are treated with SBRT to a total of 
60 Gy in 3 fractions of 20 Gy each over 1.5 to 2 weeks.  This protocol 
excludes patients with T3 tumors involving the central chest and structures 
of the mediastinum as well as patients with any T-stage tumor within or 
touching the zone of the proximal bronchial tree.  This region 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, and right and left 
lower lobe bronchi). See figure below: 
 
Figure 1.0 
 
1.3 
Rationale for Proposed SBRT Dose Schema 
 
Because the proximal bronchial tree functions more as a serial organ 
similar to the hollow viscera (e.g. GI tract) as opposed to the periphery of 
the lungs which function in parallel with inherent redundancy, focal 
radiation injury to the central lung structures such as the bronchi can 
theoretically adversely affect the distal parenchyma. For this reason and 
because of their proximity to large blood vessels, central lung tumors have 
been excluded from most SBRT trials. The tolerance of the bronchial tree 

 
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to SBRT is unknown.  Investigators at the University of Colorado have 
treated patients with central lung lesions on their SBRT trials without 
adverse consequences.  Doses of 60 Gy delivered in 3 fractions of 20 Gy 
each were tolerated by the primary or secondary bronchi (unpublished 
data).  Onishi and colleagues made no effort to restrict the location of 
eligible tumors, irrespective of whether they were located adjacent to a 
major bronchus or blood vessel. Seventeen patients (6.9%) experienced 
symptomatic radiation-induced pulmonary toxicity (grade >1), 88% of 
which had pulmonary fibrosis or emphysema prior to SBRT. Pulmonary 
symptoms resolved in most patients with or without steroid therapy. No 
vascular or cardiac complications were encountered.32 Uno and 
colleagues have reported a case of chronic radiation bronchitis in a 73 
year old woman with medically inoperable T1N0M0 adenocarcinoma of 
the lung which developed as a severe cough 6 months after treatment with 
SBRT to 50 Gy in 5 fractions of 10 Gy each. Fiberoptic bronchoscopy 
revealed thick circumferentially coated bronchial mucosa in a segmental 
bronchus which was located within the 90% dose area. A follow-up 
bronchoscopy at 12 months confirmed marked stenosis in the segmental 
bronchus without tumor progression.39 
 
The efficacy and safety of endobronchial brachytherapy (EBBT) in which 
high doses per fraction are delivered to the bronchi from within have been 
well established in the literature. This well-tolerated procedure delivers 
very high doses of radiation to the bronchial mucosa with a low 
complication rate and provides a high likelihood for durable palliation of 
symptoms that are associated with endobronchial tumors. Given the 
paucity of data evaluating the toxicity of SBRT for central lung tumors, a 
crude comparison with EBBT is reasonable.  
 
Speiser and Spratling described radiation bronchitis and stenosis 
secondary to high dose rate endobronchial irradiation which occurred in 
12% of patients.40, 41 The complication rate increased slightly with 
concurrent external beam radiation therapy, curative intent, prior laser 
photoresection, and/or large cell histology. There was no significant 
difference in complication rate between the three study groups receiving 
10 Gy at 5 mm depth via medium dose rate EBBT for three fractions, 10 
Gy at 10 mm depth via high dose rate EBBT for three fractions, or 7.5 Gy 
at 10 mm depth via high dose rate EBBT for three fractions. Radiation 
bronchitis and stenosis (RBS) was defined in this study as a spectrum of 
clinical changes which occurred in the tracheobronchial tree as seen on 
follow-up bronchoscopy 6 weeks after the EBBT treatment. Higher grade 
(grade 3 and 4) RBS was characterized by a severe inflammatory 
response with marked membranous exudates and mild to severe 
fibrosis/stenosis requiring various interventions to re-establish the full 
lumen of the airway. This degree of late toxicity developed in 6% of 
patients with means of 43 and 55 weeks for grade 3 and 4, respectively. 

 
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Intervention was typically more aggressive and difficult for grade 4 
reactions because of the circumferential fibrosis leading to progressive 
reduction in the luminal diameter of the bronchus. Fatal hemoptysis 
occurred with an overall rate of 7.3%. In all cases, patients dying of 
massive hemoptysis had residual or recurrent carcinoma seen on 
bronchoscopy, post-mortem exam, and/or radiographic studies. There 
were no proven cases of necrosis into the pulmonary artery in the 
absence of residual or recurrent carcinoma. 
 
M. D. Anderson has reported their ten-year experience with EBBT. Most 
patients received 3,000 cGy via EBBT delivered to a depth of 6 mm and 
divided into 2 fractions of 1500 cGy each over 2 weeks. Complications 
occurred in 19 out of 175 treated patients (11% crude rate) with an 
actuarial complication rate of 13% at 1 year from the time of the first EBBT 
treatment session. The most significant associated toxicity was late 
massive hemoptysis, which occurred in this study with an actuarial hazard 
ratio of 5%.42  
 
Celebioglu, et. al., have reported a very low complication rate in their 
published experience of 95 patients with inoperable endobronchial lung 
tumors treated with either 7.5 Gy times three one week apart or 10 Gy 
times two one week apart. Endobronchial irradiation was delivered to a 
1.0-cm depth using remote afterloading high dose rate brachytherapy with 
iridium-192. Sixty patients (63%) had previously received large field 
external beam radiotherapy (EBRT) to 46 Gy. Estimated BED for acute-
reacting tissues (α/β = 10) was 40 Gy for EBBT and 55.2 Gy for EBRT. 
One patient (1%) had hemoptysis in week 5 requiring hospitalization and it 
was relieved after symptomatic therapy. None of the patients experienced 
fistula or cardiovascular problems. Follow-up bronchoscopies revealed 
clinically insignificant radiation changes including dry mucosa with varying 
degrees of stenosis.43 
 
Though a direct comparison between EBBT and SBRT is not possible, the 
resilience of the proximal bronchial tree and nearby mediastinal structures 
to a high dose of radiation is clearly demonstrated. Because complications 
can be severe due to the proximity of vital structures, steps must be taken 
to optimize the delivery and fractionation of SBRT for central lung tumors 
in order to provide good local tumor control while minimizing toxicity.  
 
Accurate and precise treatment planning and delivery methods should be 
employed in an effort to reduce the deleterious effects of setup error and 
organ motion. Deep inspiration breath-hold techniques and respiratory 
gated radiotherapy in which a beam-on mode is triggered by certain 
phases of the respiratory cycle are current topics of clinical research.44, 45 
Others are studying a surrogate marker for tumor motion which is detected 
by a tracking system that allows the radiation source to follow the position 

 
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of the tumor.38 Current studies report only the feasibility of these 
approaches. Clearly, however, SBRT relies heavily upon precise target 
localization. Therefore, methods to reduce or compensate for tumor 
motion are mandatory. 
 
