NRG Oncology: RTOG 1308

NRG ONCOLOGY
RTOG 1308
(ClinicalTrials.gov NCT #01993810)
PHASE III RANDOMIZED TRIAL COMPARING OVERALL SURVIVAL AFTER PHOTON VERSUS
PROTON CHEMORADIOTHERAPY FOR INOPERABLE STAGE II-IIIB NSCLC
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network
of NCTN researchers: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Medical Research
Foundation, Inc., and SWOG.
Study Team
Principal Investigator/Radiation Oncology Radiation Oncology Co-Chairs (continued)
Zhongxing Liao, MD Ritsuko Komaki, MD
The University of Texas The University of Texas
MD Anderson Cancer Center MD Anderson Cancer Center
1515 Holcombe Boulevard, Unit 97 1515 Holcombe Blvd. Unit 97
Houston, TX 77030 Houston, TX 77030
713-563-2349/FAX 713-563-2331 713-563-2328/ FAX 713-563-2331
zliao@mdanderson.org rkomaki@mdanderson.org
Radiation Oncology Co-Chairs Bradford Hoppe, MD, MPH

Jeffrey Bradley, MD University of Florida Proton Therapy Institute
Washington University 2015 N. Jefferson Street
4921 Parkview Place Jacksonville, FL 32206
St. Louis, MO 63110 904-588-1450/FAX 904-588-1303
314-362-4633/FAX 314-362-8521 bhoppe@floridaproton.org
jbradley@wustl.edu
Eugen Hug, MD
Noah Choi, MD ProCure Proton Therapy Center
Massachusetts General Hospital 103 Cedar Grove Lane
55 Fruit Street Somerset, NJ 08873
Boston, MA 02114 732-357-2600/FAX 732-412-7438
617-726-8146/FAX 617-726-3603 Eugen.Hug@procure.com
nchoi@partners.org
Medical Oncology Co-Chair
Steven Hahn, MD Charles Lu, MD
Perelman School of Medicine The University of Texas
University of Pennsylvania MD Anderson Cancer Center
3400 Civic Center Blvd 1515 Holcombe Boulevard
TRC 2 West Houston, TX 77030
Philadelphia, PA 19104 713-792-2626/FAX 713-792-1220
215-662-7296/FAX 215-349-5923 clu@mdanderson.org
hahn@uphs.upenn.edu
Study chairs continued on next page
1
RTOG 1308; version date 10/23/14
NRG ONCOLOGY
RTOG 1308
Medical Physics Co-Chairs Outcomes Co-Chair

Michael Gillin, PhD Ben Movsas, MD
MD Anderson Cancer Center Henry Ford Health System
1515 Holcombe Blvd. Unit 94 2799 West Grand Blvd.
Houston, TX 77030 Detroit, MI 48202
713-745-5777/FAX 713-794-5272 313-916-1027/FAX 313-916-3235
MGillin@mdanderson.org bmovsas1@hfhs.org
Radhe Mohan, PhD Comparative Cost Effectiveness Co-Chairs

The University of Texas Deborah Watkins Bruner, RN, PhD
MD Anderson Cancer Center Neil Hodgson Woodruff School of Nursing
1515 Holcombe Blvd. Unit 94 Emory University
Houston, TX 77030 1520 Clifton Road - RM 323
713-745-5777/FAX 713-563-5205 Atlanta, GA 30322
rmohan@mdanderson.org 404-712-9695/FAX 404-727-8514
deborah.w.bruner@emory.edu
Translational Research Co-Chair
Steven H. Lin, MD, PhD Gregory Russo, MD
The University of Texas Boston University School of Medicine
MD Anderson Cancer Center 830 Harrison Avenue, LL
Division of Radiation Oncology Boston, MA 02118
1515 Holcombe Blvd. Unit 97 617-638-7070/FAX 617-638-7038
Houston, TX 77030 Gregory.Russo@bmc.org
713-563-2300/FAX 713-563-2366
SHLin@mdanderson.org Senior Statistician
Chen Hu, PhD
Quality of Life Co-Chair NRG Oncology
Xin Shelley Wang, MD, MPH 1818 Market Street, Suite 1600
The University of Texas Philadelphia, PA 19013
MD Anderson Cancer Center 215-940-4842/FAX 215-928-0153
1515 Holcombe Blvd. Unit 1450 huc@nrgoncology.org
Houston, TX 77030
713/745-3504/FAX 713/745-3475
xswang@mdanderson.org
Protocol Agents
Agent Supply NSC # IND #
Cisplatin Commercial N/A Exempt
Carboplatin Commercial N/A Exempt
Etoposide Commercial N/A Exempt
Paclitaxel Commercial N/A Exempt
Participating Sites
U.S. Only
Canada Only
U.S. and Canada
Approved International Member Sites
2
NRG ONCOLOGY
RTOG 1308
Document History
Version/Update Date Broadcast Date
Amendment 1 October 23, 2014 January 12, 2015
Activation February 3, 2014 February 3, 2014
Update February 3, 2014 February 3, 2014
Update November 26, 2013 November 26, 2013
Pre-Activation October 24, 2013 November 26, 2013
NRG Oncology
1-800-227-5463, ext. 4189
This protocol was designed and developed by NRG Oncology. It is intended to be
used only in conjunction with institution-specific IRB approval for study entry.
No other use or reproduction is authorized by NRG Oncology nor does NRG
Oncology assume any responsibility for unauthorized use of this protocol.
3
TABLE OF CONTENTS
SCHEMA ....................................................................................................................................................... 6
ELIGIBILITY CHECKLIST ........................................................................................................................... 10
1.0 INTRODUCTION............................................................................................................................. 11

