Clinical trial NCT00915005
Conditions: Non-Small-Cell Lung Carcinoma
Keywords: Locally-advanced non-small-cell lung carcinoma NSCLC Lung Cancer Image-Guided Adaptive Conformal Photon Proton Therapy Chemotherapy Treatment Related Pneumonitis
Sponsor: M.D. Anderson Cancer Center
Start date: 2009-06-01; Completion date: 2020-02-24
Enrollment: 275 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if, compared with regular x-ray radiation, proton radiation reduces the risk of developing, treatment-related pneumonitis (TRP) or tumor recurrence (the tumor coming back in the irradiated area after treatment) in patients with lung cancer.

Detailed description:
There are 2 types of radiation treatment being used in this study. One type of treatment is proton therapy. Proton therapy is a type of radiation therapy that uses a beam of proton particles (similar to getting an x-ray) to send radiation inside the body to the tumor. The other type of treatment is Image-Guided Adaptive Photon Therapy (IGAPT). IGAPT is a therapy that uses images to help guide the delivery of photon therapy to the tumor. Both of these types of radiation treatment are believed to help doctors to give a full dose of radiation treatment to the tumor while not damaging as much of the healthy tissue around it.

Study Groups If you are found to be eligible to take part in this study, you will go through the standard radiation treatment planning procedure, called the "marking session." After the marking session, a standard photon therapy plan (called Intensity Modulated Radiation Therapy, or IMRT) and a proton plan will be developed. If the radiation oncologist thinks that both the photon and proton plans are acceptable, you will then be randomly assigned to 1 of 2 groups. Participants in Group 1 will receive photon therapy. Participants in Group 2 will receive proton therapy.

The first 20 participants will have an equal chance to be assigned to either group. After at least 20 participants have been enrolled and there has been at least 1 occurrence of pneumonitis and/or tumor recurrence in each treatment Group, the risk of pneumonitis and/or tumor recurrence in all previous participants will be evaluated for each treatment Group, and that information will be used to calculate the chances of being assigned to either Group 1 or Group 2. This calculation will be updated after each occurrence of pneumonitis and/or tumor recurrence and after each participant returns for a follow-up visit. Once these calculations are begun, everyone who joins the study from that point on will be more likely to be assigned to the treatment Group that appears to be better in terms of pneumonitis and/or tumor recurrence.

If the tumor is too large and the standard radiation treatment plan created during the marking session is found not to be acceptable, and the radiation oncologist thinks radiation treatment it is necessary, you will still remain on study and be assigned to a third group. If you are assigned to Group 3, you will receive proton or photon treatment at a lower dose level and/or reduced length of radiation.

If you are assigned to Group 2 and your insurance provider denies reimbursement, you may chose not to receive proton therapy and receive photon therapy instead. If you chose to receive photon therapy, you will be in Group 4.

Radiation Therapy Administration Both radiation therapy treatments (photon and proton) are given through a radiation machine called an accelerator. The radiation therapy administration process is very similar to the way that a CT scan is performed. You will lay on a table and the treatment machine rotates around you without touching your body. Each daily treatment should take about 20-30 minutes to complete. Most of this time is used to position you correctly before the machine is turned on. The actual time used to give the radiation should take about 3-5 minutes each day.

While you are on this study and if you are in Groups 1 or 2, you will receive a total of 37 radiation treatments. Radiation is given 5 days a week for about 7 1/2 weeks.

If you are in Group 1, you will receive photon radiation treatment in the main hospital.

If you are in Group 2, you will receive proton therapy in the proton treatment center (PTC).

If you are in Group 3, you will receive either photon or proton therapy, whichever your doctor decides is better for you, for 6-7 1/2 weeks. If your doctor decides that photon therapy is better you will receive your treatment in the main hospital. If your doctor decides that proton therapy is better you will receive your treatment in the Proton Therapy Center.

If you are in Group 4, you will receive Photon radiation treatment in the main hospital.

Chemotherapy You will receive carboplatin and paclitaxel chemotherapy 1 time a week over 7 weeks. Each treatment will last 3-4 hours. Paclitaxel will be given by vein over 1 hour and carboplatin will be given by vein over 30 minutes. You will receive this chemotherapy combination with radiation therapy, as part of your treatment on this study.

Your chemotherapy may also be decided by your treating medical oncologist as long as the therapy is allowed by the study.

Study Visits During Chemoradiation

At least 1 time each week for all study participants, you will have study tests performed. During this weekly study visit, the following tests and procedures will be performed:

You will have a physical exam. You will be asked about any side effects you may have experienced. Blood (about 2 teaspoons) will be drawn for routine tests.

If the study doctor thinks it is needed, you will have a PET/CT scan performed to check the status of the disease during Week 4 or 5 of treatment.

Length of Study You will remain on study as long you are benefiting. You will be taken off study early if the disease gets worse, you experience intolerable side effects, or your doctor thinks that it is no longer in your best interest to receive the study treatment.

Follow-Up Visits After you have completed chemoradiation, the study staff or study nurse will contact you 1 time each month to ask you about any symptoms you may have until 6 months after chemoradiation. Each phone call should last about 10 minutes.

You will have your first follow-up visit 4-8 weeks after you have completed chemoradiation. You will have additional follow-up visits every 3-4 months for 3 years, every 6 months for the next 2 years, and then 1 time every year after that.

At the first and second follow-up visit the following tests and procedures will be performed:

You will have positron emission tomography (PET)/computed tomography (CT) scans and single proton emission tomography (SPECT) scans to check the status of your lungs and heart if the radiation or medical oncologist thinks it is necessary.

Blood (about 1 teaspoon) will be drawn for routine tests.

If the radiation oncologist or medical oncologist thinks it is needed, at the follow-up visits, you will have breathing function tests performed to check your lung function for up to 1 year after the study treatment is complete. For this test, the radiation oncologist, medical oncologist or study nurse will have you breathe into a special machine. The radiation oncologist or medical oncologist will decide how many tests are to be performed each time.

PET/CT and SPECT scans will be performed again at any time the radiation oncologist or medical oncologist thinks they are needed.

Other tests may be performed if the study doctor (radiation oncologist, medical oncologist, surgeon or pulmonologist) thinks they are needed.

This is an investigational study. Both proton radiotherapy and IGAPT are FDA approved for the treatment of lung cancer.

Up to 250 patients will take part in this multi-center research study. Up to 205 will be enrolled at M. D. Anderson.

Arms: arm 1: Group 1: Photon Therapy - 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.

Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks.

Carboplatin AUC 2 by vein 1 time each week for 7 weeks. arm 2: Group 2: Proton Therapy - 74 Gy in 2 CGE per fraction given 5 days a week for about 7 1/2 weeks.

Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks.

Carboplatin AUC 2 by vein 1 time each week for 7 weeks. arm 3: Group 3: Receives either photon or proton therapy, whichever participant's doctor decides is better, for for 6-7 1/2 weeks.

Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks.

Carboplatin AUC 2 by vein 1 time each week for 7 weeks. arm 4: Photon Therapy - Highest practical dose (74 CGE, 66 CGE) radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete.

Paclitaxel 50 mg/m2 by vein 1 time each week for 7 weeks.

Carboplatin AUC 2 by vein 1 time each week for 7 weeks.
Interventions: intervention 1: Photon Therapy intervention 2: Proton Therapy intervention 3: Paclitaxel intervention 4: Carboplatin
Intervention descriptions: intervention 1: Group 1: 74 Gy 37 radiation treatments, given 5 days a week for about 7 1/2 weeks. Each daily treatment should take about 20-30 minutes to complete. intervention 2: Group 2: 74 Gy in 2 CGE per fraction given 5 days a week for about 7 1/2 weeks.

Group 3: 66 Gy with conventional fractionation given 5 days a week for about 6-7 1/2 weeks.

Each daily treatment should take about 20-30 minutes to complete. intervention 3: 50 mg/m2 by vein 1 time each week for 7 weeks. intervention 4: AUC 2 by vein 1 time each week for 7 weeks.

Protocol documents:
Prot_000.pdf: 
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The University of Texas 
M. D. Anderson Cancer Center 
 
A Bayesian randomized trial of Image-Guided Adaptive Conformal Photon vs Proton 
Therapy, with Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung 
Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence 
 
 
Note:  This protocol is intended for multi-institutional enrollment at Masachusetts General Hospital and MD 
Anderson Cancer Center as a part of and NCI-funded P01 Program Project entitled “Optimizing Proton 
Therapy.”  The Overall PI of the P01 is Dr. Thomas Delaney of MGH and the Overall PI of the sub-contract at 
MD Anderson Cancer Center is Dr. Radhe Mohan.  The leading institution for this protocol is MD Anderson 
Cancer Center. 
 
1.0 
Background 
2.0 
Objectives 
3.0 
Patient Eligibility  
4.0 
Pretreatment Evaluations 
5.0 
Evaluation During Study 
6.0 
Schema 
7.0 
Radiotherapy 
8.0 
Chemotherapy 
9.0 
Assessments of Primary Endpoints 
10.0 
Reasons for Removal from Study 
11.0 
Adverse Event Reporting 
12.0 
Multi-Institutional Trial Registration 
13.0 
Statistical Considerations 
14.0 
Inclusion of Women and Minorities 
15.0 
References 
 
 
 
 
 
 


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1.0  Background 
1.1 Background 
Lung cancer is the second most common form of cancer in most western countries and the leading 
cause of cancer death worldwide. For locally advanced (stage II-IIIB) non-small cell lung cancer 
(NSCLC), the current treatment of choice is concurrent chemotherapy and conformal photon 
radiotherapy (XRT) (1).  However, the effectiveness of concurrent chemoradiation remains modest 
because of treatment-related pneumonitis (TRP), an acute, dose-limiting toxic effect of chemoradiation 
for NSCLC that limits the delivery of tumoricidal doses and thus can result in high rates of local and 
distant failure.  
 
TRP is mediated by the induction of proinflammatory cytokines in response to radiation damage of lung 
tissue (2). Most such cytokines, including tumor necrosis fac-tor alpha (TNF-), the interleukin (IL)-1 
family, and IL-6, are pro-duced within the treatment field and can evoke  autocrine, paracrine, or 
endocrine responses (3).   
 
The diagnosis of TRP, which typically becomes apparent 3-9 months after Radiotherapy (RT), is 
established by a history of RT, radiographic evidence (areas of ground-glass opacity and/or 
consolidation in the irradiated lungs that conform to the shape and size of the treatment portals (4)) and 
clinical presentation (most often dry cough, low-grade fever, chest pain, and shortness of breath) as 
well as ipsilateral pleural effusion and consolidation of the lung. Untreated TRP eventually advances to 
lung fibrosis, leading to loss of lung volume and poor pulmonary function, which negatively affect quality 
of life (5). Treatment for TRP is largely empirical and nonspecific, consisting of oral or intravenous 
steroids, oxygen, and sometimes assisted ventilation. Currently, the most effective way to reduce TRP 
is by avoidance and prevention through the use of biophysical risk assessment and reduction. 
 
TRP is directly linked with radiation dose and the volume of the irradiated tissue. In clinical practice, the 
total radiation dose that can be tolerated depends on the volume of tissue irradiated. Indeed, preclinical 
and clinical studies have shown that morbidity from TRP depends on the volume (6-7) and region of the 
normal lung irradiated (8-10). Dosimetric factors such as mean lung dose (MLD) (11) and percentage of 
lung volume receiving more than a threshold dose (Vdose) (11-13) are also well-known predictive 
factors for TRP. We recently demonstrated in a retrospective analysis that the actuarial incidence of 
grade >3 TRP in patients with locally advanced NSCLC receiving 3-dimensional conformal radiotherapy 
(3D-CRT) and concurrent chemotherapy was 22% at 6 months and 32% at 1 year. In univariate 
analyses, the MLD, relative V5 (rV5), and V25-V55 were significantly associated with grade > 3 TRP. In 
multivariate analyses, rV5 was highly predictive of grade > 3 TRP, with 1-year actuarial rates of 3% for 
those with rV5 < 42% and 38% for those with rV5 > 42% (P = 0.001) (10).   
 
