Phase I Study of Accelerated Hypofractionated Image-Guided Radiation Therapy (IGRT) in Patients With Stage II-IV Non-Small Cell Lung Cancer and Poor Performance Status
Phase: NA
Conditions: Non-small Cell Lung Cancer
Sponsor: University of Texas Southwestern Medical Center

 
 
 
 
Study Title: 
 
Phase I Study of Accelerated Hypofractionated Image-Guided Radiation 
Therapy (IGRT) in Patients with Stage II-IV Non-Small Cell Lung Cancer and 
Poor Performance Status 
 
 
NCT03623334 
 
Version 6  
Date August 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase I Study of Accelerated Hypofractionated Image-Guided Radiation 
Therapy (IGRT) in Patients with Stage II-IV Non-Small Cell Lung Cancer and 
Poor Performance Status 
 
 
Organizing Institution: 
University of Texas Southwestern Medical Center, Dallas, TX 
 
Principal Investigator (P.I.): 
Robert Timmerman, M.D. 
 
 
 
 
 
 
 
Department of Radiation Oncology 
 
Co-Investigators: 
Hak Choy, M.D. 
 
Department of Radiation Oncology 
 
 
 
Margaret Edwards, M.D. 
 
Department of Radiation Oncology 
 
 
Thomas Boike, M.D. 
 
Department of Radiation Oncology 
 
 
Timothy Solberg, Ph.D. 
 
Department of Radiation Oncology 
 
Xian-Jin Xie, Ph.D.  
Biostatistics    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Billy Loo, M.D. 
 
 
 
 
 
 
 
Stanford University 
 
 
 
 
 
 
 
 
Gabriel Shapiro, M.D. 
 
 
 
 
 
 
 
Internal Medicine 
 
 
Protocol Version History 
Version 1 
April 13, 2009 
Version 2 
March 22, 2010 
Version 3 
April 30, 2010 
Version 3.1 
July 30, 2010 
Version 4 
October 21, 2010 
Version 5 
November 02, 2011 
Version 6 
August 6, 2014 

INDEX 
 
 
Schema 
 
 
Eligibility Checklist  
 
 
 
 
 
 
 
 
 1.0 
Introduction 
 
 
 
 
 
 
 
 
 
 2.0 
Objectives 
 
 
 
 
 
 
 
 
 
 3.0 
Patient Selection  
 
 
 
 
 
 
 
 
 4.0 
Pretreatment Evaluations/Management 
 
 
 
 
 
 5.0 
Registration Procedures 
 
 
 
 
 
 
 
 6.0 
Radiation Therapy  
 
 
 
 
 
 
 
 
 7.0 
Drug Therapy  
 
 
 
 
 
 
 
 
 8.0 
Other Therapy 
 
 
 
 
 
 
 
 
 9.0 
Companion Protocol Enrollment 
 
 
 
 
 
 
10.0 
Patient Assessments  
 
 
 
 
 
 
 
11.0 
Data Collection 
 
 
 
 
 
 
 
 
12.0 
Statistical Considerations 
 
 
 
 
 
 
 
13.0 
Data Safety Monitoring Plan   
 
 
 
 
 
 
 
References 
 
 
Appendix I     - Sample Treatment Consent Form 
 
Appendix II    - Study Parameters  
 
 
 
 
 
 
Appendix III   - Performance Status Scoring  
 
 
 
Appendix IV   - Staging System 
 
 
 
 
 
 
Appendix V    - Comorbidity Scoring Sheet and Charlson Comorbidity Index (CCI) 
 
 
 
  
 
 

Schema    
 
 
 
Number of patients  = between 7-45 (depending on tolerance) 
Patients in each dose cohort will all be treated as a single group for dose escalation.  The 
starting dose will be 3.33 Gy per fraction for 15 fractions (total dose = 50 Gy).  Subsequent 
cohorts of patients will receive a higher dose per fraction as follows: 
 
No. Fractions  
Dose per fraction (Gy) 
Total Dose (Gy) 
No. Patients 
 
15 
 
 
3.33 
 
 
 
50 
 
 
7-15 
 
15 
 
 
3.67 
 
 
 
55 
 
 
7-15 
 
15 
 
 
4.00 
 
 
 
60 
 
 
7-15 
 
 
  
Minimum waiting periods will be assigned between each dose cohort to observe toxicity.   
 
ELIGIBILITY (See Section 3.0 for details) 
- Stages II (not eligible for definitive surgical resection or stereotactic body radiation 
therapy,), III or IV non-small cell lung cancer that would benefit from local radiation therapy 
- Recurrent non-small cell lung cancer that would benefit from local radiation therapy   
- Zubrod performance status of 2 or greater, age > 18 
- No prior radiotherapy to the chest or neck that would result in overlap of radiation therapy 
fields 
- No chemotherapy within one week prior to study registration   
- Study-specific consent form signed 
 
 
 
 
Eligible patient 
 
Image-Guided 
Radiation Therapy 
(IGRT), 15 fractions in 3 
weeks 
 
Follow for toxicity, 
locoregional control 
and overall survival 

Eligibility Checklist 
 
____________(Y) 1. Does the patient have histologically or cytologically documented 
NSCLC? 
 
____________(Y) 2. Is TNM Stage II, III or IV or does the patient have recurrent disease?  
 
____________(N) 3. Is the patient eligible for definitive surgical resection or stereotactic 
body radiation therapy? 
 
____________(N) 4. Has the patient had prior radiotherapy to the chest or neck that would 
result in overlap of radiation therapy fields? 
 
____________(Y) 5.  Is the Zubrod performance status 2 or greater?  Or 
 
 
 
Has patient lost >10% of body weight in the past 6 months? Or 
Patient is not eligible for concurrent chemoradiation as determined by 
a Medical Oncologist and Radiation Oncologist 
 
____________(Y) 6.  Is patient ≥ 18 years of age? 
 
____________(N) 7.  Has the patient had any chemotherapy within a week prior to study 
registration? 
 
___(Y/Quit/Never) 8.  Does the patient smoke? 
 
____________(Y) 9. Were all the required pre-registration evaluations administered as 
specified in Section 3, including CT with contrast of lung and upper abdomen 
within 8 weeks of registration? 
 
________(Y/NA) 10. Has the patient agreed to use an effective method of contraception? 
 
___________(N) 11. If female, is the patient pregnant or lactating? 
 
___________(Y) 12.  Has the patient signed the protocol consent? 
 

1.0  Introduction 
1.1  Locally Advanced NSCLC and Radiation Therapy 
Lung cancer is the leading cause of cancer-related mortality in the United States each 
year with an estimated 215,000 new cases and over 160,000 deaths, [1].  The majority 
of these, approximately 80%, are non-small cell lung cancers (NSCLC).  Only 15-20% 
of these cases present with early or localized disease and the rest are more advanced, 
with large tumors, regionally involved lymph nodes, or distant metastatic disease [2]. 
 
Surgical resection is the mainstay of treatment for stage I and II NSCLC, often followed 
by adjuvant chemotherapy.  For stage III NSCLC, selected cases can be treated 
surgically, while for many patients, combined chemotherapy and radiation therapy is 
the best curative option.  If a NSCLC patient has co-morbid conditions or poor 
performance status, the treatment options are more limited.  Surgery may not be 
possible for curative treatment of early stage disease, and concurrent chemoradiation 
may not be tolerable as treatment of more advanced disease.  Conventionally 
fractionated radiation therapy alone as definitive treatment for locally advanced 
NSCLC has poor survival rates, with a median survival of only 10 months in an RTOG 
trial that established 60 Gy as the standard dose for a time [3].  Since then, there have 
been many efforts to increase the efficacy of radiation therapy for locally advanced 
lung cancer.  Clinical trials have suggested a benefit from dose escalation.  For 
example, A University of Michigan phase I study that included mainly stage III NSCLC, 
showed a 5 year overall survival improvement from 4% to 28% when dose was 
increased from 63-69 Gy to 92-103 Gy [4].  Also, a median survival of 24.7 months 
was achieved in 112 patients treated on four University of North Carolina phase I/II 
trials of high dose (60-90 Gy) radiation therapy in unresectable stage III NSCLC [5].  
However, local failure remains a significant problem even with high dose radiation 
therapy, with local failure rates of 22-50% in multiple studies [5, 6]. 
 
The best method found to date for improving the efficacy of radiation therapy for locally 
advanced NSCLC is to combine it with chemotherapy.  One of the early phase III trials 
showing a benefit to chemotherapy followed by radiation therapy was the CALGB 8433 
trial, which showed a median survival increase from 9.6 to 13.7 months with the 
addition of chemotherapy [7].  Since then, multiple trials of locally advanced NSCLC in 
good performance status patients have shown even better outcomes with concurrent 
chemotherapy and radiation therapy, rather than sequential [8-12].  A recent 
randomized phase III trial even achieved a median survival time of 21.7 months in 
inoperable stage III NSCLC [13].    
 
However, the better local control and survival achievable by adding chemotherapy to 
radiation therapy comes at the expense of increased toxicity.  Some of the most 
commonly used chemotherapy combinations in locally advanced NSCLC are 
cisplatin/etoposide and carboplatin/paclitaxel.  All of these agents are associated with 
myelosuppression, nausea, and vomiting and several are associated with neuropathy 
and nephrotoxicity.  When given with radiation therapy, these toxic effects can be 
worsened; also, the adverse effects commonly seen with radiation therapy to the 
chest, such as esophagitis, can be intensified.  The CALGB 8433 trial reported higher 
rates of serious adverse effects including neutropenic infections, vomiting, and severe 
weight loss in the group of patients receiving chemotherapy and radiation therapy [14].  
Toxicity with concurrent chemoradiation therapy can be even greater than with 
sequential.  RTOG 94-10 reported higher rates of acute grade 3-4 non-hematologic 
toxicity, including esophagitis, with concurrent compared to sequential chemoradiation 

therapy [9].  In a phase III trial by the CALGB and ECOG, patients receiving 
carboplatin with radiation therapy suffered more neutropenia, thrombopenia, and 
anemia than did patients receiving radiation therapy alone [15].  These adverse effects 
can decrease quality of life for patients and cause administration of combined modality 
therapy to be impractical in poor performance status patients.  This protocol will 
attempt to provide effective local control of NSCLC in the chest, while avoiding the 
toxicity and potentially decreased quality of life caused by adding concurrent 
chemotherapy.     
 
