Stereotactic Body Radiation Therapy for Post-chemoradiation Residual Disease in Stage II/III Non-small Cell Lung Cancer
Phase: NA
Conditions: Lung Cancer
Sponsor: Ronald McGarry

07-RAD-01, v. 1.5.2 (08-JUL-2013) 
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07-RAD-01-UK/P4: 
Stereotactic Body Radiation Therapy for Post-chemoradiation 
Residual Disease in Stage II/III Non-small Cell Lung Cancer 
 
 
Principle Investigator: 
 
 
 
Ronald C. McGarry, M.D., Ph.D. 
 
 
 
Department of Radiation Medicine 
 
 
 
University of Kentucky 
 
Medical Oncology Co-Investigators: 
 
 
 
Susanne Arnold, M.D. 
 
 
 
John Rinehart, M.D. 
 
 
 
Department of Hematology/Oncology, 
 
 
 
 
University of Kentucky 
 
Imaging Co-Investigators: 
 
 
 
Partha Sinha, M.D. 
 
 
 
Gary Conrad, M.D. 
 
 
 
Department of Diagnostic Radiology, 
 
 
 
University of Kentucky 
 
 
 
 
Statistical Co-Investigator: 
 
 
 
Brent Shelton, Ph.D. 
 
 
 
Departments of Internal Medicine & Biostatistics  
 
 
 
University of Kentucky Colleges of Medicine & Public Health 
 
 
 
 
Study version 1.5.2 July 8, 2013

07-RAD-01, v. 1.5.2 (08-JUL-2013) 
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 SCHEMA 
Eligible patients with Stage II/III NSCLC# 
Completed Definitive Chemoradiation to min 5940 cGy* 
 
 
 
 
 
 
CT scan or PET/CT 21-30 days post chemo RT 
 
 SBRT boost  
Peripheral Tumors:  1000cGy X 2 to residual primary mass 
Medial Tumors:  650cGy x 3 to residual primary mass 
 
 
 
 
 
Routine Followup with CT chest and/or chest x-ray at ~3 months 
PET/CT if suspected recurrence/metastasis clinically indicated 
 
Sample size: 42 patients  
*choice of chemotherapy at the discretion of treating medical oncologist, standard 
RT to dose at discretion of treating radiation oncologist

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Table of Contents 
 
Section  
 
 
 
 
 
Page      
 
Schema 
 
 
 
 
 
2. 
1.0 Background 
 
 
 
 
3. 
2.0 Objectives 
 
 
 
 
7. 
3.0 Eligibility  
 
 
 
 
7. 
3.1 Exclusion Criteria 
 
 
 
8. 
4.0 Pretreatment Evaluations 
 
 
9. 
5.0 Treatment Plan  
 
 
 
9. 
5.1 Radiation Therapy – Primary ChemoRT 
9. 
6.0 Stereotactic Dose Specifications 
 
12. 
6.2 Treatment Planning Volumes  
 
13. 
7.0 Patient assessments 
 
 
 
16. 
8.0 Criteria for Evaluation  
 
 
16. 
9.0 Data and Safety Monitoring Plan 
 
18. 
10.0 Statistical Considerations 
 
 
19. 
11.0 Reporting Toxicity 
 
 
 
20. 
12.0 Criteria for Discontinuing Therapy  
20. 
13.0  References 
 
 
 
 
21.     
 

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1.0 Background 
Lung cancer represents one of the most challenging malignancies to manage. Cure rates 
have only marginally improved in the last 20 years. It is the most commonly fatal cancer 
in both men and women with overall 5 year survivals of 15%. Lung cancer kills more 
Americans than the next three most common malignancies combined.  
Most non small cell lung cancer (NSCLC) presents at advanced stages. Only 
approximately 25% present with stage I/II disease, 40% with stage III and 35% pts 
present with stage IV. (1) The optimal treatment of stage II/III NSCLC is complex. For 
those patients who are surgical candidates and a complete resection is technically 
feasible, radical surgery remains the standard of care. Traditionally, those patients with 
multiple N2 nodal levels or T4 disease are considered inoperable. Given that the average 
age of patients diagnosed with NSCLC is in their mid-60’s and usually have long 
smoking histories, many patients are medically inoperable.  
1.1 Current Radiation Therapy for NSCLC 
In the early 1980’s, the CALGB completed a protocol for the treatment of stage 
III NSCLC that employed chemotherapy first, which they called “proto-adjuvant.”  They 
based the treatment on two cycles of cis-platinum and 4 weekly doses of vinorelbine – no 
alkylating agents.  This landmark, paradigm shifting trial widely known as the Dillman 
trial (2) altered the course of non-surgical therapy by demonstrating that treatment 
regimens including chemotherapy were significantly better than radiotherapy alone.  The 
median survival was nearly 14 months with the chemotherapy and only in the range of 9 
months with radiotherapy alone to 60 Gy (2).  The study was replicated by an Intergroup 
effort (3).  The theory and apparent fact was that these tactics reduced distant metastasis, 
but did not alter local control and failure in the chest remains a significant problem in the 
management of NSCLC(3).  
1.2 Radiation Therapy – What dose to use. 
The optimal doses of radiation therapy are undefined but the high local failure 
rates (vary between 20 and 50%) would suggest that higher doses of radiation therapy 
could potentially improve outcome in these patients.  Local failure results in significant 
morbidity and theoretically could act as a nidus for metastasis. While various dose 