1.1.1 Intensity-modulated radiation therapy  
Techniques that reduce radiation dose and volume to the 
normal lung can reduce the incidence of TRP. One such 
technique, intensity-modulated RT (IMRT), can increase 
conformality and provide greater sparing of normal 
tissues that traditional 3D-CRT (14). Murshed et al. (15) 
reported that using IMRT led to median absolute 
reductions in V10 of 7% and V20 of 10%. This 
corresponded to a decrease of > 2 Gy in the total MLD 
and 10% in the risk of TRP. Using the parameters 
described by Murshed in predictive models (16-17), we 
estimated that the median risk of TRP would decrease 
from 13%-36% with the 3D-CRT plans to 7%-9% with 
the IMRT plans, a statistically significant reduction.  
 
In our own use of IMRT with concurrent chemotherapy  
for the definitive treatment of advanced NSCLC (15,18),  
Figure 1. Incidence of treatment-related 
pneumonitis in patients with NSCLC treated 
with 3D-CRT or IMRT and concurrent 
chemotherapy.  


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we found significant reductions in the rates of grade > 3 TRP (8% for IMRT vs  29% for 3D-CRT); at 1 
year, the corresponding rates were 9% vs 33% (P=0.028) (Fig 1). These reductions were due to 
significant reductions in irradiated volumes of and doses to normal tissue (mean dose to normal lung 
was 16.6 Gy [range, 2.5–28.5] for IMRT and 22.1 Gy [range, 1.0–38.9] for 3D-CRT). IMRT also led to 
significant decreases in median irradiated volumes at several dose levels, including V15–V65 (P < 
0.0001). However, V5, V10, and V70 were no different between the two techniques, suggesting that 
IMRT is of limited benefit in terms of minimizing lung exposure to low-dose radiation (19). 
 
1.1.2 Concerns about low-dose exposure with IMRT   
As noted above, efforts to use IMRT for lung cancer have been limited by serious concerns about 
potential increases in the volume of lung irradiated to low doses, especially V5 (15) or rV5 (10). 
Analyses of a subgroup of patients with an rV5 > 70% suggested that higher rV5 levels are associated 
with increased risk of severe pulmonary toxicity, confirming our 3D-CRT experience that rV5, in addition 
to other higher-dose factors, is a parameter that needs to be controlled (10).  
 
Other clinical studies also support the concept that low-dose radiation to large volumes of lung can 
increase the risk of toxicity. Loss of the diffusing capacity for carbon monoxide was observed in lungs 
exposed to as little as 13 Gy (20), and the risk of complications in another study rose steeply above an 
MLD of 10 Gy (21). For patients already at risk of pulmonary complications because of large tumor 
volumes requiring extensive coverage or medical conditions that compromise respiratory function, 
irradiating a large volume of lung poses a concern that cannot be addressed with the use of photon 
irradiation. 
 
1.1.3 Proton-beam therapy  
Findings from simulation and planning studies suggest that use of proton beams (rather than photon 
beams) can reduce the radiation dose to and volume of normal tissue, including low-dose volumes. 
This is of particular interest in the treatment of lung cancer, as proton therapy would reduce the volume 
of lung irradiated to a low dose, whereas IMRT involves a greater volume of the lung in low-dose 
regions if more than five beam angles are used.   
 
In our planning study comparing IMRT and proton therapy (22,23), we found that proton therapy spared 
15%–17% of total lung and 19%–23% of contralateral lung from receiving 5 Gy compared with IMRT, a 
difference that could greatly reduce lung toxicity. Photon therapy at a prescribed dose of 63 Gy led to a 
mean total lung dose of 20.1 Gy, with V5, V10, and V20 values of 58.5%, 45.3%, and 34.5%; the 
corresponding values for proton therapy at a prescribed dose of 63 cobalt Gray equivalent (CGE) were 
17.5 Gy, 43.1%, 37%, and 30.8% (P = 0.002), and those for proton therapy with dose escalation to 74 
CGE were 21.2 Gy, 44%, 39.3%, and 33.2%. Low-dose exposure (i.e., V5) in the contralateral lung 
from photon therapy was 45.5% at 63 Gy and 49.7% at 74 Gy; with proton therapy, those values were 
reduced to 26.6% at 63 CGE and 27.1% at 74 CGEProton therapy also led to reductions in mean 
whole-body nontarget integral dose: with photon therapy, the doses were 6.8 Gy at 63 Gy and 8.1 Gy at 
74 Gy, but with photon therapy they were only 4.5 Gy at 63 Gy and 5.4 Gy at 74 Gy, a 33% absolute 
improvement. Even in patients with contralateral hilar disease, proton therapy significantly reduced low-
dose exposures of contralateral lung (V5 25%) relative to IMRT (V5 45%). Doses to heart V40, spinal 
cord, and esophagus V55 were also reduced. These findings indicate that even in extreme cases that 
pose challenges for proton planning, proton therapy still achieved a better dose-volume histogram than 
did IMRT (22,23).  
 
Preliminary findings from a clinical study of 25 consecutive patients with NSCCL who underwent 
proton-beam radiation and concurrent chemotherapy showed that even with a higher median radiation 
dose (74 CGE vs 63 Gy with XT), proton-beam therapy permitted higher total doses (17%+) to be given 
with concurrent chemotherapy yet were associated with reduced esophageal reactions compared with 
3D-CRT (24).  Moreover, no increase in the incidence of TRP has been noted. 
 
 
 


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1.2 
Rationale and Hypothesis for the Proposed Trial 
On the basis of the evidence reviewed here, we believe that the incidence of TRP can be minimized by 
using proton-beam therapy. Indeed, no randomized clinical trials have compared standard photon and 
proton radiation in terms of the development of TRP.   
 
We hypothesize that proton therapy will expose significantly smaller lung volumes to damaging dose 
levels and spare larger volumes of normal tissue than does photon therapy without compromising local 
regional tumor control. 
 
Specifically, we propose that image-guided adaptive proton therapy (IGAPT) will lead to lower rates of 
TRP and equivalent tumor control compared with image-guided adaptive photon therapy (IGAXT) for 
patients with stage II-IIIB NSCLC who are receiving concurrent chemotherapy. The primary objectives 
of this Bayesian adaptive randomization trial are to compare time to the appearance of (1) grade  3 
pneumonitis (according to the NCI Common Terminology Criteria for Adverse Events version 4.0 
[CTCAE v4.0]) and (2) locoregional recurrence among patients given 74 Gy in 37 fractions (2 Gy each) 
of protons vs. photons.   
 
This clinical trial will be the first Bayesian randomization trial to compare IGAXT and IGAPT in patients 
with locally advanced, surgically unresectable NSCLC. Patients who are candidates for concurrent 
chemoradiation will be randomly assigned to undergo either standard IGAXT or IGAPT to 74 Gy in 37 
fractions of 2 Gy each. Adaptive randomization will be used so that more patients can be offered the 
treatment that is found to be more effective. 
 
We will also collect positron emission tomography (PET) images and blood samples and document 
comorbidity and symptoms by using validated test instruments for correlative and translation research.  
Inflammatory cytokines and genomic DNA will be extracted from the serum and lymphcytes to analyze 
tha correlations of these biomarker and TRP after the completion of the study. 
 
2.0  Objectives 
2.1 
Primary Objective 
2.1.1 Assess and compare the incidence and time to development of CTCAE v3.0 grade > 3 
TRP or local failure, whichever comes first, among patients with locally advanced (stage 
II-IIIb and selected stage IV) non-small cell lung cancer (NSCLC) treated with image-
guided adaptive photon therapy (IGAXT, Group 1) or proton therapy (IGAPT, Group 2) 
using Bayesian randomization. 
 
2.2 
Secondary Objectives 
2.2.1  Assess and compare the incidence and time to development of CTCAE v3.0 grade > 3 
radiation esophagitis in treatment Groups 1 and 2. 
 
2.2.2  Investigate the association of inflammatory cytokines with the incidence and time to 
development of TRP and outcomes in treatment Groups 1 and 2. 
 
2.2.3  Investigate the association of relevant pharmacogenetic markers, biomarkers, and gene 
polymorphisms with the time to development of TRP and treatment outcomes in 
treatment Groups 1 and 2. Serum of the blood samples will be transferred to 
collaborating laboratories at The Methodist Research Institute for analysis of specific 
biomarkers.  All material transfer will follow institutional policy and all transferred material 
will be de-identified.   
2.2.3.1 For the proposed research, we will use a rapid and high-throughput nanopore-
based array to enrich low molecular weight (LMW) proteins to identify circulating 
LMW peptide markers in blood samples from patients with or without NSCLC. By 
optimizing the nanotexture of silica films through the engineering of the 
physicochemical properties (e.g., pore size, pore structure, surface affinity) on 
the nanoporous silica chip, we can selectively enrich low-abundance, LMW 


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peptides from serum samples. We will process the samples on nanoporous silica 
chips for LMW protein fractionation, and analyze the isolated fractions by MALDI-
TOF mass spectrometry and principal component analysis. LMW peptide 
signatures associated with lung cancer will be identified by LC-MS/MS. 
 
2.2.4  Evaluate IGAXT using weekly computed tomography (CT) in the assessment of tumor 
response and impact on treatment planning and delivery.  
 
2.2.5  Compare overall survival, progression-free survival, and median survival time in 
treatment Groups 1 and 2. 
 
2.2.6  Evaluate the role of functional imaging with FDG-PET in assessing and predicting the 
time to the development of TRP and tumor response.  
 
2.2.7  Document and compare symptom burden weekly during treatment, monthly up to 6 
month after the treatment, and at each follow-up visit by using the M. D. Anderson 
Symptom Inventory for Lung (MDASI-Lung) in treatment Groups 1 and 2. 
 
2.2.8 For Group 3 and Group 4 patients who are treated with protons or photons depending on 
higher dose achievable, compare the local control, overall survival, progression-free 
survival, median survival and toxicities of protons vs. photons (see Section 7.5). 
 
3.0  Patient Eligibility 
3.1 Inclusion Criteria 
 
3.1.1 Pathologically proven, unresected, locoregionally advanced NSCLC without evidence of 
hematogenous metastases (stage II-IIIB disease according to the 7th edition of the 
AJCC Staging Manual) with exception as defined by inclusion #2. 
 
3.1.2 Patients with solitary brain metastasis without sign of progression in the brain at the time 
of registration will be eligible for this trial if there is clinical indication for concurrent 
chemoradiation to the primary disease in the lung. 
 
3.1.3 Suitability for concurrent chemoradiation therapy per treating radiation oncologist or 
treating medical oncologist's assessment: 
 
3.1.3.1 Karnofsky performance score of > 70, or ECOG 0-1 
 
3.1.3.2 Unintentional weight loss < 10% during the 3 months before study entry. 
 
3.1.4 Receipt of induction chemotherapy followed by referral for concurrent chemoradiation is 
allowed for this protocol. 
 
3.1.5 Measurable disease on chest x-ray, contrast-enhanced CT, or PET scan. 
 
3.1.6 Locoregional recurrence after surgical resection, if suitable for definitive concurrent 
chemoradiation, is allowed for this protocol.  
 