The availability of the most recent technological advances in adaptive 
image-guided radiotherapy provides the Siteman Cancer Center a unique 
environment to deliver SBRT and track its efficacy. Four-dimensional 
computed tomography (4D-CT) and Varian Real-time Position Monitor® 
(RPM) together allow for accurate monitoring of and compensation for 
individualized tumor movement. The Varian Trilogy® linear accelerator 
provides improved efficiency with online localization using the onboard 
cone-beam kV CT which will eliminate the need for a pretreatment CT 
simulation. Furthermore, the Trilogy has been developed specifically as a 
stereotactic radiotherapy treatment machine calibrated to a precision of 
within 0.5 mm and capable of delivering SBRT with a specific high dose 
rate 6 MV photon beam at up to 1000 MU/min. The fluoroscopic 
capabilities of the Onboard Imager® will provide additional confirmation of 
coverage of the tumor during normal breathing motion.  
 
With the improved accuracy and efficiency of the above tools, evaluation 
of SBRT for central lung tumors is feasible and desirable. We, therefore, 
propose a dose escalation schema starting with doses that are considered 
safe but suboptimal for tumor control (i.e. BED approaching 100 Gy), and 
escalating the dose per fraction to reach more optimal BED values. In 
order to reduce the toxicity of this treatment, we feel it is logical to 
increase the number of fractions from the current RTOG protocol. 
 
1.4 
Summary of Phase I Results for this trial 
 
Twenty-three patients with histologically-proven Stage I NSCLC with 
tumors located within 2 cm of the proximal bronchial tree have been 
enrolled on Phase I of this trial. The primary objective was to determine 
the maximum tolerated dose of SBRT to the proximal bronchial tree. 
SBRT consisted of 5 fractions of 9, 10, 11, and 12 Gy each on cohorts A, 
B, C, and D, respectively, over a total of 10-31 days.  A minimum of 5 
patients were enrolled per cohort and at least 3 months of minimum follow 
up were required prior to opening the next dose level to accrual.  
 
The mean (range) of follow up duration for cohorts A (n=5), B (n=6), C 
(n=6), and D (n=5) are 22.9 (6-47), 25.3 (2-42), 17.3 (13-22), and 6.6 (1-
11) months, respectively.  Two additional patients recently completed 
therapy on cohort C and are awaiting their initial follow up.  Two patients 
treated to 10 Gy x 5 fractions developed an unrelated grade 3 lung toxicity 
which resolved.  There have been no protocol-related toxicities to date. 
The overall primary tumor control rate is 95.8%.  One primary tumor failure 

 
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occurred within cohort A.  No local failures have occurred thus within 
cohorts B, C, or D.  Sixteen of 24 patients remain alive with a projected 3-
year overall survival rate of 54.3%.  Based on the outstanding local control 
achieved at 11 Gy per fraction for 5 fractions, we have chosen to proceed 
to Phase II of this trial. 
 
 
2.0 
OBJECTIVES 
 
1. The primary objective of the Phase I portion of this study is to determine the 
maximum tolerated dose of stereotactic body radiation therapy (SBRT) to the 
trachea and proximal bronchial tree. 
 
2. The primary objective of the phase II portion of this study is to determine if the 
MTD determined in Phase I achieves acceptable local control (i.e. >80%) for 
this medically inoperable population of patients with non-small cell lung 
cancer. 
 
3. The secondary objective of Phase II is to estimate the rates of regional nodal 
recurrence, disseminated recurrence, disease-free and overall survival at two 
years. 
 
 
3.0 
ELIGIBILITY 
 
1. Histologically 
confirmed 
non-small 
cell 
cancer 
by 
biopsy 
or 
cytology.  Squamous cell carcinoma, adenocarcinoma, large cell carcinoma, 
bronchioalveolar carcinoma, or non-small cell carcinoma (not otherwise 
specified) are allowed.   
2. Staging studies must identify patient as AJCC Stage I or II based on only 1 of 
following combinations of TNM staging: 
a. T1, N0, M0 
b. T2 (<7cm), N0, M0 
c. T3 (<7cm), N0, M0 
3. Primary tumor must be arising in one of the following central chest locations: 
a. Within or touching the zone of the proximal bronchial tree (a volume 2cm 
in all directions around the proximal bronchial tree [carina, R & L main 
bronchi, R & L upper lobe bronchi, intermedius bronchus, R middle lobe 
bronchus, lingular bronchus, R & L lower lobe bronchi]) - see Figure 1 
b. Adjacent to (within 5 mm) or invading the mediastinal pleura 
c. Adjacent to (within 5 mm) or invading the parietal pericardium 
4. To differentiate T3 lesions involving the mediastinal pleura from T4 lesions 
involving major vessels or organs, a chest MRI will be obtained. If any 
uncertainty remains, the patient will have four-dimensional CT scans (4DCT) 
in an effort to determine the degree of tumor motion.  A freely mobile tumor 
during ventilation will be judged to be T3 disease. 

 
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5. Patients with hilar or mediastinal lymph nodes <1cm and no abnormal hilar or 
mediastinal uptake on PET will be considered N0.  Patients with >1cm hilar or 
mediastinal lymph nodes on CT or abnormal PET (including suspicious but 
non-diagnostic uptake) may be eligible if directed tissue biopsy of all 
abnormally identified areas are negative for cancer. 
6. Primary tumor must be technically resectable by an experienced thoracic 
cancer clinician, with a reasonable possibility of obtaining a gross total 
resection 
with 
negative 
margins 
(potentially 
curative 
resection, 
PCR).  However, patients must have underlying physiological medical 
problems prohibiting PCR (i.e., problems with general anesthesia, the 
operation, the post-op recovery period, or removal of adjacent functioning 
lung) or refuse surgery.  Deeming a patient medically inoperable based on 
pulmonary function for surgical resection may include any of the 
following:  baseline FEV1 <40% predicted; post-operative predicted FEV1 
<30% predicted; severely reduced diffusion capacity; baseline hypoxemia 
and/or hypercapnia; exercise oxygen consumption <50% predicted; severe 
pulmonary hypertension; diabetes with severe end organ damage; severe 
cerebral, cardiac, or peripheral vascular disease; or severe chronic heart 
disease.  Any one of these problems will qualify a patient for this trial. 
7. Age >18. 
8. Zubrod performance status 0-2. 
9. Women of childbearing potential must use effective contraception. 
10. No direct evidence of regional or distant metastases after appropriate staging 
studies.  No synchronous primary or prior malignancy in past 2 years except 
non-melanoma skin cancer or in situ cancer. 
11. No previous lung or mediastinal radiation therapy. 
12. No plans for concomitant antineoplastic therapy (including standard 
fractionated RT, chemo, biologic, vaccine therapy, or surgery) while on this 
protocol except at disease progression. 
13. No active systemic, pulmonary, or pericardial infection. 
14. No pregnant or lactating women. 
15. PRESTUDY REQUIREMENTS: 
a. History and Physical Examination, Weight, Zubrod performance status 
(within 4 weeks pre-study entry) 
b. Evaluation by thoracic cancer clinician (within 8 weeks pre-study entry) 
c. Pregnancy test, if applicable (serum or urine, within 72 hours prior to 
treatment start.) 
d. CT* (preferably with contrast unless medically contraindicated; both lungs, 
mediastinum, liver, adrenals) 
e. PET* (using FDG with visualization of primary tumor and draining lymph 
node basins in hilar and mediastinal regions) 
f. Brain MRI or head CT with contrast 
g. PFTs  - include routine spirometry, lung volumes, diffusion capacity 
h. Signed informed consent. 
 