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escalation trials are beginning to suggest a benefit to increasing the RT dose to obtain 
better local control, thus far no prospective trials have shown benefit to escalation of the 
most common RT dose, 60Gy, established in the Dillman trial (2), probably due to the 
limitations of dose imposed by patient anatomy. Tolerance of organs such as esophagus, 
spinal cord and heart are important, but the lungs themselves are of primary importance 
with a dose limiting toxicity being pneumonitis. Pneumonitis has a dose volume 
relationship which is not clearly definable due to the variability in lung physiology (e.g. 
emphysematous bullae, upper vs. lower lobes) and attempts to develop predictive models 
for pneumonitis  are fraught with difficulties. We often examine the so-called V20 value, 
basically the volume of lung encompassed by the 20Gy isodose line in patients receiving 
standard fractionation (180-200 cGy/fraction)(4). 
Most studies of dose escalation have included patients with high stage disease. 
Due to the high risk of local recurrence, several studies have undertaken dose escalation 
using different strategies to maintain toxicity at acceptable levels. Most strategies try to 
equate dose/fractionation schemes by employing linear quadratic normalization 
(biological effective doses (BED)). This is somewhat difficult since it does not take into 
account the lengths of treatment time in hypofractionated schemes. Applying the linear 
quadratic equation (BED=nd(1+d/)  where n=the number of fractions, d=the 
dose/fraction and ratio of 10 for acute reacting tissue and tumor cells), 70 Gy will 
only have a BED of approximately  84 Gy. Using a mathematical model, Martel et al. (5) 
predicted that for NSCLC patients, the dose to achieve significant probability of tumor 
control may be at least 84 Gy (100 Gy BED at 200 cGy/fraction) for longer (>30 months) 
local progression-free survival. RTOG 9311 was a multi-institutional trial in which a total 
of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-
escalation fashion (6). Patients were stratified at escalating radiation dose levels 
depending on the percentage of the total lung volume that received >20 Gy with the 
treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 
fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, 
successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 
77.4 Gy, successively. V(20) has been used as an indicator of risk for pneumonitis (see 
below). The radiation dose was safely escalated using three-dimensional conformal 

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techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy 
for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 
2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 
patients. Elective nodal failure occurred in <10% of patients. This study showed that for 
patients receiving RT alone or radiation following induction chemotherapy, doses of 83.8 
Gy using 3-dimensional conformal RT techniques were tolerable, with excess mortality 
observed at 90.3 Gy. On a theoretical basis when converted to BED, this represents a 
borderline dose of RT to gain a high probability of local control, especially considering 
that patients entered on these trials were highly selected. 
 Since the advent of concurrent chemotherapy and 3-dimensional conformal RT 
the maximum tolerated dose of radiation has been reduced, and current indications 
suggest that the maximum tolerated dose in this setting is in the range of 70 to 74 Gy 
(4,6). Nonetheless, it has not been prospectively demonstrated that dose escalation has 
produced superior outcomes and careful planning is needed to avoid toxicities. Willner et 
al. (7) retrospectively examined the influence of total dose and tumor volumes on local 
control and survival in primary radiotherapy of non-small cell lung cancer. They 
concluded that there is a dose effect on local control and survival with doses of at least 70 
Gy (standard fractionation) and that tumors with volumes >/= 100cc may require higher 
doses. 
It thus stands to reason that improved local control may result from higher local 
radiation doses and hypofractionated stereotactically delivered radiation therapy is 
proving effective at long term control of early stage NSCL (8-10). In an analysis of 
various hypofractionated stereotactic-delivered radiation schemes, Wulf et al. (11) reports 
that for an optimal control of a stage one lung cancer, a BED of >100Gy is required in 
agreement with the Martel analysis. Moreover as tumors get larger, with greater central 
hypoxia and numbers of cancer cells to kill, the amount of radiation needed to sterilize a 
given cancer should theoretically be higher.   
1.3 Hypothesis 
 
In light of the above information, it becomes apparent that local control for 
NSCLC remains a significant problem. Conventional radiation therapy techniques have 
limitations for the dose that can be delivered to a chest tumor mass due to the adjacent 

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dose limiting organs. Mounting evidence supports the use of hypofractionated 
stereotactically delivered radiation therapy to control lung cancer with acceptable toxicity 
profiles. 
 