3.1.7  Forced expiratory volume in the first second (FEV1) ≥ 1 liters. 
 
 
 
 
3.1.8  Fluorodeoxyglucose (FDG) -PET scan within 3 months before registration. 
The pretreatment (diagnostic) PET/CT should, whenever possible, be performed 
together with the 4-D CT simulation.  PET images acquired either at the time of 
simulation or acquired separately should be registered with the planning CT to assist in 
tumor delineation. 


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3.1.9  Standard pretreatment evaluations (as decided by treating radiation oncologist,  medical 
oncologist, surgeons or pulmonalogist), to include MRI or CT scan of the brain, Whole-
body PET/CT, contrast CT scan of the thorax and upper abdomen, pulmonary function 
tests, lung and cardiac single proton emission computed tomography (SPECT), liver 
function tests (LFT), blood chemistry, renal function tests, and complete blood count. 
 
3.1.10  Age≥18 years but ≤ 85 years. 
 
3.1.11  A signed specific informed consent form before study entry. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1  Small cell histology. 
 
3.2.2 Prior thoracic radiotherapy to regions that would result in overlap of radiation therapy 
fields. 
 
3.2.3  Pregnancy (female patients of childbearing potential must practice appropriate 
contraception). 
 
3.2.4 Enrollment in a clinical trial that specifically excludes IGAPT 
treatment. 
 
3.2.5 Body weight exceeds the weight limit of the treatment couch. 
 
3.2.6 Oxygen dependent due to preexistent lung disease 
(COPD, emphysema, lung fibrosis). 
 
4.0  Pretreatment Evaluations 
 
4.1  
Complete History and Physical Examination, including documentation of history of smoking, 
COPD, cardiac disease, performance status, weight loss 
 
4.2 
Laboratory and Radiographic Tests 
 
4.2.1 Laboratory Studies and routine blood test (to be obtained within 8 weeks before study 
entry, at the direction of the treating medical oncologist or radiation oncologist):  
 
4.2.1.1 CBC, diff, platelets, and ACE (angiotensin converting enzyme).   
4.2.1.2 SMA-12 (serum creatinine, electrolytes, aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], lactate dehydrogenase [LDH], alkaline 
phosphatase, total bilirubin, total protein, albumin, uric acid, inorganic 
phosphorous, calcium, blood urea nitrogen [BUN], magnesium) within +/-50% of 
the normal reference ranges as specified by each  participating institution. 
 
4.2.1.3 Calculated creatinine clearance according to participating institutions’ standard 
(optional)  
 
4.2.2 Imaging Studies (to be obtained within 8 weeks  except for the whole body PET which 
may be completed within 3 months before registration). 
 
4.2.2.1 
Required Images: 
 


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4.2.2.1.1 Whole-body PET/CT 
 
4.2.2.1.2 Brain scan (MRI is preferred, but CT is acceptable) 
 
 
4.2.2.2 
Optional Images: 
 
4.2.2.2.1 CT scans of the chest and abdomen, with or without contrast (MRIs 
are acceptable)  
 
4.2.2.2.2 Cardiac SPECT for patients with lower lung tumor 
 
4.2.2.2.3 Lung SPECT if  FEV1≤1.4 liters 
 
4.2.2.2.4 Chest X-ray  
4.2.2.2.5 Bone scan is optional if PET scan is done 
 
4.2.3 Pulmonary function tests including DLCO 
 
4.2.4 Pregnancy blood test for female patients at risk of pregnancy 
 
4.2.5  Documentation of T and N stages according to AJCC staging manual 7th Edtion.  
 
 
5.0  Evaluation During Study/Post Treatment 
5.1 
Weekly blood (about 1 teaspoon) will be drawn for routine tests, ACE (angiotensin converting 
enzyme) will be drawn once during concurrent chemoradiation and at the first follow-up visit 
after treatment.  
 
5.2 
Weekly CT scan as clinically indicated 
 
5.3 
Patients will be clinically evaluated by a treating physician (a radiation oncologist or medical 
oncologist) at least once a week during the chemoradiation;  toxicity will be evaluated and 
MDASI-Lung scores will be obtained as part of those evaluations.   
 
5.4 
Patients will be seen by a radiation or medical oncologist for the first follow-up visit at 4–8 weeks 
after completion of the treatment, then every 3–4 months for 3 years, then every 6 months for to 
the next 2 years, and then annually thereafter.  
 
5.5 
PET/CT scanning will be performed at week 4-5 during the treatment, and 4- to 8-week follow-
up visit as medically indicated for disease restaging after completion of the chemoradiation 
treatment. 
 
5.6 
Repeat cardiac and lung SPECT will be obtained at first follow-up and at 6 months after 
completion of chemoradiation as medically indicated. 
 
5.7 
Repeat pulmonary function tests will be obtained at each follow-up visit as medically indicated. 
 
5.8 
Additional Optional Tests 
 
 
 
5.8.1 Blood samples, obtained periodically (baseline, week 1 or 2 of treatment, week 3 or 4 of 
treatment, week 6 or 7 of treatment, and 1st follow up after treatment) , for translational 
research (see appendix E for details). 
 
5.8.2 M. D. Anderson Symptom Inventory (MDASI)-Lung 


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6.0  Schema 
 6.1 Study Schedule 
 
 
a.   Modification of the treatment plan will be performed if repeat 4D CT simulation shows significant change of 
the target volume or patient anatomy. 
b. Radiation dose prescription will be according to the strategy specified in Section 
7.5 and delivered in 2 CGE per fraction  
c. Clinically indicated. 
d. The patient will be contacted monthly +/- 2 weeks to report  their symptoms of treatment related toxicity. 
The methods of contacting patients include but not limited to clinic visit, phone calls, Emails, or letters.  If 
deemed necessary, patient will come to the clinic to be evaluated in addition to their regular follow-up. 
e. MDASI-Lung Chemoradiation will be administered before, weekly during chemoradiation and after 
chemoradiation until 16 weeks, and then every other week until 6 months 
f.  PET/CT could be done during 4th or 5th week during treatment, and 1st and/or 2nd follow-up after treatment 
according to treating physician's judgment.  
g.  GQL will be administered at baseline, at the end of chemoradiation treatment, and at the first follow-up clinic 
visit. 
h.  Five times throughout the whole protocol process: baseline, week 1 or 2 of treatment, week 3 or 4 of 
treatment, week 6 or 7 of treatment, and at a follow up after treatment. 
 
 
7.0  Radiotherapy 
(Note: All procedures specified in this section will be performed by or under the direction of the treating radiation 
oncologist) 
Procedure 
Before 
CRT 
Week 
1 
week 
2 
week 
3 
week 
4 
week 
5 
week 
6 
week 
7 
week 
8 
week 
9-35 
1-2 
months 
post-TX 
Follow-ups 
3- 6 
months 
Physical Exams 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Staging & re staging 
work up 
x 
 
 
 
 
 
 
 
 
 
x 
x 
Routine blood work x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
PET/CT 
x 
 
 
 
xf 
 
 
 
 
 
xf 
xf 
Brain scan (MRI is 
preferred, but CT 
is acceptable)  
x 
 
 
 
 
 
 
 
 
 
 
 
PFTs 
x 
 
 
 
 
 
 
 
 
 
x 
xc 
Bone Scan 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Chest x-ray 
Xc 
 
 
 
 
 
 
 
 
 
 
 
SPECTc 
xc 
 
 
 
 
 
 
 
 
 
xc 
xc 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
4-D CT simulation 
x 
 
 
 
 
 
 
 
 
 
 
 
a3-D/IMRT CRT 
plan 
x 
 
 
 
 
 
 
 
 
 
 
 
b Radiation therapy  
xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xxxxx xx 
 
 
 
Chemotherapy 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
c Weekly CT 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
d Toxicity 
evaluation 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
e MDASI-Lung  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
gGQL 
x 
 
 
 
 
 
 
 
x 
 
x 
 
hOptional blood 
draw 
x 
x 
x 
x 
x 
 
x 
x 
 
 
x 
x 


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7.1  Definition of Target Volumes 
 
GTV  Gross tumor volume is all known gross disease as demonstrated on the planning CT, 
and modified as deemed necessary based on PET and other clinical studies. 
 
iGTV  GTV plus margin for tumor motion.  A structure will be created equal to the union of the 
GTV on all respiratory correlated images this will be referred to as the iGTV.  This may 
be created by auto propagation of the GTV from a reference phase to other phases or by 
directly contouring on a maximum intensity projection (MIP) dataset. The delineated 
iGTV will be compared with the actual position of the GTV on each of the respiratory 
correlated CTs and modified, if necessary, to encompass the extent of motion of the 
GTV (hence iGTV).  The iGTV may also be modified as deemed necessary based on 
PET and other clinical studies that may better distinguish the true GTV from other near 
unit density tissues. 
 
CTV  Clinical target volume is the subclinical involvement around the GTV. The CTV is the 
GTV plus an 8-mm margin for microextensions of the tumor (CTV=GTV+8 mm). 
 
ITV  
Internal target volume is the envelope of the CTV during the time of irradiation, thus 
accounting for intrafractional motion.  In this study, the ITV will be created by expanding 
the iGTV by 8 mm to include subclinical microscopic disease; this volume will be 
reviewed and edited if necessary based on clinical experience, as is our current clinical 
practice standard. 
 
PTV  Planning target volume is ITV plus a margin to ensure that the prescribed dose is 
actually delivered to the ITV. This margin accounts for variations in treatment delivery, 
including variations in setup between treatments. The ITV is expanded by 5 mm to 
generate the PTV in accordance with our current clinical practice.  The PTV is relevant 
to photon planning. 
 
7.2 
Radiation Doses 
7.2.1  The total radiation dose for the tumor target will be according to the specification in 
section 7.5 and delivered at 2 CGE per fraction, once a day, 5 fractions per week.  100% 
of the ITV will be covered by the prescribed dose.  Greater than or equal to 95% of the 
prescribed dose to the ITV will be acceptable if 100% cannot be reached. 
 
7.2.2  Normalization of the treatment plan will cover 95% of the PTV with the prescription dose. 
The minimum PTV dose must not fall below 95% of the prescription dose. For passively 
scattered proton therapy (PSPT), the PTV is assumed to be beam-specific PTV (see 
section 7.4.2.4). 
 
7.2.3 Deviations from dose prescription for target volumes: 
 
7.2.3.1 No deviation:  ≥ 99% of the PTV receives ≥ 95% of the prescribed dose, and a 
contiguous volume of no more than 2 cc inside PTV exceeds 120% of the 
prescribed dose.   
 
7.2.3.2 Minor deviation: Deviations of this magnitude are not desirable, but are 
acceptable.  Coverage that is equal to 95% of the prescribed dose and falls 
between 99% and 95% of the PTV, or a contiguous volume of no more than 2 cc 
inside the PTV exceeds 140% of the prescribed dose at the discretion of the 
attending physician. 
7.2.3.3 Treatment interruptions:  Interruption of radiation therapy up to 5  consecutive 
fractions for any reason will be considered as minor deviation.  


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7.2.4 Tolerance Limits for Critical Structures (See Table 3b) 
Note: if any portion of a critical structure is part of the planning target volume 
(PTV), the treating physician should make the decision based on medical 
necessity on the maximal radiation dose to that portion of the critical structure to 
ensure adequate tumor dose.   
 
 
7.2.4.1 Normal lung (right lung + left lung - GTV):  V20 ≤ 37%; and mean lung dose 
(MLD) ≤ 20CGE.  MLD of ≤ 22 CGE or V20 up to 40% will be acceptable as 
minor deviations. 
 
7.2.4.2 Esophagus:  33% volume must be ≤ 65 CGE, 66%  55 CGE and whole volume 
mean dose ≤ 45 CGE. 
 
7.2.4.3 Brachial Plexus:  V663.0 cc, V70  2.0 cc, V74  1.0 cc, V75  0.5 cc. For 
superior sulcus tumor or upper lobe tumors where the brachial plexus is part of 
the target volume, the involved segment should be excluded from the contour of 
the normal brachial plexus.   
 