Progress in technology has changed the delivery of radiation therapy to allow more 
precise targeting of tumor and avoidance of normal structures.  3D conformal 
radiotherapy (3-DCRT) and intensity modulated radiation therapy (IMRT), based on 
computed tomography (CT) planning, are possible due to modern computer and 
software advances.  These treatment techniques have allowed reduction of treatment 
volumes and dose escalation of fractionated radiotherapy.  RTOG 9311 showed the 
feasibility of delivering up to 83.8 Gy at 2.15 Gy per fraction for stage I-III NSCLC [6].  
Recently, there has been increasing use of image-guided radiation therapy (IGRT), 
which involves frequent imaging to account for interfraction and sometimes 
intrafraction motion of the target and thus improves the accuracy of dose delivery.  
IGRT involves modalities such as daily ultrasound, kilvoltage (kV) imaging such as x-
rays or kV cone beam CT, or megavoltage (MV) imaging such as helical MV CT or MV 
cone beam CT.  Adaptive radiotherapy is the concept of using frequent imaging to alter 
treatment based on changes in the tumor or normal tissue during the course of 
treatment.  This can be important in treatment of NSCLC since tumors can shrink 
considerably during treatment, allowing greater avoidance of normal structures when 
the treatment plan is modified.  Kupelian et.al. reported an average decrease in the 
tumor volume of 1.2% per day in a study of 10 NSCLC patients [16].   Imaging can 
also be used to account for organ motion with respiration, which is crucial in treatment 
of lung tumors.  One method to manage respiratory motion is by limiting tumor motion, 
using techniques such as abdominal compression or breath holding.  The other 
method to account for respiratory motion is to allow free tumor motion but keep the 
target constantly in the beam’s eye view when the beam is on, using techniques such 
as beam tracking, couch-based motion compensation, or respiratory gating.   
 
All of these advances in treatment planning and delivery have allowed the 
development of stereotactic body radiation therapy (SBRT) as a promising treatment 
for early stage NSCLC.  This treatment method combines the previously mentioned 
techniques with stereotactic targeting to allow a dramatic reduction in treatment 
volumes, enabling delivery of hypofractionated, ablative doses of radiation therapy.  
SBRT can be safely used in patients with co-morbid conditions or poor performance 
status and can achieve local control rates as high as 95% at 2 years [17].  The 
technological advances making possible SBRT in early stage NSCLC could be 
transferred to treatment of locally advanced NSCLC as well, to allow a shorter overall 
treatment time without increasing toxicity.  Notably, the reported dose escalation trials 
for locally advanced NSCLC utilize 3-D conformal radiation therapy but do not include 
daily image guidance or methods for compensating for tumor motion with respiration.  
With these technological advances, it should be possible to further limit dose to normal 
tissue and thus treat lung tumors to a higher dose in fewer fractions of radiation 
therapy.  This protocol will address the management of stage II-IV NSCLC who are not 
candidates for surgical resection or stereotactic body radiation therapy as definitive 
treatment.    

 
The study is designed to determine whether daily image guidance and motion 
assessment/control will allow treatment of poor performance status patients with stage 
II-IV NSCLC, who would benefit from local therapy, with an accelerated course of 
hypofractionated radiation therapy.  Poor performance status patients can be a 
heterogeneous group, with tumor-related factors, other co-morbidities, or advanced 
age placing patients in the category.  These patients have traditionally been 
underrepresented in clinical trials, and no treatment method is standard.  One phase III 
trial of “poor-risk” locally advanced NSCLC (RTOG 93-04) included just over 40% 
Karnofsky performance status 60-70 patients and showed median survival times of 9.5 
and 10.3 months with 60 Gy of conventional radiation therapy alone or with 
recombinant β-interferon [18].   
 
1.2  Rationale for Radiation Therapy Dose 
A dose of 45 Gy in 15 fractions (3 Gy per fraction), often with a one week break, has 
been commonly employed in the past to treat poor performance status NSCLC 
patients.  A pilot study of accelerated radiation therapy with concurrent 
carboplatin/paclitaxel for stage III NSCLC was closed after enrollment of only 5 
patients due to excessive toxicity.  The radiation therapy dose used was 60 Gy in 4 
weeks of daily treatment, using a concomitant boost [19].  Our protocol is different in 
that it will not permit concurrent chemotherapy, it will not allow treatment of elective 
nodal regions as was done in that trial, and it will use daily image guidance so that 
treatment volumes will be significantly smaller.  In a small study of 14 patients, 
Tsoutsou et.al. showed the feasibility of treating with 3.5 Gy daily for 15 fractions (52.5 
Gy total) with a one week break after the 10th fraction, along with concurrent 
chemotherapy, in locally advanced non-small cell lung cancer PS 0-2 patients [20].  
Slotman et.al. treated 301 stage III NSCLC patients with three different 
hypofractionated radiation therapy regimens of 40 Gy in 8-10 fractions with a one week 
break, 30-32 Gy in 6 fractions or 24 Gy in 3 fractions.  These regimens were all well 
tolerated [21]. 
 
The starting dose for this trial will be 3.33 Gy for 15 fractions to a total dose of 50 Gy 
which is higher than the commonly employed 3.0 Gy for 15 fractions yet predicted to 
be tolerated given the smaller volumes of irradiation with image guidance.  If tolerated, 
the dose will be escalated while keeping the fraction number at 15.  Doses of 3.67 Gy 
per fraction for a total of 55 Gy and then 4 Gy per fraction for a total dose of 60 Gy will 
be tested.  Critical structure dose constraints will be expressed as organ dose-volume 
limits, with limits formulated with the approval of the study investigators using known 
tolerance data, radiobiological conversion models, and norms used in current practice 
at academic centers [22]. 
 
2.0  Objectives 
 
2.1  Primary Objective 
 
2.1.1 To escalate the dose of accelerated, hypofractionated, image-guided conformal 
radiotherapy to a potent tumorcidal dose without exceeding the maximum 
tolerated dose in treatment of stage II-IV NSCLC in patients with poor 
performance status.  The maximum tolerated dose will be defined using the 
following criteria: 
 

 
For determination of appropriate dose escalation, the protocol is designed to 
capture rates of treatment-related (definitely and probably, but not possibly 
related to treatment*) grade 3 adverse events (per CTCAE, v.3.0, with the 
exception of pulmonary function tests as noted in Section 6.9.4) related to the 
following specific symptoms, including:  
 
 Gastrointestinal: dysphagia, esophagitis, esophageal 
stricture/stenosis, esophageal ulceration; 
 Cardiac: pericarditis, pericardial effusion, restrictive cardiomyopathy, 
ventricular dysfunction (left ventricular diastolic dysfunction, left 
ventricular systolic dysfunction, right ventricular dysfunction); 
 Neurologic: myelitis, neuropathy (cranial and motor); 
 Hemorrhage: pulmonary or upper respiratory; 
 Pulmonary: decline in pulmonary function as measured by pulmonary 
function tests (DLCO,and FEV1,) using the modified criteria in relation 
to baseline (see section 6.9.4), pneumonitis, pulmonary fibrosis, 
hypoxia, pleural effusion, cough, and dyspnea   
 Any grade 4 or 5 adverse event attributed to the therapy (definitely 
and probably, but not possibly related to treatment) 
 
*Patients enrolled on this study are highly likely to have associated tobacco 
related cardiopulmonary co-morbidities that would result in adverse events 
(e.g., hospitalizations) irrespective of any cancer treatment.  In published 
trials referenced in the introduction, adverse event analysis was 
confounded by problems distinguishing whether adverse events were 
treatment related versus part of the natural history of co-existing co-
morbidities.  As such, in this protocol only adverse events deemed probably 
and definitely related to treatment are considered for formal adverse event 
assessment.  Adverse events deemed possibly related will be collected and 
reviewed but not used in adverse event analysis (e.g., for defining the 
maximum tolerated dose).  
 
 
 
2.2  Secondary Objectives   
 
2.2.1    To evaluate local regional tumor control and overall survival in patients with 
stage II-IV NSCLC and poor performance status treated with accelerated, 
hypofractionated, image-guided conformal radiotherapy. 
 
3.0  Patient Selection 
 
         3.1 Conditions for patient eligibility 
 
3.1.1   All patients must be willing and capable to provide informed consent to 
participate in the protocol. 
 
      3.1.2   Patients must have appropriate staging studies identifying them as AJCC     
stage II, III or IV non small cell lung cancer, [according to AJCC Staging, 6th 
edition; see appendix III], or recurrent non small cell lung cancer.  Histologic 
confirmation of cancer will be required by biopsy or cytology. 
 

3.1.3 Patients must have the potential for benefit from local therapy (at the discretion 
of the investigator). 
 
3.1.4 Patient must have a Zubrod performance status of 2 or greater  
 
 
 
Or  
 
 
  Patient must have had >10% weight loss in the past 6 months 
 
 
 
 Or 
 
 
 
Patient is not eligible for concurrent chemoradiation as determined by a 
Medical Oncologist and Radiation Oncologist 
 
3.1.5   Age ≥ 18. 
 
3.1.6   The tumor must be ineligible for definitive surgical resection. 
 
3.1.7   The tumor must be ineligible for stereotactic body radiation therapy. 
 
3.1.8   Patients must have measurable or evaluable disease.    
 
3.1.9   Women of childbearing potential and male participants must agree to use an 
effective method of contraception. 
 
3.1.10 Patients must sign study specific informed consent prior to study entry. 
 
3.1.11  Patients must complete all required pretreatment evaluations (section 4.0) 
 
3.2 Conditions for patient ineligibility 
 
3.2.1  Evidence of small cell histology. 
 
3.2.2  Tumor eligible for definitive surgical resection. 
 
3.2.3  Tumor eligible for definitive stereotactic body radiation therapy.   
 
3.2.4  Prior radiotherapy to the region of the study cancer that would result in overlap 
of radiation therapy fields. 
 
3.2.5  Chemotherapy given within one week of study registration. 
 
3.2.6  Pregnant or lactating women, as treatment involves unforeseeable risks to the 
embryo or fetus. 
 
4.0  Pretreatment Evaluations and Management 
 
4.1  Required Evaluation and Management 
        See Section Appendix II; note that failure to perform one or more of these tests may 
result in assessment of a protocol violation.   
 

4.1.1  The following tests must be done within 8 weeks of enrollment: 
 
4.1.1.1  Computed tomographic (CT) with contrast of the lung and upper abdomen.  A 
CT done in conjunction with a Positron Emission Tomography (PET) scan is 
satisfactory as long as the images are of adequate quality to be interpreted by 
a radiologist. 
 