 

 
Protocol Version date 04/19/19 
 
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4.0 
REGISTRATION 
 
Patients must not start any protocol intervention prior to registration 
through the Siteman Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of 
the study team 
6. Copy of appropriate source documentation confirming patient 
eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
All patients must be registered through the Siteman Cancer Center 
database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this 
study.  Patients will also be identified by first, middle, and last initials.  If 
the patient has no middle initial, a dash will be used on the case report 
forms (CRFs).  All data will be recorded with this identification number on 
the appropriate CRFs. 
 
 
5.0 
RADIATION THERAPY 
 
5.1 
Dose Specifications 
 
5.1.1 Stereotactic Targeting and Treatment 
 
The term “stereotactic” for the purposes of this protocol implies the 
targeting, planning, and directing of therapy using beams of 

 
Protocol Version date 04/19/19 
 
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radiation along any trajectory in 3-D space toward a target of known 
3-D coordinates. This differs from conventional radiation therapy in 
which therapy is directed toward skin marks or bony landmarks that 
are indirectly referenced to the tumor.  This known 3D coordinate 
system may include external fiducial markers (i.e.  Elekta body 
frame), internal fiducial markers (i.e. gold seeds), or image-guided 
systems using either on-board kV or cone beam CT imaging (i.e. 
Varian Trilogy linear accelerator). 
 
5.1.2 Dose Fractionation 
 
Patients will receive 5 fractions of radiation according to Table 1. 
The dose for all patients will be 9 to 12 Gy per fraction to the 
prescription line at the edge of the PTV, depending on the dose 
level assigned for the patient.  
 
Table 1: Phase I Dose Escalation Scheme 
Dose 
Level 
Fractionation 
Biological Equivalent 
Tumor Dose 
1 
9 Gy x 5 fractions 
85.5 Gy 
2 
10 Gy x 5 fractions 
100 Gy 
3 
11 Gy x 5 fractions 
115.5. Gy 
4 
12 Gy x 5 fractions 
132 Gy 
 
* Each patient must have a minimum follow up period of 3 months 
prior to proceeding to the next dose level.  After completing accrual 
to dose levels 2 and 3 (during the 3 month assessment window) 
accrual to the trial may continue at the previous ‘safe’ dose level.  
For example, if dose level 1 proves safe, patients can be accrued 
and treated at dose level 1 during the 3 month window of toxicity 
assessment between dose levels 2 and 3.   
 
5.1.3 Premedications 
 
Unless contraindicated, it is recommended that all patients receive 
corticosteroid premedication (e.g. Decadron 4 mg p.o. in a single 
dose, or equivalent) 15-60 minutes prior to each of the three 
treatments for the intended purpose of modulating immediate 
pulmonary inflammatory effects. Analgesic premedication to avoid 
general discomfort during long treatment durations also is 
recommended when appropriate. 
 
 

 
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5.2 
Technical Factors 
 
5.2.1 Physical Factors 
 
Only photon (x-ray) beams produced by linear accelerators are 
allowed. Photon beams with energies of 6 MV are preferred.  
Photon beam energies greater than 10 MV but not more than 15 
MV will only be allowed for a limited number (≤ 2) beams that must 
travel more than a cumulative distance of 10 cm through soft tissue 
(not lung) to reach the isocenter. 
 
5.2.2 Minimum Field Aperture (Field Size) Dimension 
 
Due to uncertainties in beam commissioning resulting from 
electronic disequilibrium within small beam apertures, a minimum 
field dimension of 3.5 cm is required for any field used for treatment 
delivery. It is understood that this may exceed the technical 
requirements listed in Section 5.4 for small lesions (< 2.5 cm axial 
GTV dimension or < 1.5 cm cranio-caudal GTV dimension). In such 
cases, the prescription dose is still prescribed to the edge of the 
defined PTV.  
 
5.2.3 Dose Verification at Treatment 
 
Personal dosimeter measurements (e.g. diode, TLD, etc.) must be 
obtained for surface dose verification for accessible beams for the 
first fraction.  
 
5.3 
Localization, Simulation, and Immobilization 
 
5.3.1 Patient Positioning 
 
Patients will be positioned in a stable position capable of allowing 
accurate reproducibility of the target position from treatment to 
treatment. Positions uncomfortable for the patient should be 
avoided so as to prevent uncontrolled movement during treatments. 
A variety of immobilization systems may be utilized including 
stereotactic frames that surround the patient on three sides and 
large rigid pillows (conforming to patients external contours) with 
reference 
to 
the 
stereotactic 
coordinate 
system. 
Patient 
immobilization must be reliable enough to insure that the Gross 
Tumor Volume (GTV) does not deviate beyond the confines of the 
Planning Treatment Volume (PTV) as defined in Section 5.4 with 
any significant probability (i.e., < 5%). 
 

 
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5.3.2 Inhibition of Effects of Internal Organ Motion 
 
Special considerations must be made to account for the effect of 
internal organ motion (i.e. breathing, etc.) on target positioning and 
reproducibility. Acceptable maneuvers including reliable abdominal 
compression and accelerator beam gating with the respiratory 
cycle.  
 
5.3.3 Localization 
 
Daily CT localization of the GTV isocenter is required prior to each 
fraction.  The process is as follows:  A limited CT scan designed to 
encompass the GTV will be obtained.  The GTV will be contoured 
by the treating physician and the isocenter coordinates of that 
volume determined.  These x, y, and z coordinates will be used to 
set up the patient for stereotactic therapy.  If the patient requires 
transfer from the CT couch to the treatment couch, isocenter 
localization images (anterior/posterior and lateral) should be 
obtained prior to each treatment on the treatment unit to ensure 
proper alignment of the geometric center (i.e., isocenter) of the 
simulated fields.  
 
5.4 
Treatment Planning/Target Volumes 
 
5.4.1 Image Acquisition 
 
Computed Tomography (CT) using four-dimensional imaging 
techniques will be the primary image platform for targeting and 
treatment 
planning. 
The 
planning 
CT 
scans 
must 
allow 
simultaneous view of the patient anatomy and fiducial system for 
stereotactic targeting and must be done with IV contrast, unless the 
patient has allergic problems with contrast or has renal 
insufficiency. Contrast will allow better distinction between tumor 
and adjacent vessels or atelectasis. Axial acquisitions with gantry 0 
degrees will be required with spacing ≤ 3.0 mm between scans. 
Images will be transferred to the treatment planning computers via 
direct lines, disc, or tape. The target lesion will be outlined by an 
appropriately trained physician and designated the gross tumor 
volume (GTV). The target will generally be drawn using CT 
pulmonary windows.  However, soft tissue windows with contrast 
may be used to avoid inclusion of adjacent vessels, atelectasis, or 
mediastinal or chest wall structures within the GTV. This target will 
not be enlarged whatsoever for prophylactic treatment 
(including no “margin” for presumed microscopic extension); 
rather, only include abnormal CT signal consistent with gross 
tumor (i.e., the GTV and the Clinical Target Volume, CTV, are 

 
Protocol Version date 04/19/19 
 
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identical). An additional 0.5 cm in the axial plane and 1.0 cm in the 
longitudinal plane (cranio-caudal) will be added to the GTV to 
constitute the planning treatment volume (PTV). These margins will 
be used at all sites, even if a particular site uses equipment or 
techniques felt to be more accurate. 
 