7.2.4.4 Spinal cord:  Maximum dose to 2cc highest dose volume ≤ 50 CGE.   
 
7.2.4.5 Heart:  The mean dose to the whole heart should be ≤33CGE.  V70 ≤ 45% and 
V45≤ 70%. Dose constraints to atria and ventrical of the heart is specified in table 
3b. 
 
7.2.4.6 Liver:  V50 ≤ 35% and the whole liver must be ≤ 25 CGE.  
 
7.2.5 Major deviation: Doses outside the limits of the minor deviation for target volumes and 
exceeding normal tissue tolerance limits or greater than the limit of minor deviation 
(where indicated) will be considered major deviations and not acceptable. 
 
Interruption of radiation therapy more than 5  consecutive fractions for any reason will be 
considered as major deviation. 
 
 
7.2.6 Dose reporting:  The digital dose distribution data to be reported includes the complete 
treatment plan.  Its components include patient images, contours of all structures, beam 
configurations and characteristics including beam shaping devices or scan patterns as 
appropriate, treatment couch parameters, dose distributions, dose volume histograms 
for target volumes and critical normal structures.  In addition summary data shown in 
Table 3 will be reported for the purposes assessing compliance with protocol and for 
searching the data base.  
 
Note: Vx is defined as the total lung volume receiving a dose of 2x CGE or more 
• 
For superior sulcus tumor or upper lobe tumors where the brachial plexus is part of 
the target volume, the involved segment should be excluded from the volume of the 
normal brachial plexus AOR. 
• 
if any portion of a critical structure is part of the planning target volume (PTV), the 
treating physician should make the decision on the maximal radiation dose to that 
portion of the critical structure to ensure adequate tumor dose.   
 
 


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Note:  Vx is defined as the total lung volume receiving a dose of 2x CGE or more 
Prescription 
(CGE)
Fraction size
95%
99%
110
120%
PTV (Note 1)
74/66 CGE 
(see Sec. 7.5)
2 CGE
≥ 99% volume 
receives ≥ 
95% of 
prescription
No more than 
2 cc receives 
≥ 110% of 
prescription
≥ 95% volume 
receives ≥ 
95% of 
prescription
No more than 
2 cc receives 
≥ 120% of 
prescription
2. GTV motion in cm as assessed from 4D CT:  dX, dY, dZ, vector magnitude; Respiratory gating used:  (Y/N); Breath-hold used:  (Y/N).
Tumor motion data (see note 2)
Notes
1.  For protons, this represents beam-specific PTV.
All volumes will be reported in units of cubic centimeters.  All doses will be reported in units of CGE.  All DVH data will be reported in increments of 
0.2 CGE.  Generally, the expectation is that the cumulative DVH will be used for analysis.   The "actual"  columns will be populated by automatically 
extracting data from plans.
Table 3a.  Target Dose Specifications and Dosimetric Data to be Reported
No Deviation
Target
Minor Deviation
Dose received by the specified volume
Specification
Actual


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• 
For superior sulcus tumor or upper lobe tumors where the brachial plexus is part of the 
target volume, the involved segment should be excluded from the volume of the normal 
brachial plexus AOR. 
• 
if any portion of a critical structure is part of the planning target volume (PTV), the treating 
physician should make the decision on the maximal radiation dose to that portion of the 
critical structure to ensure adequate tumor dose.   
 
 
 
7.3 
Simulation, Immobilization, Image-Guided Radiation 
 
7.3.1  Simulation:  All simulations will be done on CT scanners capable of acquiring 4D CT 
image data sets.   
 
7.3.1.1 For proton planning, only CTs which have been calibrated for protons should be 
used. 
 
7.3.1.2 Each patient will be positioned in an immobilization device in the treatment 
 
position on a flat table. 
 
7.3.1.3 The imaging session will consist of acquisition of CT image data sets. 
These may include 4D CT, free breathing CT, and/or breath hold CTs.  
 
 
7.3.1.4 The pretreatment diagnostic PET/CT should be performed together with 4-D CT 
simulation if at all possible. 
 
7.3.2  Localization image studies with the patient in the treatment position will be obtained at 
the time of treatment. 
 
7.3.3  Image-guided adaptation 
 
7.3.3.1 Patients will be treated only on units with image guided capabilities.  Such units 
include ones with on-board imaging, CT-on-rails, or other dedicated patient 
positioning image systems, e.g. those associated with the proton delivery 
system. 
 
7.3.3.2 In addition to the CT data sets obtained for planning of treatments, CT scans will 
be obtained at least in weeks 2, 3, 4 and 7 from the start of the treatments.  
Optionally, additional CTs may be acquired in weeks 1, 5 and 6. 
 
 
7.3.3.3 The original CT will be fused with the weekly CT.  The original contours will be 
transferred to the new CT and reviewed by the attending physician or their 
designee.  If deemed necessary by him or her, new contours will be drawn and 
new dose distribution calculated using the original beam configuration.  If the 
changes in DVHs derived from new dose distribution exceed the level of minor 
deviation of the target or normal tissue dose constraints, a new treatment plan 
will be designed for the remainder of the treatments.  Target and normal tissue 
dose constraints and the limits of minor deviations are given in Table 3.   
 
7.3.3.4 Composite dose distribution received by the patient over the course of 
radiotherapy will be computed.  Such computations are necessary mainly to 
correlate dose distributions with response.  They need to be performed only at 
the time of outcomes analyses.  They involve, for each patient, computation for 


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dose distributions for each of ten phases of the respiratory cycle. These will be 
deformed to a reference phase (typically the end-exhale phase) and averaged.  
Such calculations will be performed for each of the CT scans acquired over the 
course of RT.  All these dose distributions will be deformed to the reference 
phase of the initial 4D CT and averaged.  
 
7.3.3.5 Patients randomized to be in proton therapy arm may receive up to five fractions 
with photons in the event the proton machine is not available. 
  
7.4 
Treatment Planning  
7.4.1  Critical structures  
7.4.1.1 The normal tissues including the right lung, the left lung, the esophagus, the 
heart, liver, brachial plexus, and the spinal cord need to be contoured in their 
entire region included in the simulation images.  
 
7.4.1.2 The lungs are expected to be the primary dose-limiting structure and basis for 
randomization. Every effort should be made to keep the total lung dose (defined 
as the volume of both lungs minus the GTV in the appropriate respiratory 
correlated CT image, the mid-ventilation phase of 4-D CT for ITV based 
treatments or the mid position of gated planning CTs for gated treatments) to a 
minimum. 
 
7.4.1.3 The tolerance doses to various organs shown in Table 3b above are to be used 
as guidelines. The treating radiation oncologist/dosimetrists should make every 
effort not to exceed these tolerance levels. (All tolerance doses are assumed to 
be delivered at 2 CGE/fx.) 
 
7.4.2  IGAXT and IGAPT planning 
 
7.4.2.1 All patients on this protocol will have one or more treatment plan(s) 
created for treatment with photons and one or more plan(s) created for 
treatment with protons to assess eligibility for randomization.  
 
7.4.2.2 This protocol does not mandate any specific field arrangement to be used. In 
photon planning, the PTV is to be treated with any combination of coplanar or 
noncoplanar 3D conformal fields shaped to deliver the specified dose while 
restricting the dose to the normal tissues. Field arrangements will be determined 
by 3D or inverse IMRT planning to produce the optimal conformal plan in 
accordance with volume definitions. 
 
7.4.2.3 Tumor Motion Management: If the centroid of the GTV is determined to 
move more than +/-0.5 cm, additional motion assessment tests will be 
performed either in the same simulation session or additional simulaiton 
sessions when the treatment plan is evaluated to determine if the limits of 
deviations for target coverage specified in Table 3 are exceeded.   The 
final decision on the use of any particular motion management strategies, 
such as gating, breath-hold, or the ITV approach, will depend on patient’s 
physical condition, level of irregular breathing, ability/inability to hold 
breath, and/or the availability of respiratory gating at the treatment unit 
etc., at the discretion of treating radiation oncologist. 
 
 
7.4.2.4 Definition of B-PTV (beam specific PTV) and treatment planning for 
IGAPT:  For proton planning, each beam has an individual and unique 
PTV expansion from the ITV. In the plane perpendicular to the proton 


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beam axis, the PTV expansion from the ITV is consistent with the method 
used for photons. However, along the direction parallel with the proton 
beam axis, the PTV expansion from the ITV distal margin and proximal 
margins, which are computed using established algorithms based on 
range uncertainty of the beam.   
7.4.2.5 Treatment planning parameters including distal and proximal margins, 
block margin and smearing radius will be calculated based on published 
formulae, modified locally and adopted as standard of practice. 
 
7.4.3  Dose calculation  
 
7.4.3.1 Doses are to be calculated with heterogeneity correction, i.e., correction 
is to be made for density differences between air spaces, lung, water-
density or bony tissue.  
 
7.4.3.2 Treatment planning should be performed in accordance with the 
prescribed doses to each target, together with restrictions in dose to 
normal tissues. 
 
 


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7.5 
Randomization  
Radiation therapy component of the study is shown in the flow chart below: 
 
 
 
 
7.5.1  The proton (PT) and photon (IMRT or 3DCRT) plans will be designed and 
evaluated by the treating radiation oncologist for acceptability according to current 
clinical practice, meaning that the dose constraints for normal tissue toxicity 
specified on Table 3b have been met. 
 
Radiation dose will be prescribed at 1 of 2 dose levels: 74 Gy (CGE), 66 Gy (CGE).  
If either proton or photon plan at 74 Gy (CGE) is not acceptable, prescribed tumor 
dose will be reduced to 66 Gy (CGE) and another pair of proton and photon plans 
will be designed.  If the plans at one of prescribed dose levels of 66 or 74 Gy 
(CGE) are achievable, the patient will be randomized between photons (Group 1) 
and protons (Group 2) at the highest achieved dose level.  Patients not 
randomizable will be treated in Group 3 as described in section 7.6. 
 
 
7.5.1.1 Patients randomized to Group 1 or 2 will be treated with the approved IGAXT or IGAPT 
plan.  
 
7.5.1.2 Patients randomized to Protons (Group 2) and subsequently denied insurance 
reimbursement may elect to forego treatment with Protons and be treated with Photons. 
Such patients will be removed from the randomized part of the study and moved to 
Group 4 and treated with photons at the highest practical dose (74 CGE, 66 CGE). 
 
 


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7.5.2 
Patients will be randomized to either IGAXT or IGAPT using the Clinical Trial Conduct website (  
https://biostatistics.mdanderson.org/boutiquetrials) which is housed on a secure server at 
MDCC and maintained by the MDACC Department of Biostatitics. Access to the website will be 
gained through usernames and passwords provided by the MDACC Department of Biostatistics 
to personnel at MDACC and MGH responsible for enrolling patients and updating, reviewing, 
and analyzing patient data. 
 
 
Training on the use of the Clinical Trial Conduct website to randomize and enroll patients on 
the study will be provided by Mark Munsell for the study personnel at MDACC and via WebEx 
for the study personnel at MGH. The imporance of timely updating the follow-up times and 
occurrence of events, if any, will be emphasized. 
 
 
Patients described in section 7.5.1.2 will be removed from the randomization website. 
 