4.1.1.2  An MRI of the brain with contrast (or CT if MRI is medically contraindicated). 
 
4.1.1.3  Complete Blood Count (CBC) with differential 
 
4.1.2  Pulmonary function tests including spirometry for forced expiratory volume in 1    
second (FEV-1), diffusing capacity (DLCO), and arterial blood gas (PaO-2) 
should be performed within 12 weeks of enrollment. 
 
4.1.3  The following test must be done within 3 days prior to radiotherapy: 
Urine or serum pregnancy test in females of child-bearing capacity. 
 
4.1.4  The following test must be done prior to enrollment on the study: 
Tissue biopsy or cytology confirming non-small cell lung cancer.   
 
         4.1.5  Charleston Comorbidity Index must be completed within 8 weeks of enrollment         
 
 
   4.2  Recommended Evaluations and Management 
 
FDG-PET evaluations are not required for study entry, but are generally 
recommended for staging purposes. 
 
5.0  Registration Procedures 
 
5.1  Pre-Registration 
 
5.1.1   Preregistration Requirements for diagnostic pathology review: 
There are no requirements for central review of pathology used for initial 
diagnosis. 
 
5.1.2   Pre-Registration Requirements for IGRT Treatment Approach: 
In order to utilize IGRT in this protocol, the institution must have met 
technology requirements and have provided a description of techniques, 
methods, training, and experience showing competency to the study PIs. 
 
5.2 Registration 
Prior to registration, participating investigators and institutions should review the 
eligibility checklist and confirm eligibility. Patients can be registered only after 
eligibility criteria are met.  To register a patient, the site should fax the Enrollment 
Form to the Project Manager (fax #: 214-648-5923).  A unique, participant ID 
number will then be assigned. 
 
5.3  Accreditation 
Institutional Processes: 

Prior to treating patients on protocol, the institution’s specific methods for targeting, 
dose construction, daily imaging for verification of accuracy, ongoing assessment 
of accuracy and Quality Assurance policies must be described to and approved by 
the study PI and other approved institutional PIs.  The primary purpose of 
accreditation will be to insure that dose is delivered to the targets and avoiding 
normal tissues according to protocol criteria.  This accreditation may be assessed 
by written documentation, conference calls, or direct observation via site visits.  
Additional data may be required of institutions to verify that techniques are 
performing as intended. 
 
6.0  Radiation Therapy 
6.1  Dose Specifications 
Protocol treatment must begin within 4 weeks after patient registration to the trial. 
 
6.1.1 Image Guided Radiation Therapy 
Image-guided radiation therapy (IGRT) is a process of using various imaging 
technologies to locate a tumor target prior to each treatment with radiation 
therapy. The purpose of this process is to improve the treatment accuracy and 
eliminate the need for large target margins which have traditionally been used to 
compensate for errors in localization.  As a result, the amount of healthy tissue 
exposed to radiation can be reduced, minimizing the incidence of side effects.  
An example of three-dimensional (3D) IGRT is localization of a cone-beam 
computed tomography (CBCT) dataset with the planning computed tomography 
(CT) dataset from planning.  Example of two-dimensional (2D) IGRT includes 
matching planar kilovoltage (kV) radiographs or fluoroscopy with digital 
reconstructed radiographs (DRRs) from the planning CT. 
 
6.1.2  Adaptive Radiation Therapy 
With daily imaging, the change in tumor size during the course of treatment can 
be easily monitored.  At physician discretion, the treatment plan can be modified 
if enough response is attained to meaningfully reduce dose to normal tissue.  All 
patients should have GTV, lung, esophagus and heart contoured on a scan at 
day 10 of treatment for assessment of possible normal tissue sparing with plan 
revision. 
 
6.1.3  Dose Fractionation 
Patients will receive 15 fractions of radiation.  Total dose will depend on the dose 
cohort of the study (see schema).  The starting dose level will be 3.33 Gy per 
fraction for 15 fractions (total dose = 50 Gy). 
 
6.1.4 Normalization of the treatment plan will cover 95% of the PTV with the 
prescription dose. The minimum PTV dose must not fall below 90% of the 
prescription dose. All radiation doses will be calculated with tissue density 
(heterogeneity) corrections that take into account the density differences within 
the irradiated volume (i.e., air in the lung and bone).  The following heterogeneity 
correction algorithms are not allowed because of known deficiencies:  pencil 
beam and Clarkson’s method. 
 
6.1.5 Variations of dose prescription:  
6.1.5.1   No deviation: 95% of the PTV receives the prescribed dose, ≥ 99% of the 
PTV receives ≥ 90% of the prescribed dose, and a contiguous volume of no 

more than 2 cc anywhere within the patient receives ≥ 110% of the 
prescribed dose. 
 
6.1.5.2   Minor deviation: Deviations of this magnitude are not desirable, but are 
acceptable.  95% of the PTV receives < 100% but ≥ 97% of the prescribed 
dose, ≥ 99% of the PTV receives < 90% but ≥ 87% of the prescribed dose, or 
a contiguous volume of no more than 2cc anywhere within the patient 
receives between 110-115% of the prescribed dose. 
 
6.1.5.3   Major deviation: Doses in this region are not acceptable. 95% of the PTV 
receives < 97% of the prescribed dose,  ≥ 99% of the PTV receives < 87% of 
the prescribed dose, or a contiguous volume of > 2cc anywhere within the 
patient receives ≥ 115% of the prescribed dose. 
 
6.2  Technical Factors 
 
6.2.1 Physical Factors 
Only photon (x-ray) beams produced by linear accelerators, betatrons, or 
microtron accelerators with photon energies 6-21 MV will be allowed.  Cobalt-60 
and charged particle beams (including electrons, protons, and heavier ions) are 
not allowed. 
 
6.2.2 Beam Shaping: Multi-leaf collimation (MLC) or individually-shaped custom blocks 
should be used to protect normal tissues outside of the target volume. 
 
6.3  Localization, Simulation, and Immobilization 
6.3.1  Patient Positioning 
Patients will be positioned supine 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. 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 6.4 with any significant 
probability (i.e., < 5%). 
 
6.3.2  A volumetric treatment planning CT study will be required to define gross tumor 
volume (GTV), clinical target volume (CTV), internal target volume (ITV), and 
planning target volume (PTV) (see definitions below). Each patient will be 
positioned in an immobilization device in the treatment position on a flat table. 
Contiguous CT slices, having 3 mm or less thickness through the regions 
harboring gross tumor and grossly enlarged lymph nodes, and 8-10 mm or less 
thickness of the remaining regions are to be obtained starting from the level of 
the cricoid cartilage and extending inferiorly through the entire lung volume. The 
GTV, PTV and normal organs will be outlined on all appropriate CT slices. 
 
6.3.3  Inhibition of Effects of Internal Organ Motion 
Special considerations must be made to account for the effect of internal organ 
motion (e.g., breathing) on target positioning and reproducibility. Acceptable 
maneuvers include reliable abdominal compression, accelerator beam gating 
with the respiratory cycle, tumor tracking, and active breath-holding techniques. 

All systems used to account for internal organ motion must be validated and 
accredited by the Study Committee (Principal Investigator and Co-Chairs) before 
enrolling or treating patients on this trial. Internal organ inhibition maneuvers 
must be reliable enough to insure that the GTV does not deviate beyond the 
confines of the PTV as defined in Section 6.4 with any significant probability (i.e., 
< 5%). 
 
6.3.4  Intravenous (i.v.) contrast during the planning CT is optional provided a 
diagnostic chest CT was done with contrast to delineate the major blood vessels. 
If not, i.v. contrast should be given during the planning CT if the patient can 
tolerate it.  
 
6.3.5  A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in 
the treatment position is encouraged for treatment planning. In the case where 
the PET/CT is obtained in the treatment position, the CT from this study may be 
used as the planning CT scan. 
 
6.3.6  Localization 
Isocenter or reference point port localization films should be obtained at each 
treatment on the treatment unit (or patients should undergo a tomographic 
imaging study using the linear accelerator couch, if available) immediately before 
treatment to ensure proper alignment of the geometric center (i.e., isocenter) of 
the simulated fields. Verification CT scans and portal films may be taken but are 
not required for protocol participation.  
 
6.4  Treatment Planning/Target Volumes 
6.4.1 Definition of the GTV/CTV/ITV 
The primary tumor and clinically positive lymph nodes seen either on the 
planning CT (> 1 cm short axis diameter) or pretreatment PET scan (SUV > 3) 
will constitute the GTV. This volume(s) may be disjointed. In the event of a 
collapsed lobe or lung segment, the use of PET to distinguish tumor from 
fluid/atelectasis is encouraged. The GTV should be expanded into a Clinical 
Target Volume (CTV) by adding a minimum of 5 mm and a maximum of 10 mm 
in any direction (at the discretion of the treating physician).  Elective treatment 
of nodal areas is not allowed. The ITV (if a 4D CT scan is done for planning) 
includes the envelope that encompasses the tumor motion for a complete 
respiratory cycle.  The motion quantified from the 4-D scan or real time 
fluoroscopy will be added to the CTV to constitute the ITV.  If the motion is 
greater than 10-15 mm in any direction, special maneuvers such as abdominal 
compression, gating, chasing or regimented breath hold should be used to 
reduce the final motion below 10-15 mm.  If it is observed that the tumor has no 
motion, then the CTV would be identical to the ITV. 
 
6.4.2  Definition of the PTV: 
Internal organ inhibition maneuvers, such as breath-hold, gating or abdominal 
compression, must be reliable enough to insure that the GTV does not deviate 
beyond the confines of the PTV with any significant probability (i.e., < 5%).  The 
PTV is defined as the ITV with additional margin for setup uncertainties and may 
be individualized but should not be less than 0.5 cm or greater than 1.0. Daily 
imaging is used to reposition the patient to minimize setup errors. 
 

6.5  Critical Structures   
6.5.1  Critical Organ Dose-Volume Limits 
The following table lists maximum dose limits to a point or volume within several 
critical organs. These are absolute limits, and treatment delivery that exceeds these 
limits will constitute a protocol violation (See Section 6.7). The dose is listed as for a 
total of 15 fractions. 
 
Participating centers are encouraged to observe prudent treatment planning principles 
in avoiding unnecessary radiation exposure to critical normal structures irrespective of 
these limits. 
 
In order to verify each of these limits, the organs must be contoured such that 
appropriate dose volume histograms can be generated. Instruction for the contouring 
of these organs will follow in section 6.5.2. 
 