5.4.2 Dosimetry 
 
Three-dimensional coplanar or non-coplanar beam arrangements 
will be custom designed for each case to deliver highly conformal 
prescription dose distributions. Non-opposing, noncoplanar beams 
are preferable. Typically, 7-10 beams of radiation will be used with 
roughly equal weighting. Generally, more beams are used for larger 
lesion sizes. When static beams are used, a minimum of 7 non-
opposing beams should be used. For arc rotation techniques, a 
minimum of 340 degrees (cumulative for all beams) should be 
utilized. For this protocol, the isocenter is defined as the common 
point of gantry and couch rotation for the treatment unit. Field 
aperture size and shape should correspond nearly identically to the 
projection of the PTV along a beam’s eye view (i.e. no additional 
“margin” for dose build up at the edges of the blocks or MLC jaws 
beyond the PTV). The only exception will be when observing the 
minimum field dimension of 3.5 cm when treating small lesions (see 
above). As such, prescription lines covering the PTV will typically 
be the 60-90% line (rather than 95-100%); however, higher 
isodoses (hotspots) must be manipulated to occur within the target 
and not in adjacent normal tissue. The isocenter in stereotactic 
coordinates may be determined either from fiducial markers or 
directly from the tumor using image-guidance and translated to the 
treatment record. The treatment dose plan will be made up of 
multiple static beams or arcs as described above. The plan should 
be normalized to a defined point corresponding closely to the 
center of mass of the PTV (COMPTV). Typically, this point will be 
the isocenter of the beam rotation.  However, it is not a protocol 
requirement for this point to be the isocenter. Regardless, the point 
identified as COMPTV must have defined stereotactic coordinates 
and receive 100% of the normalized dose. Because the beam 
apertures coincide nearly directly with the edge of the PTV (little or 
no added margin), the external border of the PTV will be covered 
by a lower isodose surface than usually used in conventional 
radiotherapy planning – typically around 80%, but ranging from 60-
90%. The prescription dose ranging from 45 to 60 Gy in five 
fractions (per patient dose assignment) will be delivered to the 
margin of the PTV and fulfill the requirements below. As such, a 
“hot spot” will exist within the PTV centrally at the COMPTV. 
 

 
Protocol Version date 04/19/19 
 
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For purposes of dose planning and calculation of monitor units for 
actual treatment, all tissues within the body, including lung, will be 
corrected for tissue heterogeneity.  
 
Successful treatment planning will require accomplishment of 
all of the following criteria: 
 
1. Normalization – The treatment plan should be normalized such 
that 100% corresponds to the center of mass of the PTV 
(COMPTV). This point will typically also correspond (but is not 
required to correspond) to the isocenter of the treatment beams. 
 
2. 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 (i.e., 9 Gy per fraction x 5 fractions = 45 Gy 
total), and 99% of the target volume (PTV) receives a minimum 
of 90% of the prescription dose (i.e., 8.1 Gy per fraction = 40.5 
Gy total). 
 
3. Target Dose Heterogeneity – The prescription isodose surface 
selected in number 2 (above) must be ≥ 60% of the dose at the 
center of mass of the PTV (COMPTV) and ≤ 90% of the dose at 
the center of mass of the PTV (COMPTV). The COMPTV 
corresponds to the normalization point (100%) of the plan as 
noted in 1) above. 
 
4. High Dose Spillage 
a. Location - Any dose greater than 105% of the prescription 
dose (i.e., > 9.45 Gy per fraction = 47.25 Gy total for dose 
level 1) should occur primarily within the PTV itself and not 
within the normal tissues outside of the PTV. Therefore, the 
cumulative volume of all tissue outside of the PTV receiving 
a dose greater than 105% of prescription dose (>9.45 Gy per 
fraction = 47.25 Gy total) should be no more than 15% of the 
PTV volume. 
b. Volume - Conformality of PTV coverage will be judged such 
that the ratio of the volume of the prescription isodose 
meeting criteria 1) through 4) to the volume of the PTV is 
ideally < 1.2 (See table below). These criteria will not be 
required to be met in treating very small tumors (< 2.5 cm 
axial GTV dimension or < 1.5 cm craniocaudal GTV 
dimension) where the required minimum field size of 3.5 cm 
(see Section 5.4.2) results in the inability to meet a 
conformality ratio of 1.2. 
 

 
Protocol Version date 04/19/19 
 
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5. Low Dose Spillage - The falloff gradient beyond the PTV 
extending into normal tissue structures must be rapid in all 
directions and meet the following criteria: 
a. Location - The maximum total dose over all 5 fractions in 
Gray (Gy) to any point 2 cm or greater away from the PTV in 
any direction be no greater than D2cm where D2cm is given 
by the table below. 
b. Volume - The ratio of the volume of 50% of the prescription 
dose (4.5Gy per fraction = 22.5 Gy total) isodose to the 
volume of the PTV must be no greater than R50% where 
R50% is given by the table below. 
 
Table 2 
Maximum 
PTV 
Dimension 
(cm) 
Ratio of 
Prescription 
Isodose Volume 
to the PTV 
Ratio of 50% 
Prescription 
Isodose 
Volume to the 
PTV, R50% 
Percent of 
Lung receiving 
20 Gy total or 
more, V20 (%) 
PTV 
Volum
e (cc) 
 
Deviation 
Deviation 
Deviation 
 
 
none 
minor 
None 
minor 
none 
minor 
 
2.0 
<1.2 
1.2-1.4 
<3.9 
3.9-4.1 
<10 
10-15 
1.8 
2.5 
<1.2 
1.2-1.4 
<3.9 
3.9-4.1 
<10 
10-15 
3.8 
3.0 
<1.2 
1.2-1.4 
<3.9 
3.9-4.1 
<10 
10-15 
7.4 
3.5 
<1.2 
1.2-1.4 
<3.9 
3.9-4.1 
<10 
10-15 
13.2 
4.0 
<1.2 
1.2-1.4 
<3.8 
3.8-4.0 
<10 
10-15 
21.9 
4.5 
<1.2 
1.2-1.4 
<3.7 
3.7-3.9 
<10 
10-15 
33.8 
5.0 
<1.2 
1.2-1.4 
<3.6 
3.6-3.8 
<10 
10-15 
49.6 
 
 
6.0 
CRITICAL STRUCTURES 
 
6.1 
Critical Organ Dose-Volume Limits 
 
The following table lists the guidelines for maximum dose to a point or 
volume within several critical organs. The spinal cord limit is an 
absolute limit, and treatment delivery that exceeds this limit will 
constitute a major protocol violation. The dose is listed as total over 5 
fractions and per fraction.  In order to verify each of these doses, the 
organs must be contoured such that appropriate dose volume histograms 
can be generated. Instruction for the contouring of these organs will follow. 
 