Thus we propose to increase the doses of radiation to residual masses of NSCL to 
a BED >100 Gy by the addition of 2-3 fractions of stereotactically delivered boost 
radiation therapy to residual disease post-conventional chemoradiation to at least 59.4 Gy 
in 180 cGy fractions. Using the linear quadratic equation to model doses of radiation 
therapy, 59.4 Gy would have a BED of approximately 70 Gy. Single fraction stereotactic 
body radiation therapy (SBRT) of 10 Gy would have a BED of approximately 20 Gy. 
Thus the addition of two fractions of 10Gy of SBRT to limited volumes of PET residual 
disease would theoretically result in higher degrees of local control of lung cancer 
masses, achieving a minimum cumulative BED of approximately 110Gy-equivalent.  
2.0 Objectives 
Primary  
1. to determine the toxicity of the SBRT boost dose by estimating the proportion 
of subjects enrolled who develop pneumonitis 
Secondary 
1. to determine response rates of the residual primary tumor following SBRT 
boost 
3.0 Eligibility 
1. Histological confirmation of non-small cell lung cancer (squamous cell 
carcinoma, adenocarcinoma, large cell carcinoma, bronchoalveolar cell 
carcinoma, or non-small cell carcinoma NOS) by either biopsy or cytology. 
2. Clinical AJCC stage IIA (T1N1M0), IIB (T2,N1M0, T3,N0,M0) or IIIA (T1-3, 
N1-2,M0)/selected IIIB. In all cases, patients may be included at the discretion 
of the treating radiation oncologist if it will be likely the disease can be 
encompassed by the stereotactic boost.  

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3. Patients with non-bulky (<2.0-3.0 cm)  hilar or mediastinal lymphadenopathy 
determined by pre-treatment CT scan,  PET or mediastinoscopy 
4. Must have completed a standard course of chemoradiation in accordance with 
NCCN Guidelines 
5. One month following definitive chemoradiation, CT or PET-CT revealing 
limited volume residual disease within the site of primary tumour mass (post-
chemo/RT mass </= 7.0 cm). Patients with a CR and no obvious target are not 
eligible. 
6. must be able to fit into the  Civco stereotactic immobilization device. 
7. Patients must be ≥ 18 years of age. 
8. The patient’s ECOG performance status must be 0-2. 
9. Women of childbearing potential and male participants must use an effective 
contraceptive method. 
10. Patients must sign a study-specific consent form.  
 
3.1 Exclusion Criteria 
1. Any other active cancer. 
2. No prior malignancy is allowed except for the following: adequately treated basal cell 
or squamous cell skin cancer, in situ cervical cancer or other cancer from which the 
patient has been disease-free for 5 years. 
3. Patients with other systemic illness, or have not recovered adequately from their 
primary treatment or who have evidence of progression of their lung cancer prior to 
therapy that, in the investigators opinions, would preclude their inclusion 
4. Plans for the patient to receive other concomitant antineoplastic therapy while on this 
protocol, except at disease progression.  Patients may be allowed to use bisphosphonates 
for hypercalcemia. 

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5. Pregnant or lactating women 
4.0 PRETREATMENT EVALUATIONS 
(All lab tests and radiographic studies should be done at approximately 3 weeks post 
chemoradiation) 
4.1 Complete history, physical examination, and evaluation of Zubrod Performance 
Status.  
4.2 Pathological (biopsy) or cytologically proven non-small cell lung cancer. 
4.3 Postchemoradiation  CT with contrast or PET/CT (preferred)of chest and upper 
abdomen to include the liver and adrenals; baseline brain MRI or CT scan.  
4.4 Bone scan, only if the patient has bone pain and/or and elevated alkaline phosphatase. 
4.5 Pulmonary function tests - including DLCO and FEV1 
4.6 CBC; serum chemistry tests to include alkaline phosphatase, glucose, creatinine, 
electrolytes, AST (SGOT), and total bilirubin,  
5.0 Treatment Plan 
5.1 Radiation Therapy - Primary chemoradiation 
All initial chemoradiation must be planned and delivered with CT-based 3-d planning. 
Like any radiation oncology boost therapy, as part of the pre-SBRT boost therapy 
assessment, complete and detailed dosimetry from the primary chemoradiation must be 
made available. The purpose is to ensure dose constraints on normal tissues are respected. 
The recommended radiation plan format is elucidated below and follows standard 
radiation oncology practice. Detailed chemoradiation plan must be reviewed during 
planning of the SBRT boost. 
Volume and ICRU Reference Point Definitions 
The definitions of volumes will be in accordance with the 1993 ICRU Report #50:45 
Prescribing, Recording and Reporting Photon Beam Therapy. 
5.1.1 Gross Tumor Volume (GTV) is defined by the physician as all known gross disease 
as defined by the planning CT and clinical information. Gross tumor includes the primary 
tumor (GTV-P) and abnormally enlarged regional lymph nodes > 1.0 cm (short axis 