Dose volume limits for 15 fraction XRT:  
 
Serial Tissue 
Volume (cc) 
Volume Max 
(Gy) 
Max Point 
Dose (Gy)* 
Endpoint (≥Grade 3) 
Spinal cord 
<5 cc 
39 Gy 
42.3 Gy 
myelitis 
Esophagus 
<5 cc 
51.3 Gy 
55.3 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
44.5 Gy 
50.6 Gy 
neuropathy 
Heart/Pericardium <15cc 
39.5 Gy  
48.9 Gy 
pericarditis 
Great Vessels 
<10 cc 
48.9 Gy 
54.3 Gy 
aneurysm 
Trachea and 
Large Bronchus 
<5 cc 
39.5 Gy 
45.6 Gy 
stenosis/fistula 
Rib 
<5 cc 
48.9 Gy 
52.2 Gy 
pain or fracture 
Skin 
<10 cc 
49 Gy 
55.4 Gy 
ulceration 
Parallel Tissue 
Critical 
Volume (cc) 
Critical 
Volume Dose 
Max (Gy) 
Other 
Constraints 
Endpoint (≥Grade 3) 
Lung (Right and 
Left minus GTV) 
1500 cc 
1000 cc 
15.5 Gy 
16.3 Gy 
Mean dose  
<18 Gy, 
V-18 <37% 
Basic Lung Function 
Pneumonitis 
 
* A maximum point dose is defined as the highest dose to 0.035 cc of tissue within the 
critical structure. 
 
6.5.2  Contouring of normal tissue structures 
6.5.2.1 Spinal Cord 
The spinal cord will be contoured based on the bony limits of the spinal canal, 
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.   
 
6.5.2.2 Lung (Right & Left) minus GTV 
Contour right and left lung as one structure including all parenchymal lung 
tissue but excluding the GTV and major airways (trachea and main/lobar 
bronchi). 
 
6.5.2.3 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. 
 
6.5.2.4 Brachial Plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting 
the neuroforamina on the involved side from around C5 to T2. However, for the 
purposes of this protocol, only the major trunks of the brachial plexus will be 
contoured using the subclavian and axillary vessels as a surrogate for 
identifying the location of the brachial plexus. This neurovascular complex will 
be contoured starting proximally at the bifurcation of the brachiocephalic trunk 
into the jugular/subclavian veins (or carotid/subclavian arteries) and following 
along the route of the subclavian vein to the axillary vein ending after the 
neurovascular structures cross the second rib. 
 
6.5.2.5 Heart/Pericardium 
The heart, along with the pericardial sac, should be contoured from its base to 
apex, beginning superiorly at the level of the inferior aspect of the aortic arch 
(aorto-pulmonary window) and extending inferiorly to the apex of the heart. 
 
6.5.2.6 Great Vessels 
Contour the wall and lumen of the named vessel at least 10 cm superior and 
inferior to PTV.  
 
6.5.2.7 Trachea and Large Bronchus 
Contour the trachea and cartilage rings starting 10 cm superior to the PTV 
extending inferiorly to the bronchi ending at the first bifurcation of the named 
lobar bronchus. 
 
6.5.2.8 Rib 
Contour each rib separately within 5 cm of the PTV in any direction. 
 
6.5.2.9 Skin 
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a 
rind of uniform thickness (0.5 cm) which envelopes the entire body in the axial 
planes. The cranial and caudal surface of the superior and inferior limits of the 
planning CT should not be contoured as skin unless skin is actually present in 
these locations (e.g., the scalp on the top of the head. 
 
6.6  Documentation Requirements 
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. 
 
6.7  Compliance Criteria 
 
Planning Priorities: 
1) Critical normal structure constraints (see sections 6.5): The spinal cord, brachial 
plexus, heart, and lung are considered critical normal structures and constraints on 

these structures will be prioritized.  Exceeding these limits for these structures by 
more than 5% in any circumstance constitutes a minor protocol violation.  
Exceeding these limits by more than 10% constitutes a major protocol violation.  It 
is understood that other normal structures dose limits would be exceeded in some 
patients because of their corresponding tumor distribution and meeting target 
coverage requirements.   In general, when targets are within 1 cm of normal 
structures, attempts must be made to avoid exceeding constraints on these 
structures especially sparing of the contralateral wall to avoid circumferential 
radiation.  Normal structures > 1 cm away from the target are subject to the above 
protocol violation description. 
2)   Variations of dose prescription:  
 
 
No deviation: 95% of the PTV receives the prescribed dose, ≥ 99% of the PTV 
receives ≥ 90% of the prescribed dose, and a contiguous volume of no more than 
2 cc anywhere within the patient receives ≥ 110% of the prescribed dose. 
 
 
Minor deviation: Deviations of this magnitude are not desirable, but are 
acceptable.  95% of the PTV receives < 100% but ≥ 97% of the prescribed dose, 
≥ 99% of the PTV receives < 90% but ≥ 87% of the prescribed dose, or a 
contiguous volume of no more than 2cc anywhere within the patient receives 
between 110-115% of the prescribed dose. 
 
Major deviation: Doses in this region are not acceptable. 95% of the PTV receives 
< 97% of the prescribed dose, ≥ 99% of the PTV receives < 87% of the prescribed 
dose, or a contiguous volume of > 2cc anywhere within the patient receives ≥ 
115% of the prescribed dose. 
 
6.8  Radiation Quality Assurance Reviews 
Dr. Timmerman, along with a medical physicist, will perform an RT Quality 
Assurance Review after complete data for the first 20 cases enrolled has been 
received at the University of Texas Southwestern. They will perform the next 
review after complete data for the next and subsequent 20 cases enrolled has 
been received at the University of Texas Southwestern. The final cases will be 
reviewed within 3 months after this study has reached the target accrual or as soon 
as complete data for all cases enrolled has been received, whichever occurs first. 
 
6.9  Radiation Adverse Events 
Adverse Events will be categorized and graded based primarily on the Common 
Toxicity Criteria for adverse events Version 3.0 (CTCAE version 3.0) with the 
exception of changes in pulmonary function tests (see section 6.9.4 below). 
 
Radiotherapy should be interrupted for Grade 4 in-field toxicity and resumed when that 
toxicity has decreased to Grade ≤ 2 as detailed below. If treatment is interrupted for > 
two weeks, the patient should be removed from study treatment. 
 
6.9.1 Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy. Radiation induced 
myocarditis or transverse myelitis rarely occur at doses lower than 50 Gy. 
Radiographic evidence of radiation change and subsequent fibrosis of the lung will 
occur within lung volume receiving ≥20 Gy, usually within the first six months after 

initiation of treatment. It is essential to spare as much normal lung as possible in 
order to avoid symptomatic lung injury. 
 
6.9.2 Esophagitis 
Esophageal complaints are common with thoracic radiation therapy. Esophagitis 
does not constitute a reason to interrupt or delay radiotherapy provided oral intake 
is sufficient to maintain hydration. Patients should be advised to avoid alcoholic, 
acidic, or spicy foods or beverages. Viscous Xylocaine, Carafate, or other 
medications should be used for symptomatic relief. Occasionally, narcotics may be 
required.  
It is not necessary to biopsy acute esophagitis in the first 2 weeks of therapy since 
it is rarely due to underlying viral or fungal disease.  Acute esophagitis may persist 
for 4-6 weeks.  If Grade 3 or 4 esophagitis occurs, and a treatment interruption is 
being considered, every effort should be made to limit it to 3 treatment days or 
less. Patients requiring hospitalization because of esophagitis may have their 
treatment interrupted. In this event, please notify Dr. Timmerman. 
 
Esophagitis should be graded according to the CTCAE v.3.0 
 
Table 4. Esophagitis grading system 
Grade 
Clinical Scenario 
1 
Asymptomatic pathologic, radiographic, or endoscopic findings only 
2 
Symptomatic; altered eating/swallowing (e.g., altered dietary habits, oral 
supplements), IV fluids indicated <24 hrs 
3 
Symptomatic and severely altered eating/swallowing (e.g., inadequate oral 
caloric or fluid intake), IV fluids, tube feedings, or TPN indicated >24 hrs 
4 
Life-threatening consequences 
5 
Death 
 
Treatment should be interrupted for grade 4 or greater dysphagia or odynophagia. 
Acute esophageal toxicity, which typically can occur within two weeks of the 
initiation of treatment and manifests as dysphagia, odynophagia, reflux symptoms, 
etc. should be pharmacologically managed with the following approach and should 
be initiated at the first signs or symptoms of esophageal toxicity. Recommended 
treatments are as follows: 
 
1)  Ketoconazole 200 mg PO q day OR Fluconazole 100 mg PO q day until the 
completion of radiation. 
2)  Mixture of: 2% viscous lidocaine: 60 cc, Mylanta: 30 cc, sucralfate (1 gm/cc): 10 
cc;  Take 15-30 cc PO q3-4 hrs prn.  (Contraindications: pts on Dilantin, Cipro, 
Digoxin) 
3) Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such 
as omeprazole) until the completion of radiation 
4) Grade 4 esophagitis: hold XRT until grade 2 or less. We expect a significant 
portion of patients will experience grade 3 esophagitis. 
 
6.9.3 Pneumonitis 
Radiation pneumonitis is a subacute (weeks to months from treatment) 
inflammation of the end bronchioles and alveoli. Note: It is very important that a 
Radiation Oncologist participate in the care of the patient, as the clinical picture 

may be very similar to acute bacterial pneumonia, with fatigue, fever, shortness 
of breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. 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 nonsteroidal 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 before completing therapy, therapy will be put on hold until 
symptoms resolve. At that point, a clinical decision whether to finish therapy will 
be made in conjunction with the treating physician in conjunction with Dr. 
Timmerman, study Principal Investigator. When symptomatic pneumonitis 
resolves to grade 0, CTCAE, v. 3.0, the treating physician will contact Dr. 
Timmerman for a decision to continue or terminate protocol therapy. 
 
6.9.4 Changes in Pulmonary Function Tests 
Patients enrolled to this study are allowed to have some degree of impaired 
pulmonary function as measured by pulmonary function tests (PFTs), including 
Forced Expiratory Volume in 1 second (FEV1), and Diffusing Capacity for Carbon 
Monoxide (DLCO).  The Common Toxicity Criteria (CTCAE), v. 3.0 includes 
specified criteria for grading adverse events related to these PFT parameters 
under the category of pulmonary/upper respiratory.  The grading criteria for these 
PFT changes use the “percent predicted” values from 0-100% which are 
recorded on the patient’s PFT report.  A percent predicted of 90% conveys that 
the patient is able to perform the PFT test to a result that is 90% of what would 
be expected for the normal general population of the same height, age, and sex.  
The CTCAE version 3 specified grading criteria for PFTs assumes that all 
patients have normal baseline pulmonary function.  This assumption is not 
appropriate for this protocol enrolling patients with abnormal baseline function. 
 