7.6 
Patients with target volumes too large for a clinically acceptable photon or proton plan at the 
lowest stratification dose level of 66 Gy (CGE) will be treated without  randomization (Group 3) .  
They will be treated with the modality (protons or photons) that allows the higher dose at the 
limits of normal tissue tolerances. We hypothesized that the toxicity for protons and photons will 
be similar and the modality allowing higher dose to the target will lead to improved outcomes. 
The data of such patients will be used to compare local control, overall survival, progression-
free survival, median survival and toxicities of protons vs. photons. 
 
 
7.7 Radiation Therapy Quality Assurances 
Radiation treatment plans will be reviewed by all the participating insitutions to ensure a 
common understanding of the procedures listed on 7.2 through 7.6 by each participating 
institution.   This will be done during the trial periodically as needed. 
   
7.7.1 All treatment plans will be reviewed for quality assurance according to the standard of 
peer review at each participating institution.   
 
7.7.2 All plans will also be reviewed by the responsible physicst or his/her designee at each 
participating institution for compliance with the protocol and stardard of practice at each 
institution. 
 
7.7.3 Plan review for the patients from one institution by the staff of the other institution, when 
performed, will utilize the resources of Image-Guided Therapy QA Center (ITC) at 
Washington University, St. Louis, webex, and/or other feasible resources that comply 
with HIPPA.   
 
8.0 Chemotherapy 
 
(Note: All procedures specified in this section will be performed by or under the direction of the treating medical 
oncologist) 
 
8.1 
Concurrent Chemotherapy with Radiation Treatment 
 
8.1.1 All patients on this trial will receive concurrent  weekly carboplatin and paclitaxol 
chemotherapy with radiation therapy as part of the standard treatment. Pemetrexad is 
allowed for adenocarcinoma. 
 
Paclitaxel;  50mg/m2 in NS 250 ml over 1 hour IV using non-PVC bags and connections. 
Carboplatin: AUC = 2 in D5W 150ml -250ml over 30 minutes IV. 
 
8.1.2 Carboplatin Dosing Standards: 
 
                        1)   A correction factor should NOT be used to calculate creatinine clearance 


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• IDMS-measured creatinine (the serum creatinine valued reported in ClinicStation) should 
be used to in calculations that estimate GFR. 
 
2)   The maximum value of GFR calculated by the Calvert formula to calculate AUC-based 
dosing should not exceed 125 mL/min . 
• For an AUC of 6, this would mean a maximum dose to be administered would be 900 mg 
• For an AUC of 2 the maximum dose to be administered would be 300 mg 
 
                        3)  Consider adjusting the creatinine to a higher value (i.e. 1 mg/dL) in: 
• elderly patients (those over the age of 70) 
• those with cachexia 
• patients that weigh less than 50 kg 
 
4)  When concerned about safety in a specific patient, measure the GFR (using 24-hour urine 
collection). 
 
The chemotherapy will be given once a week for seven weeks. Each treatment will last 3-4 
hours.  
 
8.1.3 Etoposide and cisplatin (EP 50/50) is allowed as an alternative non-taxane based 
chemotherapy regimen.  
 
EP 50/50 dose schedule is as follows:  
Etoposide (50 mg/m2/day IV, days 1-5) and cisplatin 50 mg/m2 IV days 1 and  8) every 
3-4 weeks 
 
 
8.2 
Induction Chemotherapy  
 
Additioinally, platinum and taxane-based induction chemotherapy as part of the standard 
treatment will be allowed.  Pemetrexad is allowed for adenocarcinoma. 
 
8.3 
Consolidation Chemotherapy 
 
8.3.1 Consolidation chemotherapy is allowed; it should be started at least  3 –8 weeks after 
the protocol treatment. 
 
8.3.2 Regimen and doses will be decided by the treating medical oncologist according to the 
institutional standard of care. 
 
8.4  
Delivery will be according to the institutional standard of care. 
 
8.5 
Patients who develop disease progression can be started on appropriate therapy any time as 
medically indicated. 
 
8.6  
Patients on other carboplatin and paclitaxel chemotherapy or targeted therapy protocols are 
eligible as long as IGAPT is allowed on those protocols. 
 
 
 
9.0  Assessments of Primary Endpoints 
 
(Note: All procedures specified in this section will be performed by a research nurse under the direction of the 
treating radiation oncologist) 
 
9.1 
Assessment of Treatment-Related Pneumonitis 


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9.1.1 TRP will be diagnosed clinically by the treating investigator.  TRP events will be graded 
per the CTCAE v3.0.  Any questions regarding the diagnosis or grade of TRP will be 
resolved by the Protocol PI or by his/her designee(s).  
 
9.1.2   The patient will be contacted monthly +/- 2 weeks to report their symptoms of treatment 
related toxicity until 6 months after chemoradiation. The methods of contacting patients 
include but not limited to clinic visit, phone calls, Emails, or letters. If deemed necessary, 
patient will come to the clinic to be evaluated in addition to their regular follow-up.  
 
9.1.3  Since TRP typically occurs 1-6 months after the completion of radiation therapy, and 
criteria used in CTCAE v3.0 are subjective, it is critical to use MDASI-lung tool to 
perform weekly symptom assessment until 6 months from the baseline. The response of 
the patients will be assessed and if clinically indicated, patient will be instructed to obtain 
medical attention and necessary radiographic imaging studies. 
 
9.2 
Tumor Response Assessment  
Tumor response and local failure will be assessed according to RECIST criteria (see appendix).  
Images suspicious for local failure will be scheduled for review monthly by the protocol PI or 
his/her designee(s).   
 
 
 
 
*Complete Response (CR):  
Disappearance of all target lesions 
 
 
 
*Partial Response (PR): 
 
At least a 30% decrease in the sum of the LD 
 
 
 
*Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of target 
lesions, takig as reference the smallest sum LD records 
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 
 
 
 
 
10.0  Reasons for Removal from Study 
10.1 
 Unacceptable adverse event (at the discretion of the treating physician)  
10.2 
 Patient choice (patients can withdraw from the study at any time, for any reason) 
 
11.0  Adverse Event Reporting 
All serious adverse experiences will be reported to the institutional review board (IRB) of The University 
of Texas M. D. Anderson Cancer Center according to institutional reporting guidelines and using 
institutional reporting forms (see Appendix A).  
 
Reports of serious adverse events will be delivered to Clinical Research Compliance and will be 
submitted to the U.S. Food and Drug Administration by the safety coordinator according to 21CFR 
312.32. 
 
All AEs at the participting institutions must be reported to the Protocol PI and the Overall PIs.   
 
11.1  Grading Criteria 
The Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0; available at 
http://ctep.info.nih.gov) will be used to grade all treatment-related adverse events. All 
appropriate treatment areas should have access to a copy of these criteria. 
 
11.2  Adverse Events to be Reported 


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The following AEs experienced by patients accrued to this protocol and attributable to the 
protocol treatment (definitely, probably, or possibly related) should be reported (from the start of 
protocol treatment to 30 days after protocol treatment): 
 
11.2.1  Death on study  
 
11.2.2  Hospitalization or prolongation of hospitalization on study  
 
11.2.3  Life-threatening event 
 
11.2.4  Persistent or significant disability or incapacity 
 
11.2.5  Congenital anomaly/birth /defect for which intervention is required to prevent permanent 
impairment/damage 
 
 
11.3 
Procedures for Reporting Adverse Events 
 
 
The following steps must be taken to report serious adverse events that occur while the patient 
is on this trial. 
 
11.3.1 Within 24 hours of discovery of the adverse event, the PI must be called and a written 
notification will be sent to the IRB . 
 
 
11.3.2  Death from any cause while the patient is receiving protocol treatment and up to 30 days 
after the last protocol treatment must be reported by telephone to the PI and the IRB 
within 24 hours of discovery. Any late death (more than 30 days after last treatment) 
attributable to the protocol treatment (possible, probable, or definite) should also be 
reported to the PI and the IRB. 
 
11.3.3  Known/expected adverse events are those that have been previously identified as 
having resulted from administration of the agent or treatment. They may be identified in 
the literature, the protocol, the consent form, the drug insert, or the Investigator’s 
Brochure. 
 
11.3.4  Unknown/unexpected adverse events are those thought to have resulted from the 
protocol treatment. 
 
12.0  Multi-Institutional Trial and Registration 
 
12.1 
This trial will be a multi-institutional study.  All patients will be enrolled by M. D. Anderson 
Cancer Center and Massachusettes General Hospital.  
 
12.2 
All patients will be registered in the CORE system at MDACC.   
 
12.3 
Protected health information will be appropriately annonymized before being transmitted to be 
shared with non-MDACC groups, e.g. MGH or ITC. 
 
12.4 
Patients will be notified of these requirements through the informed consent document.   
 
 
13.0  Statistical Considerations 
13.1  Study Endpoints 
13.1.1  Primary Endpoint 


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Time to development of CTC v3.0 grade > 3 TRP or local failure, whichever occurs first, in both 
treatment groups 
 
13.1.1.1 An outcomes review committee has been formed to discuss every patient who 
develops symptons suggesting clinical symptomatic TRP, local failure, or regional 
failure to ensure consistent and unbiased grading of study outcomes. The Charter of 
this committee is the following:  
 
Outcomes Review Committee 
 
The primary outcome for trial 2008-0133 is time to local failure or grade 3 treatment 
related pneumonitis (TRP), according to CTCAE v3. Local failure after radiation could 
be confused with lung fibrosis or infection. CTCAE v3 is a subjective grading system, 
and grading of TRP could vary between physicians and research nurses. 
 
Committee will be chaired by the Protocol PI.  Its membership will include MDACC 
thoracic radiation oncologists, MGH CO-PI, MDACC radiation physicists, dosimetrists, 
research nurses, data coordinator, and statistician participating in the conduct of this 
trial. The treating physician (or his or her designee) and at least one other radiation 
oncologists, one physicist, one research nurse, statisrician and the data coordinator 
would comprise the quorum. Meeting will be open to others provided no HIPPA 
regulations are violated. 
 
The committee will meet as needed to review all patients who are suspected of 
achieving either study outcome (local failure, TRP). All relevant medical, dosimetric, 
and treatment related information will be reviewed. The committee will reach a 
consensus as to whether the outcome has been achieved. For local failure the 
committee will reach consensus on the type of local failure (see section 13.1.1 of the 
protocol) and the date of local failure. For TRP the committee will reach consensus on 
the CTCAE v3 grade (see section 9.9 of the protocol) and attribution (i.e., relationship 
to treatment). Outcomes for a patient will not be recorded in the randomization website 
until the committee has reached consensus on the patient.  
 
The committee will also review patients who were decided to have outcomes before 
the formation of the committee. However, the outcomes and dates of outcomes for 
these past cases will not be changed in the randomization website. The committee’s 
review of each past case will be noted for inclusion in sensitivity analyses and for 
discussion in the final study report. Meeting minutes will be recorded to docume nt the 
discussion and final decision of the committee for all cases brought before it. 
 
13.1.1.2 TRP is defined and graded according to CTCAE v3.0. Since the CTCAE grading 
criteria for TRP is quite subjective, the grading of TRP could vary among individual 
treating physicians.  The outcomes review committee will meet to discuss each and 
every patient reported to have developed symptomatic TRP. The final grading of TRP 
will be decided by the outcomes review committee. 
 