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measurement) (GTV-N).46,47,48,49 These volume(s) may be disjointed. Note ICRU 
Report #50 also defines a clinical target volume (CTV) which may include 
the area of subclinical involvement around the GTV.  
5.1.2 Planning Target Volume (PTV) will provide margin around the GTV to compensate 
for variabilities in daily treatment setup and internal CTV motion due to breathing or 
motion during treatment. The PTV for which dose escalation will be occurring must 
include the entire GTV plus a minimum 3D margin of 10mm. More margin may be 
necessary if the tumor movement is increased because of physiologic movement which 
should be checked, in most cases by fluoroscopy. 
5.1.3 The ICRU Reference Point is to be located in the central part of the PTV. Typically 
this point should be located on the beam axis or at the intersection of the beam axes 
(isocenter). 
5.2  3D Planning 
5.2.1 Planning Volume (PTV) - The PTV is to be treated with any combination of 
coplanar or noncoplanar 3-dimensional conformal fields shaped to deliver the specified 
dose while restricting the dose to the normal tissues. Field arrangements will be 
determined by 3D planning to produce the optimal conformal plan in accordance with 
volume definitions. The treatment plan used for each patient will be based on an 
analysis of the volumetric dose including DVH analyses of the PTV and critical normal 
structures. 
5.2.2 Dose Specification : Radiation therapy: Patients will be have CT planning designed 
to encompass all known disease. While mediastinal coverage is recommended, fields will 
be at discretion of the treating physician in accordance with standard therapy. 
Recommended plans will give patients initial fields using AP:PA plans to approximately 
3960cGy, followed by off cord boost to a final dose of 5940 cGy or higher. Alternative 
plans respecting dose limiting organ tolerances would be acceptable. All patients will be 
treated at 180-200 cGy/day on minimum 6 mV linear accelerators or higher energies. All 
attempts are to be made to cover contoured GTV’s by minimum a 95% of prescribed 
dose.  

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5.2.3 All patients will have 3-d planning with attention to dose limiting organs. Complete 
dose volume histograms must be provided and include (at a minimum) spinal cord, 
esophagus, brachial plexus as appropriate, combined lung volumes (to estimate V20), 
heart, gross tumour volume (may have separate GTV’s for primary tumour and nodes), 
planning target volume (GTV+ 1.0-2.0 cm at the discretion of the treating physician) 
5.3 Normal Tissue Volume and Tolerances 
5.3.1 The tolerance of the lungs is related to the volume of the organ(s) irradiated. Data 
from the Washington University (12) reported that high-grade acute pneumonitis did not 
occur when the V20 was </= approximately 30%. The incidence and the grade or severity 
of pneumonitis was clearly related to the V20. Total lung volume is defined as the lung 
volume of both lungs minus the PTV. In the Washington University data, maximum dose 
(with conventional fractionation) was not related to acute pneumonitis. For this protocol 
all eligible patients the goal is to attempt to have the V20 < 30% although higher 
percentages are acceptable at the discretion of the treating physician. It is expected that 
the dose to the lungs will be the primary dose-limiting structure. Every effort to keep the 
total lung dose to a minimum should be performed. Since most lung tumors are localized 
to one lung, efforts to keep the contralateral lung at a minimum should also be performed. 
The patient's overall lung function is evaluated by the FEV1 and DLCO should also be 
evaluated in determining an individual's lung function reserve and thus the ability to 
radiate. 
5.3.2 When planning the beam arrangement to the PTV, the heart, esophagus, and spinal 
cord should be out of the field to the extent possible. The dose per fraction to the lungs, 
heart, esophagus, and spinal cord should be maintained at 2 Gy or less per fraction to the 
extent possible. If tolerance dose to any of the normal organs is exceeded, alternate beam 
arrangements should be used. 
5.3.3 Tumors will be classified as being either medial or peripheral based on the planning 
CT scan obtained for treatment planning.  This definition will be based on the same 
designation for RTOG 0813: including any tumor within the zone of the proximal 
bronchial tree”, which is a 2 cm radius around the main tracheo-bronchial tree: trachea; 

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left and right main stem bronchi; right upper, middle, and lower lobe bronchus; and left 
upper, lingular, and lower lobe bronchus.  This can be represented in the figure below: 
 