Table 3—Critical Dose Guidelines 
Organ 
Volume 
Dose (Gy) 
Spinal Cord 
Any point 
20 Gy (4 Gy per fraction) 
Esophagus 
Any point 
30 Gy (6 Gy per fraction) 
Ipsilateral Brachial Plexus 
Any point 
25 Gy (5 Gy per fraction) 
Heart 
Any point 
50Gy (10 Gy per fraction) 
Heart 
<15 cc 
<32 Gy (6.4 Gy per fraction) 

 
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6.2 
Contouring of Normal Tissue Structures 
 
6.2.1 Spinal Cord  
 
The spinal cord will be contoured based on the bony limits of the 
spinal canal. The spinal cord should be contoured starting at least 
10 cm above the superior extent of the PTV and continuing on 
every CT slice to at least 10 below the inferior extent of the PTV. 
 
6.2.2 Esophagus  
 
The esophagus will be contoured using mediastinal windowing on 
CT to correspond to the mucosal, submucosa, and all muscular 
layers out to the fatty adventitia. The esophagus should be 
contoured starting at least 10 cm above the superior extent of the 
PTV and continuing on every CT slice to at least 10 below the 
inferior extent of the PTV. 
 
6.2.3 Heart   
 
The heart will be contoured along with the pericardial sac. The 
superior aspect (or base) for purposes of contouring will begin at 
the level of the inferior aspect of the aortic arch (aortopulmonary 
window) and extend inferiorly to the apex of the heart. 
 
6.2.4 Proximal Trachea  
 
Contouring of the proximal trachea should begin at least 10 cm 
superior to the extent of the PTV or 5 cm superior to the carina 
(which ever is more superior) and continue inferiorly to the superior 
aspect of the proximal bronchial tree (see figure 1 in Section 1.2 
and definitions below). 
 
6.2.5 Proximal Bronchial Tree  
 
The proximal bronchial tree will include the most inferior 2 cm of 
distal trachea and the proximal airways on both sides as indicated 
in the diagram in Section 1.2. The following airways will be included 
according to standard anatomical relationships: the distal 2 cm of 
trachea, the carina, the right and left mainstem bronchi, the right 
and left upper lobe bronchi, the intermedius bronchus, the right 
middle lobe bronchus, the lingular bronchus, and the right and left 
lower lobe bronchi. Contouring of the lobar bronchi will end 
immediately at the site of a segmental bifurcation. 
 

 
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6.2.6 Whole Lung  
 
Both the right and left lungs should be contoured as one structure. 
Contouring should be carried out using pulmonary windows. All 
inflated and collapsed lung should be contoured.  However, gross 
tumor (GTV) and trachea/ipsilateral bronchus as defined above 
should not be included in this structure. 
 
6.2.7 PTV Plus 2 cm 
 
As part of the QA requirements for “low dose spillage” listed in 4.4.2 
above, a maximum dose to any point 2 cm away in any direction is 
to be determined. To facilitate this QA requirement, an artificial 
structure 2 cm larger in all directions from the PTV is required. Most 
treatment planning systems have automatic contouring features 
that will generate this structure without prohibitive effort at the time 
of treatment planning. 
 
 
7.0 
DOCUMENTATION REQUIREMENTS 
 
7.1 
Treatment Breaks  
 
In general, treatment interruptions should be avoided by preventative 
medical 
measures 
and 
nutritional, 
psychological, 
and 
emotional 
counseling. Treatment breaks, including indications, must be clearly 
documented on the treatment record. 
 
 
8.0 
COMPLIANCE CRITERIA 
 
8.1 
Dosimetry Compliance 
 
Exceeding the critical organ dose limits by more than 2.5% constitutes a 
minor protocol violation. Exceeding these dose limits by more than 5% 
constitutes a major protocol violation. 
 
8.2 
Treatment Delivery Compliance 
 
Set-up films will be compared to digitally reconstructed radiographs from 
the same beam’s eye view. Deviations of less than 0.5 cm in the 
transverse plane and 1.0 cm in the cranio-caudal plane will be considered 
compliant. Deviations from 0.5-1.0 cm in the transverse plane and 1.0-
1.25 cm in the craniocaudal plane will be considered minor protocol 
deviations. Deviations greater than those listed as minor will be 
considered major protocol deviations. 

 
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9.0 
RADIATION TOXICITY 
 
9.1 
Radiation Pneumonitis 
 
Radiation pneumonitis is a subacute (weeks to months from treatment) 
inflammation of the end bronchioles and alveoli. The infiltrate on chest x-
ray should include the area treated to high dose, but may extend outside 
of these regions. The infiltrates may be characteristically “geometric” 
corresponding to the radiation portal, but may also be ill defined. Patients 
reporting symptoms as above will be promptly evaluated and treated. Mild 
radiation pneumonitis may be treated with non-steroidal anti-inflammatory 
agents or steroid inhalers. More significant pneumonitis will be treated with 
systemic steroids, bronchodilators, and pulmonary toilet. Supra- and 
concurrent infections should be treated with antibiotics. Consideration of 
prophylaxis of opportunistic infections should be considered in 
immunocompromised patients.  It is unlikely that symptomatic pneumonitis 
will occur during the weeks radiation is actually delivered to the patients. 
However, if a patient experiences pneumonitis prior to completing therapy, 
therapy should be put on hold until symptoms resolve. At that point, a 
clinical decision whether to finish therapy will be made by the treating 
physician. 
 
9.2 
Bronchial Injury 
 
In the Indiana University phase I study published by Timmerman et al and 
subsequently by McGarry et al., the majority of patients treated at doses of 
20 Gy times 3 fractions = 60 Gy or higher ultimately experienced 
atelectasis (collapse) of lung downstream from the area of treatment. This 
was felt to be related to injury of bronchi or bronchioles within or near the 
treated tumor. By unknown mechanisms over a period of 3-6 months, 
pulmonary parenchyma distal to the site of bronchial injury results in this 
focal lung collapse. In the majority of patients, this effect noted on imaging 
studies was asymptomatic.  In others, the injury apparently correlated to a 
drop in diffusing capacity and arterial oxygen tension on pulmonary 
function tests. This process of collapse was not reversible in the Indiana 
University experience. This injury is the justification for reducing the dose 
per fraction in this protocol.   
 
This bronchial injury with subsequent focal collapse of lung may impair 
overall pulmonary status. It also makes further assessment of tumor 
response more difficult as the collapsed lung approximates the treated 
tumor. Since atelectatic lung and tumor have similar imaging 
characteristics, radiology reports will often describe the overall process as 
progressive disease while the actual tumor may be stable or shrinking. 

 
Protocol Version date 04/19/19 
 
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The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, 
impairment of pulmonary function test parameters, pleural effusion or 
pleuritic pain (associated with collapse), should all be graded according to 
the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). 
 