13.1.1.3 Procedure in diagnosing and grading radiation pneumonitis for 2008-0133 
(CTCAE v. 3) 
1) The following factors must exist to diagnose radiation pneumonitis (RP): 
a. Patient must have had radiation treatment that included certain volume of the 
normal lung 
b. There must be radiographic changes suggesting inflammation consistent with 
radiation dose distribution  
c. Time of scoring: 1 – 12 months after starting of chemoradiation 
d. Symptoms attributable to RP 


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2) The following steps are used in grading radiation pneumonits: 
a. Grade 1:   a + b + c + d only 
b. Grade 2:  (1), a + b + c + d, plus (2), or (3), or plus (2)+(3).   (2) Symptomatic 
with one or more related symptoms (e. g. persistent dry cough, shortness of 
breath, reduced exercise tolerance, short term ER visit, oral steroids, cough 
medicine, etc)  and/or (3) affect activities of daily living (ADL) related to work 
c. Grade 3: (1), a+b+c+d plus (2), or (3), or (4), or plus any combination of (2) or 
(3) or (4).   (2) Symptomatic (severe) requires hospitalization, (3) O2 indicated, 
(4) bed ridden or unable to care for self due to RP 
d. Notes:  The following toxicity should be scored as independent category 
i. 
Pleural effusion will be diagnosed and scored under pleural effusion 
ii. Hypoxia without a+b+c+d will be scored under the category of hypoxia 
iii. ARDS will be scored under the category of ARDS  
The differential between RP and ARDS is best made as follows:  A CT scan 
of the chest should be obtained.  If the inflammatory changes correspond to 
the radiation therapy dose distribution as seen on the axial slices, one can 
assume it is RP.  On the other hand, if the symptoms are acute and the CT 
reveals generalized interstitial infiltrates outside the radiation treatment 
volume, e.g. infiltrates in the lower lobes when only an upper lobe tumor 
was treated, the diagnosis is ARDS or other type of inflammation such as 
aspiration or pneumonia. 
iv.  Fibrosis is scored under the category of fibrosis 
v. Pulmonary edema is scored under the category of pulmonary edema 
vi. Pulmonary embolism is scored under the category of pulmonary embolism  
vii. Hemoptysis is scored under the category of Hemoptysis 
viii. Pneumonia is scored under the category of Pneumonia 
 
13.1.1.4 Local failure is defined as any of the following that occurs inside the PTVp and/or 
PTVn, or ≤ 1cm outside the margin of the PTVp and/or PTVn: 
 
a) Tumor recurrence after achieving complete response, 
b) Residual tumor enlargement of 20% or more on CT according to RECIST criteria, 
c) Recurrence of PET FDG Avidity after achieving complete metabolic response, 
d) Increase in FDG avidity in residual tumor, 
e) Pathologically proven recurrence.  
 
Regional failure is defined as disease occurrence on the same side of the thorax that 
is > 1 cm outside the PTVp and/or PTVn boundary. 
 
The PET or CT images that reported local failure will be fused with the radiation dose 
distribution to allow accurate assessment of the location of the local failure. Biopsy to 
allow difnitive documentation of local failure is highly recommended whenever 
possible, but not required. When in question, the case will be discussed  by the 
outcomes review committee to make final decision.  
 
 
 
13.1.2  Secondary endpoints 
 
13.1.2.1 
Assess and compare the incidence and time to development of CTCAE v3.0 
grade > 3 radiation esophagitis in treatment groups 1 and 2. 
 
 
13.1.2.2 
Investigate the association of inflammatory cytokines with the incidence and time 
to development of TRP and outcomes in treatment groups 1 and 2. 
 


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13.1.2.3 
Investigate the association of relevant pharmacogenetic markers, biomarkers, 
and gene polymorphisms with the time to development of TRP and treatment 
outcomes in treatment groups 1 and 2. 
 
 
13.1.2.4 
Evaluate IGAXT using weekly computed tomography (CT) on-rail or cone beam 
CT in the assessment of tumor response and impact on treatment planning and 
delivery.  
 
 
13.1.2.5 
Compare overall survival, progression-free survival, and median survival time in 
treatment groups 1 and 2. Disease progression is defined as: 1) local failure as 
defined above, 2) regional failure as defined above, 3) distant metastases (any 
disease that occurs outside of the thorax and/or disease that occurs in the 
contralateral lung). 
 
 
13.1.2.6 
Evaluate the role of functional imaging with FDG-PET in assessing and 
predicting the time to the development of TRP and tumor response.  
 
 
13.1.2.7 
Document and compare symptom burden weekly during treatment, monthly up to 
6 month after the treatment, and at each follow-up visit by using the M. D. 
Anderson Symptom Inventory for Lung (MDASI-Lung) in treatment groups 1 and 
2. 
13.1.2.8 
For Group 3 and Group 4 patients who are treated with protons or photons 
depending on higher dose achievable, compare the local control, overall survival, 
progression-free survival, median survival and toxicities of protons vs. photons. 
 
 
 
13.2 
Sample Size Calculation and Data Analysis Plan 
 
13.2.1 
Hypothesis 
 
The primary endpoint of the study is time to treatment failure, defined as the interval from 
the time of randomization to the development of treatment-related pneumonitis (TRP) or 
local failure, whichever occurs first.  We are interested in studying whether IGAPT can 
reduce the TRP rate compared with IGAXT. Although local disease control rates are thought 
to be similar for IGAPT and IGAXT, this assumption needs to be prospectively tested, and 
hence we chose a combined endpoint of TRP and local failure as the primary endpoint.  
 
 
Our primary outcome is time to treatment failure. Treatment failure is defined as TRP or 
local failure. These 2 types of failure are equally important. Based on the preliminary data, it 
is assumed that the time to treatment failure follows a log-normal distribution, with 6-month 
and 12-month treatment failure rates for the IGAXT arm of 30% and 40%, respectively (27). 
We also assume that under the null hypothesis (H0), failure in the IGAPT arm is the same 
as failure in the IGAXT arm, and under the alternative hypothesis (H1), IGAPT can reduce 
the corresponding failure rates to 20% and 25%, respectively.   
 
 
Eligible patients will be assigned to receive either IGAXT or IGAPT based on the Bayesian 
adaptive randomization method.  Adaptive randomization will allocate more patients to the 
treatment that yields more favorable outcomes based on the interim observed data. This 
design is appealing ethically because if a difference is found in treatment efficacy, more 
patients in the trial can be treated with the more effective treatment.  If no difference is found 
in treatment efficacy, patients will be assigned with equal probability to either treatment, as 
is the case in the conventional randomized trials with equal allocation ratio.  With a 
maximum of 150 eligible  patients, we will have 81% power to detect this difference with a 
one-sided type I error rate of 10% or less (see subsequent sections and Table 4 [Operating 
Characteristics] for details).  Under H1, there is a 48% chance of early stopping with about 


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58% of the patients randomized into the IGAPT group in a median sample size of 128. The 
sample size calculation assumes an accrual rate of 7 patients per month with 32 months of 
accrual plus an additional 24 months of follow-up.  The total sample size is up to 250 
patients, to account for patients being ineligible or lost to follow-up. 
 
 
Patients randomized to IGAPT may be denied insurance reimbursement for this treatment, 
and therefore, they may elect not to be treated with IGAPT. These patients will be 
transferred to Group 4, as described in section 7.5, and they will be treated with the highest 
dose of IGAXT possible (74 CGE, 66 CGE). 
 
 
13.2.2 Model specification for Bayesian adaptive randomization design using time-to-treatment-
failure as the endpoint. 
The time to treatment failure is assumed to follow a log-normal distribution.  A Bayesian 
lognormal regression model with adaptive randomization will be used. Let ti be the time to 
development of CTCAE v3.0 grade > 3 treatment-related TRP or local failure for individual i; 
then the distribution of ti  will be 
 
                    log(ti) ~ N(IGAXT, IGAXT2) if ti   is in IGAXT group,  
                    log(ti) ~ N(IGAPT, IGAPT2), if ti   is in IGAPT group. 
 
We assume conjugated prior, i.e., the prior distributions are normal distribution (1, 100) 
distributions for β’s and gamma (0.0001, 0.0001) distributions for the inverses of the ’s.  
We are particularly interested in treatment failure rates for each treatment group, which give 
us an insight about the treatment effect (IGAXT vs. IGAPT).   
 
The probability for treatment assignment in the adaptive randomization is chosen to be 
proportional to the posterior 1-year treatment failure rate.  Two steps are followed to 
complete the assignment of treatments for the next patient given current data. 
 
(1) Determine the parameters, ’s and ’s, based on their posterior estimates. 
 
, 
, 
 
where datai contains the information of previous i subjects. 
 
(2) Estimate the 1-year treatment failure rates (TF),TFIGAXT and TFIGAPT based on the 
s.  
 
 
 
Then, the chance that the next patient is assigned to the IGAPT group will be  
              
1 - TFIGAPT / (TFIGAXT + TFIGAPT). 
 
13.2.3 
Decision rule for comparing treatment efficacy 
 
 IGAPT is considered better than IGAXT (i.e., with lower failure rates than IGAXT) if  
 
                         
Pr( tIGAPT > tIGAXT | tIGAXT < 24 OR tIGAPT < 24, data ) > PL. 
 
 
 
 
On the other hand, IGAXT is considered better if                        
)
|
(
ˆ
i
data
median 
=
)
|
(
ˆ
i
data
median 
=
ˆ
))
ˆ
,ˆ
(
~
)
log(
|
12
Pr(
2


N
t
month
t
TF

=


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Pr( tIGAXT > tIGAPT | tIGAXT < 24 OR tIGAPT < 24, data ) > PL. 
 
 
 
 
 
Specifically, we will conclude that IGAPT is better if, given the current data, the probability of 
time to treatment failure for IGAPT being longer than for IGAXT is greater than PL.  The 
proposed design allows continuous monitoring.  The trial can be stopped early should the 
interim results indicate a high probability of one treatment being better than the other.  
Specifically, we set PL = 0.70 for interim monitoring.  If the trial continues to the end without 
being stopped early, we set PL = 0.59 in the final analysis.  The probability calculation is 
confined to within the 24-month period, which corresponds to the clinical implication of the 
relevance and importance of recurrence or TRP during this period. 
 
Patients will be randomized to the achievable radiation dose [74, 66] as described in section 
7.5. We assume that approximately 1/3 of patients will be randomized to each dose level. 
However, we do not expect any differences between doses with respect to the treatment 
effects on TRP or local failure. The calculations of randomization probabilities and decision 
rules described above will include all data across dose levels. 
 
 
13.2.4 Operating characteristics 
The operating characteristics from 1,000 simulation runs are summarized in Tables 4a, 4b 
and 4c.  According to the specifications given in the above two sections, a total of 150 
eligible patients are uniformly enrolled during the 24-month accrual period. An event of 
either grade > 3 TRP or local failure is defined as a treatment failure. The first 20 patients 
are equally randomized into one of the two groups. After enrolling the first 20 patients and 
after one event is observed in each group, patients are adaptively randomized based on the 
posterior 1-year failure rate estimates of the two groups. Failure or losses to follow-up for 
randomized patients are updated as they occur, i.e., the observed failure or loss to follow-up 
is updated as it happens. In addition, when new patients enter the study, the censoring time 
is updated for all patients who are still on study but have not yet developed an events. The 
early stopping rule applies after a total of 20 events is observed in the entire sample. The 
decision rules for declaring that one treatment is better than the other are given in the 
previous section. 
 
 
Under H0 (Scenario 0 in Table 4a), where IGAPT is assumed to produce the same 1-year 
treatment failure rate (40%) as IGAXT, there is a 4.9% chance of early stopping because 
IGAPT is better than IGAXT and a 5.3% chance of early stopping because IGAXT is better. 
The 2.5th, 50th, and 97.5th percentiles for the proportion of patients randomized into the 
IGAPT group are 37%, 50%, and 65%, respectively. The median sample sizes are 75 and 
74 for the IGAPT and IGAXT groups, respectively. There is an 8.7% chance to claim IGAPT 
as being better and an 8.1% chance to claim IGAXT as being better at the end of the study. 
The average trial length is 3.70 years. 
 