5.3.4. General considerations for organ tolerances 
 
6.0 Stereotactic Dose Specifications 
6.1.1  Stereotactic Targeting and Treatment 
Targeting, planning, and directing of therapy will be accomplished using beams of 
radiation along any trajectory in 3-D space focusing on the target, which will be of 
known 3-D coordinates.   A fixed 3-D coordinate system defined by fiducials will be 

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used.  This coordinate system will be directly related to the radiation producing device in 
a reproducible and secure fashion and will be used to define the position of the target(s) 
within the patient.  Each treatment is designed to direct the radiation toward an isocentre 
according to known 3-D coordinates determined during treatment planning.  In this study, 
the fiducials will be radio-opaque markers placed at known locations within a frame 
adjacent to the patient.   
6.1.2 Patient Positioning 
The patient’s position must be accurately reproducible from treatment to treatment.  
Uncomfortable positions should be avoided to prevent movement during treatment.  The 
immobilization system used in this trial will be a stereotactic frame that surrounds the 
patient on three sides and references the stereotactic coordinate system.  Within this 
frame, the patient will be positioned on large, rigid pillows that conform to patients’ 
external contours.   
6.1.3 Inhibition of Effects of Internal Organ Motion 
Reliable abdominal compression (the effectiveness of which will be checked via 
fluoroscopy) will be used to minimize the effect of internal organ motion (i.e. breathing, 
etc.) on target positioning and reproducibility.  This will be performed such that the GTV 
does not deviate beyond the confines of the PTV with any significant probability (i.e. 
<5%).    
6.1.4 Localization 
Immediately before each treatment, isocentre port localization films (anterior/posterior 
and lateral) will be obtained on the treatment unit to ensure proper alignment of the 
isocentre.   
 
6.2 Treatment Planning/Target Volumes 
 
6.2.1 Image Acquisition 
Treatment planning will utilize Computed Tomography (CT).  The planning CT will be 
obtained with the patient in the body frame to allow simultaneous view of the patient’s 
anatomy and the fiducial system.  To better delineate between tumor and adjacent vessels 
or atelectasis, IV contrast will be used during planning CT acquisition unless 

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contraindicated (i.e. the patient has poor renal function or allergy to contrast media).  
3.0mm thick axial slices will be obtained with the gantry at 0 degrees.  An appropriately 
trained physician will outline the target lesion and designate it as the Gross Tumor 
Volume (GTV).  This will be accomplished using pulmonary windows or soft tissue 
windows with contrast.  Only abnormal density on CT consistent with gross tumor will 
be included in the GTV, with no enlargement of the target for “margin” to account for 
presumed microscopic extension (i.e. GTV and Clinical Target Volume (CTV) are to be 
identical).  The Planning Treatment Volume (PTV) will consist of the GTV with an 
additional 0.5 cm in the axial plane and 1.0 cm in the longitudinal (cranio-caudal) plane.    
6.2.2 Dosimetry 
Each case will have three-dimensional non-coplanar (and occasionally coplanar) beam 
arrangements custom designed to deliver highly conformal prescription dose distributions 
per the UK institutional standard.  7 or more beams (minimum 7 beams) with roughly 
equal weighting will be used, with more beams being used for larger lesions.  The 
isocentre will be defined as the common point of gantry and couch rotation for the 
treatment unit.  The isocentre in stereotactic coordinates will be determined from system 
fiducials and translated to the treatment record.  The field aperture size and shape will 
correspond nearly identically to the projection of the PTV along a beam’s eye view, 
except when observing the minimum field dimension of 3.5 cm in the treatment of small 
lesions.  Prescription lines covering the PTV will generally be the 80% line.  Hotspots 
will be manipulated to occur within the target and not within adjacent normal tissue.    
 
The prescription dose of with inhomogeneity correction to the 80% isodose line 
times 2 fractions will be delivered to the margin of the PTV covering a minimum of 95% 
of the PTV.  For purposes of dose planning and calculation of monitor units for actual 
treatment, all tissues within the body, including lung, will be assumed to have unit 
(water) density (no correction for tissue heterogeneity). 
6.2.3 Dose and Fractionation 
 
The dose and fractionation scheme utilized will be based on the location of the 
patient’s residual disease.  For patients with: 
  Peripheral Tumors: Treatment will consist of 2 fractions of radiation, with a minimum 
of 40 hours separating each fraction.  Two fractions of 10 Gy with inhomogeneity 

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correction will be delivered to the prescription line at the edge of the PTV for a total of 
20 Gy.  This will yield a total BED of 110 Gy. 
 
  Medial Tumors:  Treatment will consist of 3 fractions of radiation, with a minimum of 
40 hours separating each fraction.  Three fractions of 6.5 Gy with inhomogeneity 
correction will be delivered to the prescription line at the edge of the PTV for a total of 
19.5 Gy.  This will yield a total BED 102.2 Gy. 
 