As a remedy to monitor treatment effects on PFTs, we will define a protocol 
specific toxicity classification for PFTs that adjusts for baseline abnormalities.  
Changes that occur after therapy will be referenced to the baseline for a given 
patient, which will be abnormal for most patients.  We have defined a 
proportional decline from the baseline.  Grade 1 toxicity will be a decline from 
baseline to a level 0.90 times the baseline, grade 2 will be a decline to a level 
0.75 of baseline, grade 3 will be a decline to a level 0.5 of baseline, grade 4 will 
be a decline to a level 0.25 of baseline, and grade 5 will be death.  This scheme 
is depicted in the table below and graphically represented in the following figure . 
 
As an example, a patient who enters the study with a percent predicted DLCO of 
55% who experiences a post treatment decline to a percent predicted DLCO of 
40% would have a grade 3 event in the original CTCAE version 3 criteria; 
however, under this modified PFT toxicity classification for patients with abnormal 

baseline, his decline would constitute a decrease to 0.72 of the baseline value 
which is between 0.75 and 0.5 or a grade 2 event. 
 
 
 
The SBRT Pulmonary Toxicity Scale  
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
FEV-1 Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
Forced Vital 
Capacity 
Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
DLCO Decline 
0.90-0.75 
times the 
patient’s 
baseline 
value 
 
<0.75-0.50 
times the 
patient’s 
baseline 
value 
<0.50-0.25 
times the 
patient’s 
baseline 
value 
<0.25 times 
the patient’s 
baseline 
value 
Death 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.10  Serious Adverse Event Reporting 
Electronic Research Grant Organizer (ERGO) constitutes a mechanism for 
reporting serious adverse events to the UTSW IRB for reporting purposes.   
 
Any adverse event equivalent to CTCAE V.3 grade 3, 4, or 5 or which precipitates 
hospitalization or prolongs an existing hospitalization must be reported regardless 
of designation (expected or unexpected) along with the attribution. This includes all 
deaths that occur within 30 days after the patient was discontinued from the study 
regardless of attribution AND any events that occur beyond 30 days and are 
considered probably related to treatment. 
 
Participating sub-sites must file an SAE report (the CRF plus information 
describing the event, the grade, and the attribution) within 48 hours of the 
investigator’s awareness of the occurrence of the event.  
 
Attribution of an event can be categorized as:  
• 
Not Related 
• 
Possibly Related 
• 
Probably Related 
 
• 
Definitely Related 
 
Adverse events (below grade 3) do not need to be submitted immediately.  Rather, 
they should be documented in the Adverse Events CRF along with a brief 
description of the event, grade, and attribution). 
 
All SAE reports should be made via FAX transmission to: 
 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention:  Jean Wu, Project Manager 
FAX #: 214-648-5923 
PFT(FEV-1, FVC, DLCO) Decline 
0
25
50
75
100
Percent Predicted
Baseline
Grade 1
Grade 2
Grade 3
Grade 4

 
7.0  Drug Therapy 
Not applicable to this trial. 
 
8.0  Other Therapy 
Patients must not receive other concomitant antineoplastic therapy (including standard 
fractionated radiotherapy to the chest, chemotherapy, biological therapy, vaccine 
therapy, and surgery) within a week prior to, during, or within one week after 
completing hypofractionated image-guided radiation therapy on protocol. 
 
8.1  Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. 
 
8.1.1  Antiemetics 
8.1.2  Anticoagulants 
8.1.3  Antidiarrheals 
8.1.4  Analgesics 
8.1.5  Hematopoietic Growth Factors 
8.1.6  Herbal products 
8.1.7  Nutritional supplementation 
 
9.0  Companion Protocol Enrollment 
Not applicable to this study. 
 
10.0  Patient Assessments 
10.1 Study Parameters: Please see Appendix II for the patient assessment schedule. 
Patients will be followed until death.  
 
10.2  Criteria for Toxicity 
All acute and late adverse events from protocol radiation therapy will be reported and 
scored for severity using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0. A copy of the CTCAE v3.0 can be downloaded from the CTEP 
home page (http://ctep.info.nih.gov). 
 
Please note that this study will not be using separate toxicity scales for acute and late 
radiation adverse events. 
 
10.3  Response Assessment (RECIST Criteria) 
Response will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3): 
205-216, 2000]. See 
http://ctep.cancer.gov/protocolDevelopment/docs/therasserecistjnci.pdf for further 
details. 
 
Response Criteria: Evaluation of target lesions 
*Complete Response (CR):    Disappearance of all target lesions 
*Partial Response (PR):          At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 

*Progressive Disease (PD):    At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance 
of one or more new lesions 
*Stable Disease (SD):             Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum LD since the treatment started 
 
10.4  Target lesion assessment guidelines 
The longest diameter (LD) for the target lesion (or lesions) will be calculated from the 
treatment planning CT scan using pulmonary and/or mediastinal windowing and 
reported as the baseline LD. The baseline LD will be used as a reference by which to 
characterize the objective tumor. 
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 in which it is indeterminate whether consolidation represents residual 
tumor or treatment effect, it should be assumed that abnormalities are residual tumor. 
 
10.4  Criteria for Removal from Protocol Treatment 
All reasons for discontinuation of treatment must be documented. All patients will be 
followed until death or 5 years post treatment (whichever time point comes first).  If 
protocol treatment is discontinued for any reason other death, follow up and data 
collection will continue as specified in the protocol. 
 
10.4.1  Unacceptable toxicity. 
10.4.2  A greater than two week delay in protocol treatment, as specified in Sections 
6.0. 
10.4.3  Development of intercurrent, non–cancer-related illnesses that prevent either 
continuation of therapy or regular follow-up.   
 
10.5  Other response parameters 
10.5.1  Time to Local Progression: The time to progression will be measured from the 
date of study entry to the date of documented local progression as determined 
by clinical exam. 
 
10.5.2  Overall Survival: The survival time will be measured from the date of accession 
to the date of death. All patients will be followed for survival. Every effort should 
be made to document the cause of death. 
 
10.5.3  Disease-Specific Survival :  Disease-specific survival will be measured from the 
date of study entry to the date of death due to lung cancer. The following will be 
considered as failure events in assessing disease specific survival: 
Death certified as due to lung cancer. 
Death from other causes with active malignancy (clinical progression). 
Death due to complications of treatment, irrespective of the status of 
malignancy. 
Death from other causes with previously documented relapse but inactive at 
the time of death will not be considered in disease-specific survival, but will be 
analyzed separately. 
 

10.6  Comorbidity Data and Rating 
The Charlson Comorbidity index will be used to assess pretreatment comorbidity 
status per Appendix V. 
 
11.0  Data Collection 
Data should be submitted to: 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention:  Jean Wu, Project Manager 
5801 Forest Park Road 
Dallas, Texas  75390-9183 
FAX #: 214-648-5923 
 
Patients will be identified only by initials (first middle last) and a unique study ID number 
assigned to each study participant; if there is no middle initial, a hyphen will be used (first-
last). Last names with apostrophes will be identified by the first letter of the last name. 
Participating sub-sites must remove or black-out identifiers from source documentation that 
is sent to UTSW.   
 
 
Item 
Due 
Demographics 
Within 2 weeks of study entry 
Eligibility and Entry Characteristics, 
including baseline H&P and Zubrod 
PS 
Within 2 weeks of study entry 
Pathology Report  
Within 2 weeks of study entry 
Follow-up H&P data  
At post XRT follow-up at 1, 3, 6, 9, and 
12 months, then q 4 months year 2, 
after 2 years at the discretion of the 
investigator/institution 
Tumor response evaluation 
At post XRT follow-up at 3, 6, 9, and 12 
months, then q 4 months year 2,  after 2 
years 
at 
the 
discretion 
of 
the 
investigator/institution 
 Adverse Event assessment 
After each weekly treatment visit, then 
post XRT follow-up at 1, 3, 6, 9, and 12 
months, then q 4 months year 2, after 2 
years at the discretion of the 
investigator/institution 
 
 
 
12.0  Statistical Considerations 
12.1 Study Endpoints 
12.1.1 Primary endpoint 
The primary endpoint of the study is to either reach the maximum tolerated 
dose (MTD) or a dose of 60 Gy total (whichever comes first) by escalating the 
dose of hypofractionated IGRT toward the total dose of 60 Gy.  Patients will be 
treated in cohorts of seven to fifteen.   
 

A dose limiting toxicity (DLT) is defined as treatment-related (definitely and 
probably, but not possibly related to treatment*) grade 3 adverse events (per 
CTCAE, v.3.0, with the exception of pulmonary function tests as noted in 
Section 6.9.4) related to the following specific symptoms, including:  
 
 Gastrointestinal: dysphagia, esophagitis, esophageal 
stricture/stenosis, esophageal ulceration; 
 Cardiac: pericarditis, pericardial effusion, restrictive cardiomyopathy, 
ventricular dysfunction (left ventricular diastolic dysfunction, left 
ventricular systolic dysfunction, right ventricular dysfunction); 
 Neurologic: myelitis, neuropathy (cranial and motor); 
 Hemorrhage: pulmonary or upper respiratory; 
 Pulmonary: decline in pulmonary function as measured by pulmonary 
function tests (DLCO,and FEV1,) using the modified criteria in relation 
to baseline (see section 6.9.4), pneumonitis, pulmonary fibrosis, 
hypoxia, pleural effusion, cough, and dyspnea  
  
In addition, a DLT will include any grade 4 or 5 adverse event attributed to the 
therapy (definitely and probably, but not possibly related to treatment). 
 
*Patients enrolled on this study are highly likely to have associated tobacco 
related cardiopulmonary co-morbidities that would result in adverse events 
(e.g., hospitalizations) irrespective of any cancer treatment.  In published trials 
referenced in the introduction, adverse event analysis was confounded by 
problems distinguishing whether adverse events were treatment related versus 
part of the natural history of co-existing co-morbidities.  As such, in this protocol 
only adverse events deemed probably and definitely related to treatment are 
considered for formal adverse event assessment.  Adverse events deemed 
possibly related will be collected and reviewed but not used in adverse event 
analysis (e.g., for defining the maximum tolerated dose). 
 
All reported DLTs will be verified by study chair and data monitoring committee, 
before final determination that a DLT has in fact occurred.   Doses will be 
escalated an additional 0.33 Gy per treatment for 15 treatments (total 5 Gy per 
increment).  The study will be completed when either of the following events 
occur:  1) the MTD for a cohort is reached or 2) when the highest dose level 
allowed by the protocol is treated and tolerated (4 Gy per fraction, total 60 Gy). 
 