9.3 
Other Significant Toxicity 
 
If other severe toxicity resulting in withholding therapy is encountered, the 
details will be documented. 
 
 
10.0 STUDY CALENDAR 
 
 
 
Assessments 
Pre-Study 
Entry 
Each 
Day of 
Tx  
6 Wks 
Post-Tx 
12 Wks 
Post-Tx 
Follow 
up 
History/physical 
Xa 
 
X 
X 
Xh 
Weight 
Xa 
 
X 
X 
Xh 
Zubrod performance status 
Xa 
 
X 
X 
Xh 
Evaluation by Thoracic Cancer 
Clinician 
Xb 
X 
X 
X 
Xh 
Pregnancy Test 
Xc 
 
 
 
 
Toxicity Evaluationj 
 
X 
X 
X 
Xh 
Chest X-ray (OPTIONAL) 
 
 
 
Xf 
Xf 
CT scan (including liver and adrenals) 
Xe,f 
 
Xf 
 
Xf 
PET scan (whole body) 
Xe 
 
 
 
Xg 
Brain MRI or CT with contrast 
Xe 
 
 
 
 
PFTsd 
X 
 
 
X 
Xi 
a. 
A medical history, physical examination, weight, and assessment of Zubrod performance status must be 
completed within 4 weeks prior to study entry. 
b. 
Evaluation by an experienced thoracic cancer clinician should be performed within 8 weeks prior to study 
entry. 
c. 
For women of childbearing potential only, a serum or urine pregnancy test should be performed within 72 
hours prior to start of protocol treatment. 
d. 
Includes routine spirometry, lung volumes and diffusion capacity; should be performed within 8 weeks prior to 
study entry. 
e. 
Should be performed within 45 days prior to study entry. 
f. 
CT scans should be done at 12 weeks and 6 months, and then every 3 months for the first 2 years and every 
6 months for the next 2 years.  CT scans may be alternated with chest X-ray (with initial CT scan done at first 
follow up visit)For the purposes of this protocol, a PET/CT may replace a CT of the chest, liver, and adrenal 
glands. 
g. 
Strongly encouraged; PET scans within 2 years post-treatment are required only if the criteria for local 
enlargement on CT is realized.  The PET scan should occur within 3 months of the CT that defined local 
enlargement. Post-treatment PET scans done outside of the required criteria for assessment of local 
progression or after 2 years post-treatment may be done at the investigator’s discretion but are not required. 
h. 
Follow-up evaluations (including toxicity evaluation, progress notes and physical, performance status 
assessment, and weight) should occur at week 12, followed by every 3 months for 1.5 years, then every 6 
months for the next 2 years.  If the patient is unavailable to come for follow up during these periods, or for 
patients who are not compliant with follow up appointments, “missed” imaging studies will be obtained at first 
available opportunity. Patients will be followed for a total of 4 years or until disease progression or death, 
whichever comes first.  At minimum all patients in the Phase II portion of the study must be followed for 
survival for 2 years post treatment. 
i. 
Every 3 months for the first year.  Use PFTs to monitor for signs of radiation pneumonitis (see Section 9.1). 
j. 
Adverse events grade 2 or higher shall be recorded on the toxicity record 
 
 

 
Protocol Version date 04/19/19 
 
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11.0 DATA SUBMISSION SCHEDULE 
 
Paper forms 
Data Due 
Original signed consent form 
At least 24 hours prior to registration 
Eligibility checklist 
Prior to registration 
Dose Level Accrual Tracking 
Spreadsheet 
At the time of patient enrollment and each study 
visit 
SBRT Treatment Planning Statistics 
Upon treatment plan approval (completed by 
Dosimetry staff) 
Toxicity Assessment Form 
At each follow-up visit  
(Toxicity assessments during weekly treatment 
will be entered into IMPAC by PI) 
QASM SAE Form 
At the time of any SAE, to be reported according 
to institutional guidelines 
SBRT Registration 
At the time of enrollment 
SBRT Treatment Record 
Upon completion of treatment 
SBRT Evaluation of Response 
12 weeks post treatment 
Q 3 months for 2 years 
SBRT Toxicity Record 
At the time a study-related toxicity occurs  
SBRT Off Treatment Record 
At completion of treatment or at the time the 
patient goes off study 
SBRT Follow-Up Form 
12 weeks post treatment 
Every 3 months for first 1.5 years 
Every 6 months for following 2 years 
 
 
12.0 CRITERIA FOR EVALUATION  
 
12.1 Baseline documentation of “Target” and “Non-Target” Lesions 
 
Patients enrolled to this protocol should have clinical stage I (T1 or T2, N0, 
M0) non-small cell lung cancer. At time of treatment, they should only 
have one site of gross disease in the lung with no metastases. The 
primary lung tumor should be identified as the target lesion and recorded 
and measured at baseline and with each follow-up imaging evaluation. 
The longest diameter (LD) for the target lesion will be calculated from the 
treatment planning CT scan using pulmonary windowing and reported 
as the baseline LD. The baseline LD will be used as reference by which to 
characterize the objective tumor. For follow-up assessment, diagnostic CT 
scans performed using a 5 mm contiguous reconstruction algorithm using 
pulmonary windowing taken as part of scheduled protocol follow-up are 
preferred as the method of evaluation for response. When CT scans are 
not available, chest x-ray determination will be allowed as long as the 
target lesion is clearly visible. Changes in serum tumor markers will not be 
allowed for assessment of either local tumor progression or metastatic 
progression. 
 

 
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Local treatment effects in the vicinity of the tumor target may make 
determination of tumor dimensions difficult. For example, bronchial or 
bronchiolar damage may cause patchy consolidation around the tumor 
that over time may coalesce with the residual tumor. In cases where it is 
indeterminate whether consolidation represents residual tumor or 
treatment effect, an FDG-PET scan may be used to determine the clinical 
suspicion of residual cancer.  The FDG-PET should be interpreted with the 
original diagnostic FDG-PET.  Lesions with a high suspicion of residual 
cancer should be biopsied. 
 
All other lesions (or sites of disease) that appear after treatment (e.g., 
regional lymph nodes and distant metastases) should be identified as 
non-target lesions and should also be recorded at the point of their 
appearance and with each follow up. Non-target lesions should constitute 
measurable disease, which by definition requires having an appearance 
suspicious for carcinoma and having a dimension of at least 1.0 cm. 
Assessment of regional lymphatic or metastatic progression will be made 
in comparison to the required pretreatment staging studies or any other 
pretreatment imaging evaluations available. Only non-target lesions 
appearing at the margin of the PTV (i.e., within 1.0 cm) will have recorded 
measurements (see Marginal Failure in the table below). Recorded 
measurements of all other non-target lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
12.2 Criteria for Removal from Protocol Treatment 
 
All reasons for discontinuation of treatment must be documented. All 
patients will be followed until death for 4 years post-treatment or disease 
progression or death, whichever time point comes first.  At minimum, all 
patients in the phase II portion of the study must be followed for survival 
for 2 years post treatment 
 
• 
Disease progression at any time during therapy or the follow up 
period; the patient should be re-staged and sites of recurrence 
and/or progression documented. Re-biopsy is strongly encouraged. 
• 
Grade 4 or 5 toxicity. 
• 
The patient may elect to withdraw from study treatment at any time 
for any reason. 
• 
Development of intercurrent, non-cancer related illnesses that 
prevent either continuation of therapy or regular follow up. 
 