 
6.3 Technical Factors 
6.3.1 Physical Factors 
Treatment radiation will consist of photon (x-ray) beams produced by linear accelerators.  
6MV energies will be used under most circumstances, with energies of 15-16MV used 
only in a limited number (maximum of 2) beams that must travel a cumulative distance of 
more than 10cm through soft tissue (not lung) to reach the isocentre.   
 
6.3.2  Minimum Field Aperture (Field Size) Dimension 
A minimum field dimension of 3.5 cm is required for any field used for treatment 
delivery.  If the minimum field exceeds the technical requirements for small lesions (<2.5 
cm axial GTV dimensions or < 1.5 cm cranio-caudal GTV dimension), the prescription 
dose is still prescribed to the edge of the defined PTV.   
 
6.3.3 Critical Organ Dose-Volume Limits 
All critical organ dose volume limits must take into account the initial dose delivered 
during chemoradiation. All initial chemoradiation must have been planned with 3-d CT 
planning. Typically, chemoradiation is given to 59.4-66 Gy and organs such as spinal 
cord and esophagus reach significant doses of radiation. Commonly the tolerance of 
spinal cord is considered to be 50 Gy (180-200cGy/fraction). Prior to boost stereotactic 
radiotherapy, all previous radiation plans must be reviewed with dose-volume histogram 
analysis to determine critical organ doses. In considering the stereotactic plan, if a 
minimum of 7 beams are used, each is contributing only approximately 140cgy of the 

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total prescribed dose. If any beam traverses a critical organ, the dose delivered will be 
considered and a maximum point dose to any organ considered. 
Table 5.3.3 lists maximum dose limits to a point or volume within several critical organs 
to be considered when standard (180-200cGy) fractionation is given.  Size of fraction 
delivered to each organ during stereotactic treatments must be considered, since not all 
beams will either enter or exit through a structure. Every attempt to keep entrance and 
exit doses of each fraction of SBRT traversing a critical organ to as close to a maximum 
of 200 cGy as possible to help estimate critical structure doses. All critical organs will be 
contoured and doses calculated in a standard fashion. Composite plans incorporating the 
initial radiotherapy and the stereotactic boost must be created to accurately assess 
tolerances.  
7.0 Patient assessments 
 
Assessments 
Pre-Study 
entrya 
1mof Post 
SBRT 
3mof Post 
SBRT 
Follow 
Upg 
As 
Indicated 
History/physical 
X 
X 
X 
X 
 
Pregnancy testb 
X 
 
 
 
 
Toxicity evalc 
 
X 
X 
Xc 
 
PET-CT 
X 
 
 
X 
CXray/CT 
 
Xd
Xd 
Xd 
X 
PFT’se 
X 
X 
X 
 
X 
CMP/CBC 
X 
 
 
 
 
a. 
Pre-study evaluations typically done 3-4 weeks after completion of primary chemoradiation. CT simm 
typically done approximately 1 week following study entry, with SBRT delivery done approximately 1 
week after CT simm. 
b. 
Pregnancy test if indicated and not done prior to chemo-RT 
c. 
Toxicity evaluation through 6 months 
d. 
Ideally alternate CT/Chest rays on routine visits post-treatment 
e. 
Pulmonary function tests to include spirometry, lung volumes and diffusion capacity 
f. 
Approximate timeframe 
g. 
Routine follow-up visits scheduled as per institutional standard (strict FU scheduled not required). 
 
8.0. Criteria for Evaluation 
  
8.1. Response determination –  This protocol will use a modified version of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 

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(RECIST) Committee (JNCI 92(3): 205-216, 2000). Additional definitions beyond the 
RECIST guidelines specific to this protocol are incorporated to define local control as 
defined below.  
8.2 Baseline documentation of Target and Non-target lesions 
 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 the reference by which to characterize the objective tumor 
response. For follow-up assessment, diagnostic CT scans using lung windows are the 
preferred modality. Local treatment effects in the vicinity of the tumor target may make 
determination of tumor dimensions difficult e.g. patchy consolidation. 
All other lesions which appear or enlarge after treatment e.g. regional lymph nodes and 
distant metastses should be identified as non-target lesions and should be recorded at the 
time of their appearance/suspicious enlargement.  Patients who have suspicious CT scans 
may have PET/CT to assess local failure/distant metastasis as per clinical judgment.  
8.2.1. Post treatment followup -  Followup evaluation will be performed approximately 30 
days after completion of all protocol treatment to assess toxicity and tumor response.  
Follow-up for evaluation of toxicity will continue for 6 months following SBRT delivery.  
Additional follow-up for local control and survival will continue until death or study 
withdrawal. 
 