12.1.2  Dose escalation 
This study is designed to end if the rate of DLTs within 90 days from the start of 
treatment is 33% or higher.  For each dose level cohorts, a total of seven to 
fifteen patients will be enrolled.  If zero out of the first seven with 90 day follow-
up, two or fewer out of the first nine with 90 day follow-up, three or fewer out of 
the first twelve with 90 day follow-up, or four or fewer out of the first fifteen of 
patients with 90 day follow-up experience a DLT as defined above, then the 
dose will escalate to the next dose level.  If three or more of the first nine 
patients, four or more of the first twelve, or five or more of the first fifteen 
patients experience a DLT, then the MTD will be considered to have been 
exceeded.  The MTD will be defined as the immediately previous lower dose 
level tolerated.   
 

12.1.3 Waiting period 
Dose escalation on this study should not occur until a sufficient waiting period 
has occurred after patients have been treated.  A period of 90 days must pass 
in order to assess toxicity.  If 90 days have transpired without DLT in each of 
the first seven (7) patients enrolled to a specific dose level, then dose 
escalation to the next level may proceed.  Patients will continue to be enrolled 
to  each dose level (up to a maximum of 15 patients) with ongoing assessment 
of those reaching 90 day follow-up so long as either criteria for defining the 
MTD (section 12.1.2) or criteria for further dose escalation is not reached.  If 
fifteen patients are enrolled to a given dose level yet criteria for adequate 
follow-up are not reached in a representative sample of patients (section 
12.1.2), further enrollment to the protocol will be suspended until adequate 
follow-up is reached. 
 
12.1.4 Other endpoints 
A secondary endpoint is to evaluate local regional tumor control and overall 
survival by actuarial analysis. 
 
12.2  Analysis Plan 
Interim Reports: Interim reports will be prepared every six months until the 
results of the study are published or the study is closed.  In general, the interim 
reports will contain information about patient accrual rate with projected 
completion dates of the trial, status of QA review and compliance rate of 
treatment per protocol, and the frequencies and severity of toxicity. 
12.2.1  Estimation of Secondary Endpoints Related to the Efficacy: Cumulative 
incidence approach [23] will be used to estimate the failure rate for local-
regional and distant failures. Kaplan-Meier method [24] will used to estimate 
the overall survival rate. 
 
13.0  Data Safety and Monitoring Plan 
13.1  Data Safety Monitoring Committee and Institutional IRB reporting 
A data safety monitoring committee including radiation oncologists not 
participating in this trial will be formed to review toxicity endpoints and efficacy 
data. The data safety monitoring committee will review and verify all reported 
DLTs. In particular, this committee will scrutinize the grading of adverse events 
and the attribution to therapy previously assigned by the investigators.  This 
panel will have access to basic patient information so as to have the ability to 
critically review toxicity events.  This study will use this committee to perform 
ongoing safety assessment at regular defined intervals defined in the statistics 
section of this protocol.  Unexpected toxicities occurring between defined 
interim analyses points will be reported to the treating center’s IRB and also to 
the University of Texas Southwestern IRB.  Simmons Cancer Center Data 
Safety Monitoring Committee (DSMC) will review reported serious adverse 
events and contact Radiation Oncology DSMC for any discrepancies. 
 
     
 
     
 
 
 
 
 

 
 
 
References 
 
1. 
Jemal A, e.a., Cancer Statistics 2008. CA: a cancer journal for clinicians, 2008. 58: p. 
71–96. 
2. 
Shields, T.W., Surgical therapy for carcinoma of the lung. Clin Chest Med, 1993. 
14(1): p. 121-47. 
3. 
Perez, C.A., et al., A prospective randomized study of various irradiation doses and 
fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the 
lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer, 1980. 
45(11): p. 2744-53. 
4. 
Kong, F.M., et al., High-dose radiation improved local tumor control and overall 
survival in patients with inoperable/unresectable non-small-cell lung cancer: long-
term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys, 2005. 
63(2): p. 324-33. 
5. 
Lee, C.B., et al., Late complications of high-dose (>/=66 Gy) thoracic conformal 
radiation therapy in combined modality trials in unresectable stage III non-small cell 
lung cancer. J Thorac Oncol, 2009. 4(1): p. 74-9. 
6. 
Bradley, J., et al., 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 Radiat Oncol Biol Phys, 2005. 61(2): 
p. 318-28. 
7. 
Dillman, R.O., 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, 1996. 88(17): p. 1210-5. 
8. 
Belani, C.P., et al., Combined chemoradiotherapy regimens of paclitaxel and 
carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II 
locally advanced multi-modality protocol. J Clin Oncol, 2005. 23(25): p. 5883-91. 
9. 
Curran, W., et al., Long-term benefit is observed in a phase III comparison of 
sequential vs concurrent chemo-radiation for patients with unresectable NSCLC: 
RTOG 9410. Proceedings of ASCO, 2003. 22: p. 621a. 
10. 
Le Chevalier, T., et al., Radiotherapy alone versus combined chemotherapy and 
radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a 
randomized trial in 353 patients. J Natl Cancer Inst, 1991. 83(6): p. 417-23. 
11. 
Sause, W.T., et al., Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern 
Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in 
regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst, 
1995. 87(3): p. 198-205. 
12. 
Schaake-Koning, C., et al., Effects of concomitant cisplatin and radiotherapy on 
inoperable non-small-cell lung cancer. N Engl J Med, 1992. 326(8): p. 524-30. 
13. 
Hanna, N., et al., Phase III study of cisplatin, etoposide, and concurrent chest 
radiation with or without consolidation docetaxel in patients with inoperable stage III 
non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin 
Oncol, 2008. 26(35): p. 5755-60. 
14. 
Dillman, R.O., et al., A randomized trial of induction chemotherapy plus high-dose 
radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med, 
1990. 323(14): p. 940-5. 
15. 
Clamon, G., et al., Radiosensitization with carboplatin for patients with unresectable 
stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia 

Group B and the Eastern Cooperative Oncology Group. J Clin Oncol, 1999. 17(1): p. 
4-11. 
16. 
Kupelian, P.A., et al., Serial megavoltage CT imaging during external beam 
radiotherapy for non-small-cell lung cancer: observations on tumor regression during 
treatment. Int J Radiat Oncol Biol Phys, 2005. 63(4): p. 1024-8. 
17. 
Timmerman, R., et al., Excessive toxicity when treating central tumors in a phase II 
study of stereotactic body radiation therapy for medically inoperable early-stage lung 
cancer. J Clin Oncol, 2006. 24(30): p. 4833-9. 
18. 
Bradley, J.D., et al., A phase III comparison of radiation therapy with or without 
recombinant beta-interferon for poor-risk patients with locally advanced non-small-
cell lung cancer (RTOG 93-04). Int J Radiat Oncol Biol Phys, 2002. 52(5): p. 1173-9. 
19. 
Machtay, M., C. Washam, and P. Devine, Pilot study of accelerated radiotherapy 
with concurrent chemotherapy for stage III non-small cell lung cancer. Semin Oncol, 
2005. 32(2 Suppl 3): p. S9-12. 
20. 
Tsoutsou, P.G., et al., Hypofractionated/accelerated radiotherapy with cytoprotection 
(HypoARC) combined with vinorelbine and liposomal doxorubicin for locally 
advanced non-small cell lung cancer (NSCLC). Anticancer Res, 2008. 28(2B): p. 
1349-54. 
21. 
Slotman, B.J., et.al., Hypofractionated Radiation Therapy in Unresectable Stage III 
Non-Small Cell Lung Cancer. Cancer, 1993. 72(6): p. 1885-1893. 
22. 
Park, C., et al., Universal survival curve and single fraction equivalent dose: useful 
tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys, 
2008. 70(3): p. 847-52. 
23. 
Gray, R., A class of K-sample tests for comparing the cumulative incidence of a 
competing risk. Ann Stat, 1988. 16: p. 1141-1154. 
24. 
Kaplan, E., Meier, P, Nonparameteric estimation from incomplete observations. J. 
Amer. Statist. Assoc., 1958. 53: p. 457-481. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Appendix I:  Sample Treatment Consent Form 
 
Study Title: 
Phase I Study of Accelerated Hypofractionated Image-Guided Radiation 
Therapy (IGRT) in Patients with Stage II-IV Non-Small Cell Lung Cancer and 
Poor Performance Status 
 
INVITATION:  You are invited to participate in this research because you have lung cancer. 
 
NUMBER OF PARTICIPANTS:  Up to 45 patients (depending on how the treatment is 
tolerated). 
 
PURPOSE:  The purpose of this study is to find the highest reasonably safe daily dose of 
radiation therapy that can be delivered to treat lung cancer.  Modern technology uses 
frequent imaging and other techniques that allow precise delivery of a large radiation dose 
to a tumor while avoiding normal tissue.  The higher dose technique may work better to 
kill cancer cells. 
 
What will happen if I take part in this research study? 
 
Before you begin the study … 
You will need to have the following exams, tests or procedures to find out if you can be 
in the study. These exams, tests or procedures are part of regular cancer care and may 
be done even if you do not join the study. If you have had some of them recently, they 
may not need to be repeated. This will be up to your study doctor. 
1. History and physical examination 
2. A biopsy of your tumor proving you have cancer 
3. CT scan of the chest and upper abdomen or a PET/CT 
4. MRI scan of the brain (or CT if the MRI cannot be performed for medical 
reasons) 
5. Pulmonary function studies 
6. Routine blood tests 
 
During the study … 
If the exams, tests and procedures show that you can be in the study, and you choose to 
take part, then you will need the following tests and procedures. They are part of regular 
cancer care. 
1. Physical exam – following completion of radiation therapy at 1 month, 3 months, 
6 months, 9 months, 12 months, and every 4 months for the second year, every 
6 months for years 3-5, and then yearly. 
2. CT imaging to follow the cancer – following completion of radiation therapy at 3 
months, 6 months, 9 months, 12 months, and every 4 months for the second 
year, every 6 months for years 3-5, and then yearly. 
3. Pulmonary function testing at 6 and 12 months after completing therapy. 
 
How long will I be in the study? 

You will receive radiation therapy for 3 weeks. Follow up visits and exams will continue for 
the rest of your life according to the schedule given above, in order to monitor the status of 
your cancer. 
 