 
 

 
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13.0 ADVERSE EVENT REPORTING 
 
 
 
13.1 Adverse Events (AEs) 
 
Adverse events grade 2 or above will be tracked as described below; 
grade 1 events will not be collected. 
 
Definition:  any unfavorable medical occurrence in a human subject 
including any abnormal sign, symptom, or disease. 
 
Grading: The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
will be utilized for all toxicity reporting.  A copy of the CTCAE version 3.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
ctcaev3.pdf).  
 
Attribution (relatedness), Expectedness and Seriousness:  the 
definitions for the terms listed that should be used are those provided by 
the Department of Health and Human Services’ Office of Human 
Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm. 
 
13.2 Unanticipated Problems 
 
Definition: 
 
• Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
• Related or possibly related to participation in the research; and 
• Suggest that the research places participants or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized. 
 
13.3 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional 
policies that govern human subjects research or failure to follow the 
determinations of the IRB.  Noncompliance may occur due to lack of 

 
Protocol Version date 04/19/19 
 
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knowledge or due to deliberate choice to ignore regulations, institutional 
policies, or determinations of the IRB. 
 
13.4 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that result in 
substantial harm to subjects or others, or that materially, compromises the 
rights or welfare of participants. 
  
13.5 Reporting to the Human Research Protection Office (HRPO) 
and the Quality Assurance and Safety Monitoring Committee 
(QASMC): 
 
The PI is required to promptly notify the IRB of the following events: 
• Any unanticipated problems involving risks to participants or others 
which occur at WU, any BJH or SLCH institution, or that impacts 
participants or the conduct of the study. 
• Noncompliance with federal regulations or the requirements or 
determinations of the IRB. 
• Receipt of new information that may impact the willingness of 
participants to participate or continue participation in the research 
study 
 
These events must be reported to the IRB within 10 working days of the 
occurrence of the event or notification to the PI of the event.  The death of 
a research participant that qualifies as a reportable event should be 
reported within 1 working day of the occurrence of the event or notification 
to the PI of the event. 
 
13.6 Reporting of AE Information Following Study Completion 
 
All SAEs must be collected which occur within 30 days of discontinuation 
of dosing or completion of the patient’s participation in the study if the last 
scheduled visit occurs at a later time.  
 
13.6.1 Follow Up Reports 
 
Follow up reports are only required to be submitted if the new 
information changes the original assessment or indicates, in the 
light of new information, that there is an increased risk of harm to 
the participant or others. 
 
13.7 SBRT Adverse Event Reporting 
 
All acute and late adverse events from protocol radiation therapy will be 
reported and scored.  Since the principal investigator is responsible for the 

 
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treatment and follow-up for each of these patients, he is responsible for 
reporting adverse events to the study coordinator.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be used 
to score adverse events.  A copy of the CTCAE v3.0 can be downloaded 
from the CTEP home page: 
 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
ctcaev3.pdf). 
 
For purposes of this protocol, serious adverse events related to 
stereotactic radiation therapy include those listed as Grade 3-5 within the 
CTCAE document. 
 
With respect to scoring dyspnea within the pulmonary toxicity criteria, an 
SAE will be scored if dyspnea meets grade 3 criteria AND is more severe 
than the baseline prior to treatment. 
 
With respect to scoring FEV1 and DLCO as reported on pulmonary 
function tests, an SAE will be scored relative to the % change from 
baseline.  Changes will be referenced to the baseline for a given patient 
(which will be abnormal for most patients), using a defined proportional 
decline.  This scheme is depicted in the table below. 
 
 

 
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SBRT Pulmonary Toxicity Scale 
Grade 
Adverse 
Event 
1 
2 
3 
4 
5 
FEV-1 
Decline 
0.90-0.75 
times 
patient’s 
baseline 
value 
<0.75-
0.50 
times 
patient’s 
baseline 
value 
<0.50-
0.25 
times 
patient’s 
baseline 
value 
<0.25 
times 
patient’s 
baseline 
value 
Death 
DLCO 
Decline 
.90-0.75 
times 
patient’s 
baseline 
value 
<0.75-
0.50 
times 
patient’s 
baseline 
value 
<0.50-
0.25 
times 
patient’s 
baseline 
value 
<0.25 
times 
patient’s 
baseline 
value 
Death 
 
13.8 Life-Threatening, Grade 4, and Grade 5 Events 
 
All life-threatening events (events, which in view of the investigator, place 
the patient at immediate risk of death from the reaction) or Grade 4 or 
Grade 5 events that are definitely, possibly, or probably related to protocol 
treatment using radiation therapy must be reported to the Study Chair and 
study coordinator within 24 hours of discovery for up to 30 days following 
completion of treatment. 
 
 
14.0 DATA AND SAFETY MONITORING 
 
The Principal Investigator will review all patient data at least every six months, 
and provide a semi-annual report to the Quality Assurance and Safety Monitoring 
Committee (QASMC). This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data 
coordinator name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO 
approval/revision, date of HRPO expiration, date of most recent QA audit, 
study status, and phase of study 
• History of study including summary of substantive amendments; summary 
of accrual suspensions including start/stop dates and reason; and 
summary of protocol exceptions, error, or breach of confidentiality 
including start/stop dates and reason 
• Study-wide target accrual and study-wide actual Protocol activation date  
• Average rate of accrual observed in year 1, year 2, and subsequent years  
• Expected accrual end date,   

 
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• Objectives of protocol with supporting data and list the number of 
participants who have met each objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of 
participants who have met the early stopping rules 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the 
study  
 
The study principal investigator and Research Patient Coordinator will monitor for 
serious toxicities on an ongoing basis. Once the principal investigator or 
Research Patient Coordinator becomes aware of an adverse event, the AE will 
be reported to the HRPO and QASMC according to institutional guidelines. 
 
 
15.0 STATISTICAL CONSIDERATIONS 
 
15.1 Statistical Methods for Phase I Portion 
 
15.1.1 Objective and Endpoint 
 
The primary objective of Phase I is to estimate the rate of acute and 
late treatment-related grade 3 or 4 toxicity (per CTCAE, v.3.0) 
related to specific symptoms, including: 
• Gastrointestinal: dysphagia, esophagitis, esophageal stricture, 
esophageal ulceration; 
• Cardiac: pericarditis, pericardial effusion, cardiomyopathy, 
ventricular dysfunction; 
• Hemorrhage: pulmonary or upper respiratory; 
• Pulmonary: decline in pulmonary function as measured by 
pulmonary function tests, pneumonitis, pulmonary fibrosis, 
hypoxemia, pleural effusion   
• Or any other grade 4 or 5 toxicity attributed to the therapy. 
 