8.3 Response Criteria 
          8.3.1 Evaluation of Target Lesions 
Complete Response (CR) – disappearance of the target lesion, ideally on PET/CT 
although assessment by CT is acceptable. 
Partial Response (PR) – At least a 30% decrease in the LD of the target lesion, 
taking as reference the baseline LD. Ideally this determination will be on CT 
evaluation. 
Stable Disease (SD) – Neither sufficient shrinkage to qualify for CR/PR as above, 
nor sufficient increase to qualify for LE as below, taking as reference the smallest 
LD since treatment started. 
Local Enlargement (LE) – At least a 20% increase in the LD of the target lesion 

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with respect to the LD based on followup  
Local Failure (LF) – refers to the primary treated tumor after protocol treatment 
and corresponds to meeting both of the following criteria: 1. increase in tumor 
dimension of 20% as defined for the above LE; 2. The measurable tumor with 
criteria meeting LE should be avid on PET/CT with uptake of similar intensity as 
the pretreatment staging PET/CT 
9.0 Data and Safety Monitoring Plan 
The study principal investigator has primary responsibility for monitoring the safe 
conduct of this study.  Additionally, the Markey Cancer Center Quality Assurance 
Committee (QAC) provides oversight and monitoring of all cancer clinical trials.  The 
Committee is responsible for reviewing data to identify patient safety and protocol 
compliance issues.  The Markey Protocol Review Committee (PRC) assigns studies a 
QAC review timeline based on the phase, origination of the study and known safety 
issues.   
The members of the QAC consist of Medical Oncologists, a Pharmacist, a Nurse 
Manager, a Certified Clinical Research Professional and a Reporter.  These members 
were selected based on their experience, reputation for objectivity and knowledge of 
clinical trial methodology.   All members should view themselves as representing the 
interest of the study patients and not that of the institution.   
At each meeting, representatives for each study on the agenda present their study data 
to the QAC for review.  The Principal Investigator, CRA and/or Study Coordinator 
present the following data for active patients: treatment issues, serious adverse events 
(SAEs) per FDA’s definition, dose levels, dose modifications, and responses as 
applicable. 
The QAC will reviews protocols to assure the following: 
 progress of the trial and safety of participants, 
 compliance with requirements regarding the reporting of severe adverse 
events, 
 that any action resulting in a temporary or permanent suspension of this NIH-
funded clinical trial is reported to the responsible NIH grant program director, 
and 

07-RAD-01, v. 1.5.2 (08-JUL-2013) 
19
 data accuracy and protocol compliance. 
The QAC, the Protocol Review Committee (PRC), the responsible disease-specific 
Clinical Care and Research Team (CCART) and/or the UK/VA IRB are empowered to 
immediately suspend accrual to any study under its purview for any of the following:  
 Failure to comply with AE/SAE reporting requirements, 
 poor study enrollment, 
 protocol violations, or   
 issues related to patient safety. 
 
10.0 Statistical Considerations 
10.1. Sample size justification : 
In this pilot protocol, it is anticipated that 37 patients will be enrolled to receive boost 
therapy.  This number of patients will provide a 10% level of precision (half-width of a 
90% confidence interval) for the true (unknown) proportion of subjects that will 
experience toxicity-limiting pneumonitis.  The investigators believe this proportion will 
be no greater than 20% and have used this number in the sample size justification based 
on the 90% confidence interval width. 
 
10.2 Stopping rules for severe pneumonitis:   
We anticipate that pneumonitis may be the most common radiation-related side effect, 
and patients will be closely monitored for development of severe pneumonitis in this 
study.  An historical rate of severe pneumonitis rate has been documented to be as high as 
15% but varies depending on the volume of lung being irradiated (12). Treatment of most 
stage III lung cancers carry risks in the 15% and higher range due to volumes of lung 
irradiated.  As such, the protocol will be stopped if sufficient evidence exists suggesting 
that, among patients receiving therapy, the true incidence of severe pneumonitis exceeds 
15%.   Sufficient evidence will be statistically defined in the form of an estimate for the 
severe pneumonitis rate (binomial proportion) whose lower 90% confidence limit 
exceeds 15%, and these estimates will be made after every 5th enrolled patient to the 
study.  Operationally, any of the following observed ratios (# experiencing severe 

07-RAD-01, v. 1.5.2 (08-JUL-2013) 
20
pneumonitis of total number observed) would lead to exceeding such a limit:  3 or more 
of the first 5; 4 or more of the first 10;  5 or more of the first 15; and 6 or more of the first 
20.  
If the true probability of severe pneumonitis incidence is 10%, the probability of stopping 
the study under these rules is less than 1% after enrollment of 5 patients on the study, 
<1.3% after enrollment of the first 10, and roughly <1% after enrollment of 20 patients 
on the study.  If the true probability is 20%, then the probability of stopping after 5, 10, 
and 20 patients is 6%, 12% and 19%, respectively.  If the true probability is 40%, the 
probability of stopping after 5, 10, and 20 patients is approximately 32%, 62%, and 88%, 
respectively.   
 