 
Under H1 (Scenario 1 in Table 4a), where IGAPT is assumed to produce lower 1-year 
treatment failure rates than IGAXT (25% versus 40%), there is a 48% chance of early 
stopping because IGAPT is better than IGAXT, but there is virtually no chance of early 
stopping because IGAXT is better. The 2.5th, 50th, and 97.5th percentiles for the proportion 
of patients randomized into the IGAPT group are 44%, 58%, and 73%, respectively. The 
median sample sizes are 74 for the IGAPT group and 54 for the IGAXT group. There is an 
81% chance to claim IGAPT as being better and virtually no chance to claim IGAXT as 
being better at the end of the study. The average trial length is 2.70 years. 
 
Additional simulations summarized in Table 4a show that we have more than a 90% chance 
to claim IGAPT as being better and virtually no chance to claim IGAXT as being better at the 
end of the study for a situation where the treatment failure rate decreases with dose for both 


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IGAXT and IGAPT (Scenario 2). We also have more than an 80% chance to claim IGAPT as 
being better and virtually no chance to claim IGAXT as being better at the end of the study 
for a situation where the difference in treatment failure rates between IGAXT and IGAPT 
decreases with dose (Scenario 3). 
 
Simulations summarized in Table 4b show that with 10% of patients randomized to IGAPT 
and then denied insurance coverage for their treatment, we still have at least 80% power for 
Scenarios 1-3 and about a 10% significance level under Scenario 0. With 10% of patients 
randomized to IGAPT and then denied insurance coverage for their treatment the trial will 
need to enroll a few more patients on average, it will last a little longer, and the proportion of 
patients treated on IGAPT will be a 2%-3% less than if there was no insurance denial. 
 
Simulations summarized in Table 4c show that with 25% of patients randomized to IGAPT 
and then denied insurance coverage for their treatment, we still have at least 80% power for 
Scenarios 1 and 2, about 80% power for Scenario 3, and about a 10% significance level 
under Scenario 0. With 25% of patients randomized to IGAPT and then denied insurance 
coverage for their treatment the trial will need to enroll a few more patients on average, it will 
last a little longer, and the proportion of patients treated on IGAPT will be a 7%-8% less than 
if there was no insurance denial. 
 
In both cases of 10% or 25% insurance denial, the trial will have only modest (<10%) 
increases in the total sample size and study duration. 
 
 
 


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Table 4. Operating characteristics (n=150 eligible patients). Assumes 90% of patients at 74 CGE and 10% 
of patients at 66 CGE. Also assumes 10% of patients assigned to IGAPT dropped due to insurance denial. 
 
 
Scenario 0 (H0) 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.40, 0.40 
Total Sample Size 
(including insurance 
denial) 
 
Percentile 
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
33 
27 
74 
50.0% 
77 
70 
156 
97.5% 
96 
90 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.33 
 
50.0% 
 
0.47 
 
97.5% 
 
0.63 
 
 
 
 
 
 
Probability of early stopping 
 
0.050 
0.059 
 
Probability of final selection 
 
0.084 
0.104 
 
Average trial length (years) 
 
3.77 
 
 
 
Scenario 1 (H1) 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.25, 0.25 
Total Sample Size 
(including insurance 
denial) 
 
Percentile 
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
26 
38 
76 
50.0% 
58 
71 
153 
97.5% 
86 
95 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.41 
 
50.0% 
 
0.56 
 
97.5% 
 
0.71 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.473 
 
Probability of final selection 
 
0.0 
0.811 
 
Average trial length (years) 
 
2.80 
 
 
 
Scenario 2 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.30 
IGAPT 
0.25, 0.15 
Total Sample Size 
(including insurance 
denial) 
 
Percentile 
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
27 
41 
81 
50.0% 
58 
69 
153 
97.5% 
90 
94 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.39 
 
50.0% 
 
0.55 
 
97.5% 
 
0.71 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.493 
 
Probability of final selection 
 
0.0 
0.815 
 
Average trial length (years) 
 
2.76 
 
 
 
Scenario 3 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66,CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.20, 0.25 
Total Sample Size 
(including insurance 
denial) 
 
Percentile 
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
26 
40 
81 
50.0% 
46 
68 
117 
97.5% 
82 
96 
162 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.43 
 
50.0% 
 
0.58 
 
97.5% 
 
0.73 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.692 
 
Probability of final selection 
 
0.0 
0.952 
 
Average trial length (years) 
 
2.26 
 
 


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13.2.5. Statistical analyses and additional statistical considerations 
Standard statistical methods including descriptive statistics and exploratory data analysis will 
be applied for checking data quality; identifying outliers, patterns, or associations; and 
providing summaries of the data distribution.  Patients’ medical-demographic information at 
baseline will be tabulated by treatment group to assess comparability between the IGAXT 
and IGAPT groups. Student’s t tests or Wilcoxon rank sum tests will be used to compare 
continuous variables between the two different groups.  Chi-square tests or Fisher’s exact 
tests will be applied to assess the association between two categorical variables.  Time-to-
event outcomes, including overall survival, progression-free survival, time to radiation 
esophagitis, time to treatment-related pneumonitis (TRP), time to local failure, as well as 
time to treatment failure, will be estimated by using the Kaplan-Meier method.  Log-rank 
tests will be used to test the difference in time-to-event distributions between treatment 
groups. Cox proportional hazards models will be used for multi-covariate time-to-event 
analysis to test the treatment effect adjusted by other important covariates such as dose and 
inflammatory cytokines.   In addition, the association of relevant pharmacogenetic endpoints 
and gene polymorphisms with the time to the development of TRP or local failure will also 
be analyzed by the Cox model and other exploratory tools.  Toxicity data will be summarized 
using frequency tables. Associations between the types and severity of toxicity and 
treatment will be evaluated as well. We will also perform subset analyses by dose level. 
Patients who are not randomized (Group 3 and Group 4) will be analyzed using descriptive 
statistics separately from those who are randomized. Patients in Group 3 and Group 4 will 
be analyzed separately. Exploratory analyses may also be performed by combining Group 3 
and Group 4. 
 
14.0 Inclusion of Women and Minorities 
In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard to 
inclusion of women and minorities in clinical research, we have also considered the possible 
interactions between sex and treatments and race and treatments. Participation rates of men and 
women will be examined in the interim analyses. 
 
15.0  References 
1. 
Westeel V, Depierre A. Combined modality treatment of non-small-cell lung cancer. Am J Respir Med 
2003;2:477-490. 
2. 
Williams J, Chen Y, Rubin P, et al. The biological basis of a comprehensive grading system for the 
adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:182-188. 
3. 
Coleman C, Harris J. Current scientific issues related to clinical radiation oncology. Radiat Res 
1998;150:125-133. 
4. 
Movsas B, Raffin TA, Epstein AH, et al. Pulmonary radiation injury. Vol 111; 1997. pp. 1061-1076. 
5. 
Martel M, Ten Haken R, Hazuka M, et al. Dose-volume histogram and 3-D treatment planning 
evaluation of patients with pneumonitis. Int J Radiat Oncol Biol Phys 1994;28:575-581. 
6. 
Travis EL, Liao Z-X, Tucker SL. Spatial heterogeneity of the volume effect for radiation pneumonitis in 
mouse lung. Int J Radiat Oncol Biol Phys 1997;38:1045-1054. 
7. 
Khan MA, Van Dyk J, Yeung IWT, et al. Partial volume rat lung irradiation; assessment of early DNA 
damage in different lung regions and effect of radical scavengers. Radiother Oncol 2003;66:95-102. 
8. 
Liao Z-X, Travis EL, Tucker SL. Damage and morbidity from pneumonitis after irradiation of partial 
volumes of mouse lung. Int J Radiat Oncol Biol Phys 1995;32:1359-1370. 
9. 
Moiseenko VV, Battista JJ, Hill RP, et al. In-field and out-of-field effects in partial volume lung 
irradiation in rodents: Possible correlation between early dna damage and functional endpoints. Int J 
Radiat Oncol Biol Phys 2000;48:1539-1548. 


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10. 
Wang S, Liao Z, Wei X, et al. Analysis of clinical and dosimetric factors associated with treatment-
related pneumonitis (TRP) in patients with non-small-cell lung cancer (NSCLC) treated with 
concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). Int J Radiat 
Oncol Biol Phys 2006;66:1399-1407. 
11. 
Fay M, Tan A, Fisher R, et al. Dose-volume histogram analysis as predictor of radiation pneumonitis 
in primary lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 2005;61:1355-
1363. 
12. 
Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system 
for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-181. 
13. 
Seppenwoolde Y, De Jaeger K, Boersma LJ, et al. Regional differences in lung radiosensitivity after 
radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;60:748-758. 
14. 
Hong L, Alektiar KM, Hunt M, et al. Intensity-modulated radiotherapy for soft tissue sarcoma of the 
thigh. Int J Radiat Oncol Biol Phys 2004;59:752-759. 
15. 
Murshed H, Liu HH, Liao Z, et al. Dose and volume reduction for normal lung using intensity-
modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 
2004;58:1258-1267. 
16. 
Burman C, Kutcher G, Emami B, et al. Fitting of normal tissue tolerance data to an analytic function. 
Int J Radiat Oncol Biol Phys 1991;21:123-135. 
17. 
Hayman JA, Martel MK, Ten Haken RK, et al. Dose Escalation in Non-Small-Cell Lung Cancer Using 
Three-Dimensional Conformal Radiation Therapy: Update of a Phase I Trial. Vol 19; 2001. pp. 127-
136. 
18. 
Liu HH, Wang X, Dong L, et al. Feasibility of sparing lung and other thoracic structures with intensity -
modulated radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1268-
1279. 
19. 
Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage 
non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated 
radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:94-102. 
20. 
Gopal R, Tucker SL, Komaki R, et al. The relationship between local dose and loss of function for 
irradiated lung. Int J Radiat Oncol Biol Phys 2003;56:106-113. 
21. 
Yorke ED, Jackson A, Rosenzweig KE, et al. Dose-volume factors contributing to the incidence of 
radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal 
radiation therapy. Int J Radiat Oncol Biol Phys 2002;54:329-339. 
22. 
Chang M, Lee H, Lee B, et al. Differential protein expression between esophageal squamous cell 
carcinoma and dysplasia, and prognostic significance of protein marker. Pathol Res Pract 
2005;201:417-425. 
23. 
Chang JY, Zhang X, Wang X, et al. Significant reduction of normal tissue dose by proton radiotherapy 
compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or 
Stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;65:1087-1096. 
24. 
Cox J, Chang J, Liao Z. Acute esophageal reactions from proton beam therapy and concurrent 
chemotherapy for non-small cell lung cancer (NSCLC): Reduction in incidence and sevrity despite 
higher doses. Int J Radiat Oncol Biol Phys 2007. 
25. 
Moyers M, Miller D. Range, range modulation, and field radius requirements for proton therapy of 
prostate cancer. Technol Cancer Res Treat 2003;5. 
26. 
Urie M, Goitein M, Wagner M. Compensating for heterogeneities in proton radiation therapy. Phys 
Med Biol 1983;29:553-566. 
27. 
Huang E, Liao Z, Cox J, et al. Comparison of outcomes for patients with unresectable, locally 
advanced non-small-cell lung cancer treated with induction chemotherapy followed by concurrent 
chemoradiation vs. concurrent chemoradiation alone. Int J Radiat Oncol Biol Phys 2007;68:779-785. 
 