15.1.2 Dose Escalation Schema 
 
In order to establish the maximum tolerated dose (MTD) of 
radiotherapy, in terms of Gy per fraction, that can be delivered 
using stereotactic body radiation therapy (SBRT) for central lung 
tumors, acceptable morbidity criteria must be defined. Since some 
of toxicities in the current study are life threatening, we hope to 
control the dose limiting toxicity (DLT: defined as a Grade 3 or 
Grade 4 non-hematologic toxicity) rate in a relatively low level. The 
design will take a “5+3” strategy rather than the conventional “3+3” 
design (see below).  

 
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This study consists of four escalating dose levels, only one of which 
will be open for accrual at any time.  Dose Level A (9 Gy x 5 = 45 
Gy; BED = 85.5 Gy*) will open first.  Five (maximally eight) patients 
will be accrued to this dose level.  After Dose Level A is closed, 
accrual will begin to Dose Level B (10 Gy x 5 = 50 Gy; BED = 100 
Gy*). New dose levels cannot be opened until the preceding RT 
dose is deemed to be acceptable. At a given dose level, after 5 
evaluable patients have been followed for a minimum of 90 days 
from the start of RT, these patients will be carefully evaluated with 
respect to treatment morbidity. Dose escalation will be determined 
as follows: 
• If there are no acute dose limiting toxicities (DLTs: defined as a 
grade 3 or 4 non-hematologic toxicities) in the first 5 patients 
(0/5), then the current dose will be deemed to be acceptable 
and will be escalated. 
• If there is 1 acute DLT observed in the first 5 patients (1/5), then 
an additional 3 patients will be recruited and followed for a 
minimum of 90 days. If there is 1 acute DLT observed (1/8), 
then the current dose will be deemed to be acceptable and will 
be escalated. If there are 2 or more acute DLTs observed 
(≥2/8), then the current dose will be deemed over-toxicity and 
the previous dose level will be considered as MTD for the Phase 
II trial (the study will be terminated if Level A is the current 
dose). 
• If there are 2 or more acute DLTs observed in the first 5 patients 
(≥2/5), the current dose will be considered over-toxicity and the 
previous dose level will be considered as MTD for the Phase II 
trial (the study will be terminated if Level A is the current dose). 
• However, the final decision for MTD will be based on a cohort of 
8 patients and no re-escalation will be considered after “step-
down” to the previous dosage level.  
• If at any time a grade 5 toxicity (death) is observed, accrual will 
be suspended and the event will be reviewed by the Principal 
Investigator. 
• This study is designed with 4 possible SBRT dose levels.  If the 
4th dose level is achieved, then the maximum sample size for 
this study is 32 patients. Nominally, such a “5+3” design will 
control the DLT around 12.5% level. 
• After completing accrual to dose levels 2 and 3 (during the 3 
month assessment window) accrual to the trial may continue at 
the previous ‘safe’ dose level.  For example, if dose level 1 
proves safe, patients can be accrued and treated at dose level 1 
during the 3 month window of toxicity assessment between 
dose levels 2 and 3.   
 

 
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*BED = nd(1 +d//), where n = number of fractions, d =  dose 
per fraction, and / = 10 for acute-reacting tissue 
 
15.2 Statistical Methods for Phase II Portion 
 
15.2.1 Endpoints 
 
The primary endpoint of Phase II is to estimate the local control rate 
at two years and the secondary endpoint of Phase II include the 
rates of local recurrence, regional recurrence, disease-free and 
overall survival at two years. 
 
15.2.2 Study Design 
 
This phase II study aims to improve the two-year local control rate 
from 60% to 80%, assuming that a control rate less than 60% is not 
of interest and that a 2-year control rate of 80% or more would 
definitely be of interest. Based on Fleming’s single-stage design, 43 
patients will be recruited during the phase II portion to detect such 
an improvement with 80% power and at a 2-sided Type I error rate 
of 0.05. However, the above sample size is a conservative estimate 
because it is based on Fisher’s exact test for binary data. In the 
final analysis for local control rate, we will use survival data analysis 
(i.e., log-rank test) where more information (i.e., the exact times to 
local failures) will be utilized. 
 
15.2.3 Data analysis 
 
Unless otherwise noted, the efficacy analysis will be based on all 
patients who have completed the treatment and had primary 
efficacy measurements available while the safety analysis will be 
based on patients who received one or more fractions of SBRT. 
     
Demographic and clinical characteristics of the sample, as well as 
response, toxicity by grade and loss to follow up will be 
summarized using descriptive statistics. Kaplan-Meier product limit 
estimator will be used to describe the distribution of local-failure 
free survival. The median time to local-failure and its 95% 
confidence interval will be estimated. The Kaplan-Meier product 
limit estimator will also be used to graphically describe progression 
free survival, overall survival as well as regional nodal recurrence-
free survival. The proportion of patients who respond (completely or 
partially) will also be estimated and the corresponding 95% 
confidence intervals will be computed. 
 

 
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15.3 Monitoring the Study for Early Stopping Due to Unacceptable 
Toxicity  
 
Early stopping of this trial will be based on unacceptable toxicity, defined 
as acute (within 90 days of the start of treatment) or late (more than 90 
days from the start of treatment) grade 3 or 4 toxicity (per CTCAE, v.3.0) 
related to specific symptoms as detailed in Section 16.1 or any grade 4 or 
5 toxicity attributed to the therapy. If a patient has more than one 
unacceptable toxicity, they will only be counted as one unacceptable 
toxicity for this analysis.   
 
By assuming that a toxicity rate of 10% or less is acceptable and that a 
toxicity rate of 20% or more would definitely be unacceptable. Based on 
the sequential probability ratio test (SPRT) with 80% power and 0.05 
significance level, the study will be halted if 4 of the first 4, or 5 of the first 
11, or 6 of the first 18, or 7 of the first 25, or 8 of the first 32, or 9 of the 
first 39 patients experience unacceptable toxicities, or if the 10th 
unacceptable toxicity is observed before the last (43th) patient has 
completed the trial.  If a grade 5 toxicity (death) is observed at any time, 
accrual will be suspended and the event will be reviewed by the study 
chair.  
 
15.4 Accrual 
 
The rate of accrual for the study is expected to be about 1 patient per 
month.  It is expected that the accrual period of the study for phase I will 
be completed in approximately 36 months, depending on the DLT 
reached. Accrual for Phase II should be completed in 24 months. The 
whole study is anticipated to be finished in approximately 9 years.  
 
15.5 Interim Analysis 
 
An interim analysis will be conducted when 15 patients have at least 1-
year follow-up.  Because 10 patients from Phase I portion can be carried 
over to the Phase II, we anticipate that this will happen around the mid 2nd-
year after the initiation of Phase II. If 10 or less local controls are observed 
out of these 15 patients, then the trial will be stopped because we will 
have 95% confidence that the “true” local control rate is no larger than 
82%. Note that in the phase II setting, a trial usually will be stopped only 
because of futility. This trial will be continued even an overwhelming 
efficacy is observed in the interim analysis, and thus to have a more 
reliable estimation for the true treatment efficacy.    
. 
 
 
 

 
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