11. Reporting Toxicity  
11.0 All patients will be assessable for toxicity, and those with measurable disease will be 
assessable for response.  All grade 4 or grade 5 toxicities that are attributable to radiation 
therapy will be reported to the DSMB and Institutional Review Board within 24 hours of 
discovery. The boost therapy is given in a two to three day period, and definitions of 
acute vs. late effects are used as below. Monitoring of late effects of radiation therapy 
(most commonly pneumonitis) will continue for 6 months following completion of the 
boost therapy. 
11.1 Acute Radiation Toxicity Monitoring: Acute (≤ 90 days from RT start) side effects 
of radiation therapy will be documented using the NCI Common Toxicity Criteria version 
3.0. A copy of the CTCAE version 3.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  
11.2 Late Radiation Toxicity Monitoring: Late (> 90 days from RT start) side effects will 
be documented using the NCI Common Toxicity Criteria version 3.0. 
 11.3 Death from any cause while the patient is receiving protocol treatment and up to 30 
days after the last protocol treatment, will be reported directly to the DSMB and IRB  
 
12.0 Criteria for Study Withdrawal 
Patients will be removed from the study for the following:  
1. Noncompliance with protocol requirements.  

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2. Patient withdrawal of consent.  
 
13.0 References. 
 
1. 
Cancer Facts and Figure. American Cancer Society, Atlanta, Ga. 2006. 
2. 
Dillman RO, Herndon J, Seagren S et al. Improved survival in stage III 
non-small cell lung cancer: seven year follow-up of cancer and 
leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-15. 
1996. 
3. 
Arriagada R, LeChevalier T, Quoix E et al. ASTRO (American Society 
of Therapeutic Radiation Oncology) plenary: Effect of chemotherapy 
on locally advanced non-small cell lung carcinoma: a randomized study 
of 353 patients. Int J Radiat Oncol Biol Phys 1183-90. 1991  
4. 
Bradley, J. A review of radiation dose escalation trials for non-small 
cell lung cancer within the Radiation Therapy Oncology Group. Sem. 
Oncol. 32 (2 suppl 3): S111-3. 2005.  
5. 
Martel, M., Ten Haken, R., Hazuka, M., et al. Estimation of tumor 
control probability from 3-D dose distributions of non-small cell lung 
cancer patients. Lung Cancer. 24: 31-37. 1999 
6. 
Bradley, J.,  Graham, M.V. Winter, K., Purdy, J.A., Komaki, R,  Roa, 
W. H., Ryu, J K., Bosch, W., Emami, B. Toxicity and outcome results 
of RTOG 9311: a phase I-II dose-escalation study using three-
dimensional conformal radiotherapy in patients with inoperable non-
small-cell lung carcinoma. Int. J. Rad. Onc. Biol. Phys.  61(2):318-28. 
2005. 
7. 
Willner, J., Baier, K, Caragiani, E. et al.  Dose, Volume and Tumor 
Control Predictions in Primary Radiotherapy of Non-small Cell Lung 
Cancer. Int. J. Rad. Onc. Biol. Phys. 52: 382-389. 2002. 
8. 
Timmerman, R., Papiez, L., McGarry, R., Likes, L., DesRosiers, C., 
Bank, M., Frost, S., Randall, M., and Williams, M. Extracranial 
stereotactic radioablation: results of a phase I study in medically 

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inoperable stage I non-small cell lung cancer patients. Chest. 124: 
1946-1955. 2003. 
9. 
McGarry, R.C., Papiez, L., Williams, M., et. al. Int. J. Rad. Onc. Biol. 
Phys.  Stereotactic Body Radiation Therapy of Early Stage Non-small 
Cell Lung Carcinoma: Phase I Study. Int. J. Rad. Onc. Biol. Phys.63: 
1010-1015. 2005. 
10. 
Hiraoka, M., Nagata, Y. Stereotactic Body Radiation therapy for early-
stage non-small-cell lung cancer. Int. J Clin. Oncol. 9:352-355. 2004. 
11. 
Wulf, J., Baier,K., Mueller, G., Flentje, M.P. Dose-response in the 
stereotactic irradiation of lung tumors. Radiother. and Oncol. 77:83-87. 
2005. 
12. 
Graham MV, Purdy JA, Emami BE, et al. Clinical Dose Volume 
Histogram Analysis for pneumonitis after 3D treatmentfor non-small 
cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 45(2):323-
329. 1999.