Can I stop being in the study? 
Yes. You can decide to stop at any time.  It is important to tell the study doctor if you are 
thinking about stopping so any risks from the treatment can be evaluated by him/her. 
Another reason to tell your study doctor that you are thinking about stopping is to discuss 
what follow-up care and testing could be most helpful for you.  The study doctor may stop 
you from taking part in this study at any time if he/she believes it is in your best interest; if 
you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study? 
While on the study, you are at risk for the side effects listed below.  You should discuss 
these with the researcher and/or your regular doctor.  There may be other side effects that 
we cannot predict.  Many side effects go away soon after you stop being treated with  
radiation therapy.  But in some cases, side effects can be serious, long lasting, 
or may never go away.  Drugs may be given to make side effects less serious and 
uncomfortable.   It is also possible that your cancer may not respond to radiation therapy. 
 
Risks and side effects related to radiation therapy to the chest include those which 
are: 
Likely (>10%):  
 
Difficulty, pain, or a burning sensation when swallowing, which is temporary 
 
Fatigue, which is temporary 
 
Tanning, redness of the skin, and hair loss within the treatment area, which is 
temporary 
 
Skin in the treatment area may remain permanently dry, and chest hair may 
not grow back 
 
Cough and some difficulty in breathing due to lung damage 
 
Less Likely: 
 
Decrease in blood counts while undergoing treatment that may result in 
bleeding, and bruising easily 
 
Fever 
 
Chest wall discomfort or pain 
 
Rib fracture, which may cause pain 
 
Narrowing of the esophagus causing difficulty swallowing meals (requiring 
internal dilation or a feeding tube) 
 
Rare, but serious:   
 
Pericarditis – irritation of the heart sac causing a rapid heart rate, chest 
discomfort, or chest pain 
 
Myocarditis – irritation of the heart muscle causing shortness of breath, chest 
pain, or permanent heart muscle damage 
 
Transverse myelitis – irritation of the spinal cord causing weakness or 
paralysis 
 
Bleeding from the airway 
 
Narrowing of the airway causing shortness of breath 
 
Death 

 
Chest radiotherapy can cause changes in normal lungs. These changes can be as 
unimportant as small amounts of "scarring" seen on x-rays that does not cause symptoms. 
Sometimes chest radiotherapy can cause lung damage that leads to symptoms such as 
chest pain, shortness of breath, cough, or fever. Rarely, these symptoms can be severe or 
life threatening.  Treatment for this lung damage involves pain medicines, antiinflammatory 
medicines (corticosteroids), and rarely, oxygen therapy, which may be permanent. You 
should tell your doctors immediately if you have any of these symptoms. 
 
Risks from radiation exposure from diagnostic tests:   
There is no additional risk of harm from radiation as a result of your participation in this study 
except as standard care for your medical condition. 
 
Risks from blood samples:   
You may experience discomfort, bleeding, and/or bruising.  You may feel dizzy or faint.  On 
a rare occasion, an infection could develop at the site where the blood was collected. 
 
Risks from Loss of Confidentiality:  
Any time information is collected; there is a potential risk for loss of confidentiality.  Every 
effort will be made to keep information confidential; however, this cannot be guaranteed. 
 
Reproductive Risks:  
You should not become pregnant or father a baby while on this study because the radiation 
therapy in this study can affect an unborn baby. If you are a woman able to have children 
and have not been surgically sterilized (tubal ligation or hysterectomy), you must have a 
pregnancy test before enrolling in this study. Women should not breastfeed a baby while on 
this study. It is important you understand that you need to use birth control while on this 
study. Check with your study doctor about what kind of birth control methods to use and how 
long to use them. Some methods might not be approved for use in this study. 
 
For more information about risks and side effects, ask your study doctor. 
 
How you can help reduce some of the risks:   
During your participation in this research, your study doctor will watch closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 
Ask questions about anything you do not understand. 
 
Keep appointments. 
 
Follow the study doctor’s instructions. 
 
Let your study doctor know if your telephone number changes. 
 
Tell your study doctor before you take any new medication even if it is 
prescribed by another doctor for a different medical problem. 
 
Tell your regular doctor about your participation in this research. 
 
Talk to a family member or friend about your participation in this research. 
 
What to do if you have problems:   
If you have any problems such as unusual symptoms or pain at any time during your 
participation in the research, your study doctor can recommend treatment.  Please report 
the problem to your study doctor promptly.  Telephone numbers where your study doctor 
may be reached are listed on the first page of this consent form.   

 
If you suddenly have a serious problem (such as difficulty breathing) or severe pain, go to 
the nearest hospital emergency room, or call 911 (or the appropriate emergency telephone 
number in your area).  Tell emergency personnel about your participation in this research.  
Ask them to telephone your study doctor immediately. 
 
Are there benefits to taking part in the study? 
Benefit to you:  Taking part in this study may or may not make your health better. While 
doctors hope accelerated hypofractionated, image-guided radiation therapy will be more 
useful against your lung cancer compared to the usual treatment, there is no proof of this 
yet.  
 
Benefit to other people with lung cancer:  In the future, other people with lung cancer could 
benefit from the results of this research.  Information gained from this research could lead to 
improved medical care for them.  However, your study doctor will not know whether there 
are benefits to other people with lung cancer until all of the information obtained from this 
research has been collected and analyzed. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
 
 
Getting treatment or care for your cancer without being in a study 
 
Taking part in another study 
 
Getting no treatment 
 
Talk to your study doctor about your choices before you decide if you will take part in 
this study. 
 
What are the costs of taking part in this study? 
Expenses related to standard medical care for lung cancer are your responsibility (or the 
responsibility of your insurance provider or government program).   
 
All tests and procedures performed during your treatment and follow up visits will be billed 
as standard of care. 
 
There are no funds available to pay for parking expenses, transportation to and from the 
research center, lost time away from work and other activities, lost wages, or child care 
expenses. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
Compensation for an injury resulting from your participation in this research is not available 
from The University of Texas Southwestern Medical Center. 
You will get medical treatment if you are injured as a result of taking part in this study. 
You and/or your health plan will be charged for this treatment. The study will not pay 
for medical treatment. 
 
What are my rights if I take part in this study? 

You have the right to agree or refuse to participate in this research.  If you decide to 
participate and later change your mind, you are free to discontinue participation in the 
research at any time.  You retain your legal rights during your participation in this research. 
 
Refusal to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled.  Refusal to participate will not affect your legal rights or the quality of health care 
that you receive at this center. 
 
NEW INFORMATION:  Any new information which becomes available during your 
participation in the research and may affect your health, safety, or willingness to continue in 
the research will be given to you. 
 
Will my medical information be kept private? 
Information about you that is collected for this research study will remain confidential unless 
you give your permission to share it with others, or as described below.  You should know 
that certain organizations that may look at and/or copy your medical records for research, 
quality assurance, and data analysis include: 
 
Representatives of government agencies, like the U.S. Food and Drug 
Administration (FDA), involved in keeping research safe for people 
 
Qualified personnel at The UT Southwestern Medical Center 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details about 
how your information will be used for this research study, and who may see and/or get 
copies of your information. 
 
To help us further protect the information, the investigators will obtain a Certificate of 
Confidentiality from the U.S. Department of Health and Human Services (DHHS).  This 
Certificate adds special protections for research information that identifies you and will help 
researchers protect your privacy.   
 
With this Certificate of Confidentiality, the researchers cannot be forced to disclose 
information that may identify you in any judicial, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level.  There are situations, however, 
where we will voluntarily disclose information consistent with state or other laws, such as: 
 
to DHHS for audit or program evaluation purposes; 
 
information regarding test results for certain communicable diseases to the 
Texas Department of State Health Services, including, but not limited to HIV, 
Hepatitis, Anthrax, and Smallpox; 
 
if you pose imminent physical harm to yourself or others; 
 
if you pose immediate mental or emotional injury to yourself; 
 
if the researchers learn that a child has been, or may be, abused or 
neglected; or 
 
if the researchers learn that an elderly or disabled person has been, or is 
being, abused, neglected or exploited. 
 
The researchers will not, in any case, disclose information about you or your participation in 
this study unless it is included in the Authorization for Use and Disclosure of Protected 
Health Information for Research Purposes as stated above. 

The Certificate of Confidentiality does not prevent you or a member of your family from 
voluntarily releasing information about your involvement in this research study.  In addition, 
the researchers may not use the Certificate to withhold information about your participation 
in this research study if you have provided written consent to anyone allowing the 
researchers to release such information (including your employer or an insurance company).  
This means that you or your family must also actively protect your privacy. A Certificate of 
Confidentiality does not represent an endorsement of this research project by the 
Department of Health & Human Services or any other Federal government agency. 
 
YOUR QUESTIONS:  Your study doctor is available to answer your questions about this 
research at 214-645-8525.  The Chairman of the IRB is available to answer questions about 
your rights as a participant in research or to answer your questions about an injury or other 
complication resulting from your participation in this research.  You may telephone the 
Chairman of the IRB during regular office hours at [enter IRB contact number]. 
 
You will get a copy of this form. If you want more information about this study, ask 
your study doctor. 
 
 
Signature: 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this 
form. I have read it or it has been read to me. I understand the information and have 
had my questions answered. I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________ 
 
 
 
 
 
 
 
Interpreter Statement: 
 
I have interpreted this consent form into a language understandable to the subject 
and the subject has agreed to participate as indicated by their signature above. 
 
Name of Interpreter (printed) 
_________________________________________ 
 
 
Signature of Interpreter 
 
_________________________________________ 
 
Date 
 
 
 
 
_________________________________________ 
 
 
 
 
 
 

 
 
Appendix II:  Study Parameter Table 
 
 
Pre- 
Registration 
During XRT 
 Follow-Up (months after therapy) 
 
Within 
8 
weeks  
Within 
12 
weeks  
Within 3 
days 
prior to 
XRT 
Weekly 
1 
month  
3 
months  
6 
months 
9 
months 
12 
months 
Q 4 months during year 2, after 2 
years at the discretion of the 
investigator/institution 
History / Physical 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Zubrod PS 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Biopsy / cytology 
X 
 
 
 
 
 
 
 
 
 
 
CT of Chest1 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
MRI Brain2 
 
X 
 
 
 
 
 
 
 
 
 
PFT’s (including 
DLCO and 
FEV1) 
 
 
X 
 
 
 
 
X 
 
X 
 
CBC w/ diff 
 
X 
 
 
 
 
 
 
 
 
 
Serum or urine 
pregnancy test (if 
applicable) 
 
 
 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Comorbidity 
index (Appendix 
V) 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Tumor response 
evaluation 
 
 
 
 
 
 
X 
X 
X 
X 
X 
1preferably with IV contrast unless medically contraindicated 

2CT if MRI medically contraindicated 
 

 
APPENDIX III 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90-100). 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light housework, 
office work (Karnofsky 70-80). 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours (Karnofsky 50-
60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours (Karnofsky 30-40). 
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed 
or (Karnofsky 10-20). 
 