 
 
 
 
 
 


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SAP_001.pdf: 
Protocol: 2008-0133 
February 19, 2013 
Version 17 
Page 1 
  
The University of Texas 
M. D. Anderson Cancer Center 
2008-0133: A Bayesian randomized trial of Image-Guided Adaptive Conformal Photon 
vs Proton Therapy, with Concurrent Chemotherapy, for Locally Advanced Non-Small 
Cell Lung Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence 
 
 
Version 17
Acceoted on 2/19/2013 
 
 
 
13.2 
Sample Size Calculation and Data Analysis Plan 
 
13.2.1 
Hypothesis 
 
  
The primary endpoint of the study is time to treatment failure, defined as the interval from the 
time of randomization to the development of treatment-related pneumonitis (TRP) or local 
failure, whichever occurs first.  We are interested in studying whether IGAPT can reduce the 
TRP rate compared with IGAXT. Although local disease control rates are thought to be similar 
for IGAPT and IGAXT, this assumption needs to be prospectively tested, and hence we chose 
a combined endpoint of TRP and local failure as the primary endpoint.  
 
 
Our primary outcome is time to treatment failure. Treatment failure is defined as TRP or local 
failure. These 2 types of failure are equally important. Based on the preliminary data, it is 
assumed that the time to treatment failure follows a log-normal distribution, with 6-month and 
12-month treatment failure rates for the IGAXT arm of 30% and 40%, respectively (27). We 
also assume that under the null hypothesis (H0), failure in the IGAPT arm is the same as 
failure in the IGAXT arm, and under the alternative hypothesis (H1), IGAPT can reduce the 
corresponding failure rates to 20% and 25%, respectively.   
 
 
Eligible patients will be assigned to receive either IGAXT or IGAPT based on the Bayesian 
adaptive randomization method.  Adaptive randomization will allocate more patients to the 
treatment that yields more favorable outcomes based on the interim observed data. This 
design is appealing ethically because if a difference is found in treatment efficacy, more 
patients in the trial can be treated with the more effective treatment.  If no difference is found 
in treatment efficacy, patients will be assigned with equal probability to either treatment, as is 
the case in the conventional randomized trials with equal allocation ratio.  With a maximum of 
150 eligible  patients, we will have 81% power to detect this difference with a one-sided type 
I error rate of 10% or less (see subsequent sections and Table 4 [Operating Characteristics] 
for details).  Under H1, there is a 48% chance of early stopping with about 58% of the patients 
randomized into the IGAPT group in a median sample size of 128. The sample size calculation 
assumes an accrual rate of 7 patients per month with 32 months of accrual plus an additional 
24 months of follow-up.  The total sample size is up to 250 patients, to account for patients 
being ineligible or lost to follow-up. 
 
 
Patients randomized to IGAPT may be denied insurance reimbursement for this treatment, 
and therefore, they may elect not to be treated with IGAPT. These patients will be transferred 
to Group 4, as described in section 7.5, and they will be treated with the highest dose of IGAXT 
possible (74 CGE, 66 CGE). 


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13.2.2 Model specification for Bayesian adaptive randomization design using time-to-treatment-
failure as the endpoint. 
The time to treatment failure is assumed to follow a log-normal distribution.  A Bayesian 
lognormal regression model with adaptive randomization will be used 
Specifically, we will conclude that IGAPT is better if, given the current data, the probability of 
time to treatment failure for IGAPT being longer than for IGAXT is greater than PL.  The 
proposed design allows continuous monitoring.  The trial can be stopped early should the 
interim results indicate a high probability of one treatment being better than the other.  
Specifically, we set PL = 0.70 for interim monitoring.  If the trial continues to the end without 
being stopped early, we set PL = 0.59 in the final analysis.  The probability calculation is 
confined to within the 24-month period, which corresponds to the clinical implication of the 
relevance and importance of recurrence or TRP during this period. 
 
Patients will be randomized to the achievable radiation dose [74, 66] as described in section 
7.5. We assume that approximately 1/3 of patients will be randomized to each dose level. 
However, we do not expect any differences between doses with respect to the treatment 
effects on TRP or local failure. The calculations of randomization probabilities and decision 
rules described above will include all data across dose levels. 
 
 
13.2.4 Operating characteristics 
The operating characteristics from 1,000 simulation runs are summarized in Tables 4a, 4b 
and 4c.  According to the specifications given in the above two sections, a total of 150 eligible 
patients are uniformly enrolled during the 24-month accrual period. An event of either grade 
> 3 TRP or local failure is defined as a treatment failure. The first 20 patients are equally 
randomized into one of the two groups. After enrolling the first 20 patients and after one event 
is observed in each group, patients are adaptively randomized based on the posterior 1-year 
failure rate estimates of the two groups. Failure or losses to follow-up for randomized patients 
are updated as they occur, i.e., the observed failure or loss to follow-up is updated as it 
happens. In addition, when new patients enter the study, the censoring time is updated for all 
patients who are still on study but have not yet developed an events. The early stopping rule 
applies after a total of 20 events is observed in the entire sample. The decision rules for 
declaring that one treatment is better than the other are given in the previous section. 
 
 
Under H0 (Scenario 0 in Table 4a), where IGAPT is assumed to produce the same 1-year 
treatment failure rate (40%) as IGAXT, there is a 4.9% chance of early stopping because 
IGAPT is better than IGAXT and a 5.3% chance of early stopping because IGAXT is better. 
The 2.5th, 50th, and 97.5th percentiles for the proportion of patients randomized into the 
IGAPT group are 37%, 50%, and 65%, respectively. The median sample sizes are 75 and 
74 for the IGAPT and IGAXT groups, respectively. There is an 8.7% chance to claim IGAPT 
as being better and an 8.1% chance to claim IGAXT as being better at the end of the study. 
The average trial length is 3.70 years. 
 
 
Under H1 (Scenario 1 in Table 4a), where IGAPT is assumed to produce lower 1-year 
treatment failure rates than IGAXT (25% versus 40%), there is a 48% chance of early 
stopping because IGAPT is better than IGAXT, but there is virtually no chance of early 
stopping because IGAXT is better. The 2.5th, 50th, and 97.5th percentiles for the proportion 
of patients randomized into the IGAPT group are 44%, 58%, and 73%, respectively. The 
median sample sizes are 74 for the IGAPT group and 54 for the IGAXT group. There is an 
81% chance to claim IGAPT as being better and virtually no chance to claim IGAXT as 
being better at the end of the study. The average trial length is 2.70 years. 
 


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Additional simulations summarized in Table 4a show that we have more than a 90% chance 
to claim IGAPT as being better and virtually no chance to claim IGAXT as being better at the 
end of the study for a situation where the treatment failure rate decreases with dose for both 
IGAXT and IGAPT (Scenario 2). We also have more than an 80% chance to claim IGAPT as 
being better and virtually no chance to claim IGAXT as being better at the end of the study for 
a situation where the difference in treatment failure rates between IGAXT and IGAPT 
decreases with dose (Scenario 3). 
 
Simulations summarized in Table 4b show that with 10% of patients randomized to IGAPT 
and then denied insurance coverage for their treatment, we still have at least 80% power for 
Scenarios 1-3 and about a 10% significance level under Scenario 0. With 10% of patients 
randomized to IGAPT and then denied insurance coverage for their treatment the trial will 
need to enroll a few more patients on average, it will last a little longer, and the proportion of 
patients treated on IGAPT will be a 2%-3% less than if there was no insurance denial. 
 
Simulations summarized in Table 4c show that with 25% of patients randomized to IGAPT 
and then denied insurance coverage for their treatment, we still have at least 80% power for 
Scenarios 1 and 2, about 80% power for Scenario 3, and about a 10% significance level under 
Scenario 0. With 25% of patients randomized to IGAPT and then denied insurance coverage 
for their treatment the trial will need to enroll a few more patients on average, it will last a little 
longer, and the proportion of patients treated on IGAPT will be a 7%-8% less than if there was 
no insurance denial. 
 
In both cases of 10% or 25% insurance denial, the trial will have only modest (<10%) 
increases in the total sample size and study duration. 
 
 
 


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Table 4. Operating characteristics (n=150 eligible patients). Assumes 90% of patients at 74 CGE and 10% 
of patients at 66 CGE. Also assumes 10% of patients assigned to IGAPT dropped due to insurance denial. 
 
 
Scenario 0 (H0) 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.40, 0.40 
Total Sample Size 
(including insurance 
denial) 
 
Percentile
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
33 
27 
74 
50.0% 
77 
70 
156 
97.5% 
96 
90 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.33 
 
50.0% 
 
0.47 
 
97.5% 
 
0.63 
 
 
 
 
 
 
Probability of early stopping 
 
0.050 
0.059 
 
Probability of final selection 
 
0.084 
0.104 
 
Average trial length (years) 
 
3.77 
 
 
 
Scenario 1 (H1) 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.25, 0.25 
Total Sample Size 
(including insurance 
denial) 
 
Percentile
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
26 
38 
76 
50.0% 
58 
71 
153 
97.5% 
86 
95 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.41 
 
50.0% 
 
0.56 
 
97.5% 
 
0.71 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.473 
 
Probability of final selection 
 
0.0 
0.811 
 
Average trial length (years) 
 
2.80 
 
 
 
Scenario 2 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66 CGE: 
IGAXT 
0.40, 0.30 
IGAPT 
0.25, 0.15 
Total Sample Size 
(including insurance 
denial) 
 
Percentile
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
27 
41 
81 
50.0% 
58 
69 
153 
97.5% 
90 
94 
163 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.39 
 
50.0% 
 
0.55 
 
97.5% 
 
0.71 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.493 
 
Probability of final selection 
 
0.0 
0.815 
 
Average trial length (years) 
 
2.76 
 
 
 
Scenario 3 
 
True 1-Year Treatment Failure Rates for  
Doses 74, 66,CGE: 
IGAXT 
0.40, 0.40 
IGAPT 
0.20, 0.25 
Total Sample Size 
(including insurance 
denial) 
 
Percentile
 
 
 
 
 
 
 
 
Distribution of number of patients 
after adaptive randomization 
  2.5% 
26 
40 
81 
50.0% 
46 
68 
117 
97.5% 
82 
96 
162 
Distribution of the proportion of 
patients randomized to IGAPT 
  2.5% 
 
0.43 
 
50.0% 
 
0.58 
 
97.5% 
 
0.73 
 
 
 
 
 
 
Probability of early stopping 
 
0.0 
0.692 
 
Probability of final selection 
 
0.0 
0.952 
 
Average trial length (years) 
 
2.26 
 
 


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13.2.5. Statistical analyses and additional statistical considerations 
Standard statistical methods including descriptive statistics and exploratory data analysis will 
be applied for checking data quality; identifying outliers, patterns, or associations; and 
-demographic information at 
baseline will be tabulated by treatment group to assess comparability between the IGAXT and 
t tests or Wilcoxon rank sum tests will be used to compare 
continuous variables between the two different groups.  Chi-
tests will be applied to assess the association between two categorical variables.  Time-to-
event outcomes, including overall survival, progression-free survival, time to radiation 
esophagitis, time to treatment-related pneumonitis (TRP), time to local failure, as well as time 
to treatment failure, will be estimated by using the Kaplan-Meier method.  Log-rank tests will 
be used to test the difference in time-to-event distributions between treatment groups. Cox 
proportional hazards models will be used for multi-covariate time-to-event analysis to test the 
treatment effect adjusted by other important covariates such as dose and inflammatory 
cytokines.   In addition, the association of relevant pharmacogenetic endpoints and gene 
polymorphisms with the time to the development of TRP or local failure will also be analyzed 
by the Cox model and other exploratory tools.  Toxicity data will be summarized using 
frequency tables. Associations between the types and severity of toxicity and treatment will 
be evaluated as well. We will also perform subset analyses by dose level. Patients who are 
not randomized (Group 3 and Group 4) will be analyzed using descriptive statistics separately 
from those who are randomized. Patients in Group 3 and Group 4 will be analyzed separately. 
Exploratory analyses may also be performed by combining Group 3 and Group 4.