5 
Death (Karnofsky 0). 
 
KARNOFSKY PERFORMANCE SCALE 
 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
 
 
 
 
 

 
 
APPENDIX IV  
 
AJCC STAGING SYSTEM 
AJCC Staging,  Lung, 6
th Edition, 2002  
 
Primary Tumor (T)  
 
TX  
Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells 
in sputum or bronchial washings but not visualized by imaging or bronchoscopy.  
T0  
No evidence of primary tumor.  
Tis  
Carcinoma in situ  
T1  
Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus,* (i.e., not in 
the main bronchus)  
T2  
Tumor with any of the following features of size or extent: More than 3 cm in greatest 
dimension; Involves main bronchus, 2 cm or more distal to the carina; Invades the 
visceral pleura; Associated with atelectasis or obstructive pneumonitis that extends to the 
hilar region but does not involve the entire lung  
T3  
Tumor of any size that directly invades any of the following: chest wall (including superior 
sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main 
bronchus less than 2 cm distal to the carina, but without involvement of the carina; or 
associated atelectasis or obstructive pneumonitis of the entire lung.  
T4  
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; 
or tumor with a malignant pleural effusion.**  
 
*Note: The uncommon superficial tumor of any size with its invasive component limited to the 
bronchial wall, which may extend proximal to the main bronchus, is also classified T1.  
 
**Note: Most pleural effusions associated with lung cancer are due to tumor. However, there are 
a few patients in whom multiple cytopathologic examinations of pleural fluid are negative 
for tumor. In these cases, fluid is non-bloody and is not an exudate. Such patients may 
be further evaluated by videothoracoscopy (VATS) and direct pleural biopsies. When 
these elements and clinical judgment dictate that the effusion is not related to the tumor, 
the effusion should be excluded as a staging element and the patient should be staged 
T1, T2, or T3.  
 
Regional Lymph Nodes (N)  
 
NX 
Regional lymph nodes cannot be assessed.  
N0  
No regional lymph nodes metastasis  
N1  
Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and 
intrapulmonary nodes including involvement by direct extension of the primary tumor  
N2  
Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)  
N3  
Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
 
 
 
 
 

 
 
APPENDIX IV (continued) 
 
AJCC STAGING SYSTEM 
AJCC Staging  
Lung, 6
th Edition, 2002  
 
 
Distant Metastasis (M)  
 
MX  
Distant metastasis cannot be assessed  
M0  
No distant metastasis  
M1  
Distant metastasis present  
 
Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral)  
 
STAGE GROUPING  
 
Occult Carcinoma   
TX  
 
N0  
 
M0  
Stage 0  
 
 
Tis  
 
N0  
 
M0  
Stage IA  
 
 
T1  
 
N0  
 
M0  
Stage IB  
 
 
T2  
 
N0  
 
M0  
Stage IIA  
 
 
T1  
 
N1  
 
M0  
Stage IIB  
 
 
T2  
 
N1  
 
M0  
T3  
 
N0  
 
M0  
Stage IIIA  
 
 
T1  
 
N2  
 
M0  
T2 
  
N2  
 
M0  
T3  
 
N1  
 
M0  
T3  
 
N2  
 
M0  
Stage IIIB  
 
 
Any T   
N3  
 
M0  
T4 
 
Any N   
M0  
Stage IV  
 
 
Any T   
Any N   
M1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Appendix V: Comorbidity Scoring 
 
Instructions for completing the CHARLSON COMORBIDITY INDEX (CCI): 
1. Complete all patient information. 
2. Follow the “Rules for Completing The Charlson Comorbidity Index” in this appendix. 
3. Complete The Charlson Comorbidity Index” by noting “yes” or “no” for each disease. 
 
Instructions for completing THE COMORBIDITY RECORDING SHEET: 
1. Complete all patient information. 
2. Extract all comorbidity elements you can identify and note them on the Recording Sheet. 
Place the elements in the most appropriate category. Be comprehensive.  
3. Include past surgeries, diseases, smoking history, and functional problems, such as 
incontinence or constipation. 
4. For each condition include: 
􀂃 When (e.g., 6 months ago, 5 years ago, etc.); 
􀂃 Current symptoms; 
􀂃 Related treatment (e.g., surgery, stent placement, hearing aides, glasses, etc.); 
􀂃 Related laboratory values (e.g., CR, bilirubin); 
􀂃 Medications (scheduled/prn). 
5. If a functional problem appears to be related to tumor or treatment, place TR after the 
diagnosis. 
6. Specify as much as possible the dose/frequency of medications; the rater may use this 
information to rate the severity of a disease. 
7. Leave the scoring column blank. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Appendix V 
 
Rules for Completing the Charlson Comorbidity Index (CCI)  
(Charlson et al. J Chron Dis. 40:373-383, 1987) Adaptation: Do not count non-melanotic 
skin cancers or in situ cervical carcinoma.  
Myocardial infarct  
Hx of medically documented myocardial 
infarction  
Congestive heart failure  
Symptomatic CHF w/ response to specific 
treatment  
Peripheral vascular disease  
Intermittent claudication, periph. arterial 
bypass for insufficiency, gangrene, acute 
arterial insufficiency, untreated aneurysm 
(>=6cm)  
Cerebrovascular disease (except hemiplegia)  
Hx of TIA, or CVA with no or minor 
sequelae  
Dementia  
chronic cognitive deficit  
Chronic pulmonary disease  
symptomatic dyspnea due to chronic 
respiratory conditions (including asthma)  
Connective tissue disease  
SLE, polymyositis, mixed CTD, 
polymyalgia rheumatica, moderate to 
severe RA  
Ulcer disease  
Patients who have required treatment for 
PUD  
Mild liver disease  
cirrhosis without PHT, chronic hepatitis  
Diabetes (without complications)  
diabetes with medication  
Diabetes with end organ damage  
retinopathy, neuropathy, nephropathy  
Hemiplegia (or paraplegia)  
hemiplegia or paraplegia  
Moderate or severe renal disease  
Creatinine >3mg% (265 umol/l), dialysis, 
transplantation, uremic syndrome  
2nd Solid tumor (non metastatic)  
Initially treated in the last 5 years  
exclude non-melanomatous skin cancers 
and in situ cervical carcinoma  
Leukemia  
CML, CLL, AML, ALL, PV  
Lymphoma, MM...  
NHL, Hodgkin's, Waldenström, multiple 
myeloma  
Moderate or severe liver disease  
cirrhosis with PHT +/- variceal bleeding  
2nd Metastatic solid tumor  
self-explaining  
AIDS  
AIDS and AIDS-related complex  
Suggested: as defined in latest definition  
 
 
 
 
 
 
 
 
 

 
APPENDIX V (Continued)  
CHARLSON COMORBIDITY INDEX (CCI)  
Scoring Sheet  
 
Name/Number:__________________________________________________________  
Patient Initials (First Middle Last):______________ Number:___________________  
Name of Person Completing Sheet:_____________________________ 
Phone Number:_____________  
Date Completed:__-___-_____  
 
 
 
Comorbidity  
Present (Y or N)  
Points  
Myocardial infarct  
 
1  
Congestive heart failure  
 
1  
Peripheral vascular disease  
 
1  
Cerebrovascular disease (except hemiplegia)  
 
1  
Dementia  
 
1  
Chronic pulmonary disease  
 
1  
Connective tissue disease  
 
1  
Ulcer disease  
 
1  
Mild liver disease  
 
1  
Diabetes (without complications)  
 
1  
Diabetes with end organ damage  
 
2  
Hemiplegia  
 
2  
Moderate or severe renal disease  
 
2  
2nd Solid tumor (nonmetastatic)  
 
2  
Leukemia  
 
2  
Lymphoma, MM...  
 
2  
Moderate or severe liver disease  
 
3  
2nd Metastatic solid tumor  
 
6  
AIDS  
 
6  
 
 
 
 
 
 
 

 
APPENDIX V (Continued) 
  
Completing the Comorbidity Recording Sheet  
Examples of conditions in each category are listed below. The list is not all-inclusive.  
Please list other conditions that are present. All conditions, including abnormal values, are 
before the start of therapy.  
 
Heart: MI, Arrhythmia, CHF, Angina, Pericardial disease, Valvular disease  
Vascular/Hematopoietic: Hypertension, Peripheral vascular disease, Aneurysms, Blood 
abnormalities (anemia, leukopenia, etc.)  
Respiratory: Bronchitis, Asthma, COPD, Tobacco history (pack/year)  
HEENT: Vision impairment, Sinusitis, Hearing loss, Vertigo  
Upper GI (esophagus, stomach, duodenum): Reflux, PUD  
Lower GI (intestines, hernia): Constipation/Diarrhea, Hemorrhoids, Diverticulitises  
Liver/Pancreas/GB: Cholelithiasis/Cholecystectomy, Hepatitis/pancreatitis  
Renal: Creatinine, Stones  
GU (ureters, bladder, urethra, prostate, genitals, uterus, ovaries): Incontinence, UTI, BPH, 
Hysterectomy, Abnormal PAP smear, Bleeding  
Musculoskeletal/Skin: Arthritis, Osteoporosis, Skin cancer, Psoriasis  
Neurological: Headaches, TIAs/Stroke, Vertigo, Parkinson’s Disease/MS/ALS  
Endocrine (record height and weight): Diabetes, Hypo/hyperthyroid, Obesity  
Psychiatric: Dementia, Depression  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
APPENDIX V (Continued)  
COMORBIDITY RECORDING SHEET  
 
Name/Number:__________________________________________________________  
Patient Initials (First Middle Last):______________ Number:___________________  
Name of Person Completing Sheet: _____________________________Phone 
Number:_____________  
Date Completed:__-___-_____  
 
Comorbidities  
(Add TR if related to tumor or its treatment)  
Score  
Heart  
 
Vascular (Hemoglobin:_____)  
 
Respiratory (include tobacco history)  
 
Eyes and ENT  
 
Upper GI  
 
Lower GI  
 
Liver and Pancreas  
 
Renal (Creatinine:            )  
 
GU  
 
Musculoskeletal/Integument  
 
Neurological  
 
Endocrine/Metabolic and Breast  
(Weight:             Height:               ) 
 
Psychiatric  
 
 
 
Medications (prn or scheduled):