1.1 Patient-Reported Outcome Study ............................................................................................... 16
1.2 Comparative Cost Effectiveness Analysis .................................................................................. 19
1.3 Changes in Pulmonary Function After Concurrent Chemoradiation for NSCLC ........................ 21
1.4 Physics and Technological Considerations ................................................................................ 22
2.0 OBJECTIVES .................................................................................................................................. 22

2.1 Primary Objective ........................................................................................................................ 22
2.2 Secondary Objectives ................................................................................................................. 22
3.0 PATIENT SELECTION.................................................................................................................... 22

3.1 Conditions for Patient Eligibility ................................................................................................... 22
3.2 Conditions for Patient Ineligibility ................................................................................................ 23
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT ..................................................................... 24

4.1 Required Pretreatment Evaluations/Management ...................................................................... 24
4.2 Highly Recommended Evaluations/Management ....................................................................... 24
5.0 REGISTRATION PROCEDURES................................................................................................... 24

5.1 RT-Specific Pre-Registration Requirements ............................................................................... 25
5.2 Digital RT Data Submission to RTOG Using TRIAD................................................................... 26
5.3 Dry Run/Knowledge Assessment................................................................................................ 27
5.4 Regulatory Pre-Registration Requirements ................................................................................ 27
5.5 Registration ................................................................................................................................. 28
6.0 RADIATION THERAPY................................................................................................................... 29

6.1 Dose Specifications ..................................................................................................................... 29
6.2 Technical Factors [Equipment, Energies] ................................................................................... 30
6.3 Simulation, Immobilization, Motion Assessment, and Motion Management ............................... 30
6.4 Target Definitions, Target Delineation, and Normal Anatomy Delineation ................................. 31
6.5 Treatment Planning and Quality Assurance ............................................................................... 33
6.6 Compliance Criteria ..................................................................................................................... 35
6.7 Treatment Delivery ...................................................................................................................... 36
6.8 R.T. Quality Assurance Reviews................................................................................................. 38
6.9 Radiation Therapy Adverse Events............................................................................................. 39
7.0 DRUG THERAPY............................................................................................................................ 41

7.1 Treatment .................................................................................................................................... 41
7.2 Cisplatin Agent Information ......................................................................................................... 43
7.3 Etoposide Agent Information ....................................................................................................... 43
7.4 Carboplatin Agent Information .................................................................................................... 44
7.5 Paclitaxel Agent Information ....................................................................................................... 45
7.6 Dose Modifications ...................................................................................................................... 45
7.7 Modality Review .......................................................................................................................... 48
7.8 Adverse Events ........................................................................................................................... 49
7.9 CTEP-AERS Expedited Reporting Requirements ...................................................................... 50
8.0 SURGERY ...................................................................................................................................... 52
4
9.0 OTHER THERAPY.......................................................................................................................... 52
9.1 Permitted Supportive Therapy .................................................................................................... 52
9.2 Non-Permitted Supportive Therapy............................................................................................. 52
10.0 TISSUE/SPECIMEN SUBMISSION................................................................................................ 52

10.1 Tissue/Specimen Submission ..................................................................................................... 52
10.2 Tissue Collection for Banking for Future Research .................................................................... 52
10.3 Serum, Plasma, and Whole Blood for DNA Collection for Banking for Future Research ........... 53
10.4 Storage Conditions for All Specimens ........................................................................................ 53
10.5 Specimen Collection Summary ................................................................................................... 54
10.6 Submit materials for Banking as follows: .................................................................................... 54
10.7 Reimbursement ........................................................................................................................... 55
10.8 Confidentiality/Storage ................................................................................................................ 55
11.0 PATIENT ASSESSMENTS ............................................................................................................. 55

11.1 Study Parameters ....................................................................................................................... 55
11.2 Quality of Life/Cost-Effectiveness ............................................................................................... 55
11.3 Response Assessment (RECIST Criteria) Measurement of Response Prior to Study Entry ..... 55
11.4 Criteria for Discontinuation of Protocol Treatment ...................................................................... 56
12.0 DATA COLLECTION....................................................................................................................... 56

12.1 Summary of Data Submission..................................................................................................... 56
12.2 Summary of Dosimetry Digital Data Submission ........................................................................ 58
13.0 STATISTICAL CONSIDERATIONS ................................................................................................ 59

13.1 Primary Endpoint ......................................................................................................................... 59
13.2 Secondary Endpoints .................................................................................................................. 59
13.3 Sample Size and Power Justification .......................................................................................... 60
13.4 Randomization ............................................................................................................................ 62
13.5 Patient Accrual ............................................................................................................................ 62
13.6 Statistical Analysis Plan .............................................................................................................. 62
13.7 Interim and Final Analysis ........................................................................................................... 66
13.8 Gender and Minorities ................................................................................................................. 68
REFERENCES ............................................................................................................................................ 69
APPENDIX I ................................................................................................................................................ 74
APPENDIX II ............................................................................................................................................... 77
APPENDIX III .............................................................................................................................................. 78
APPENDIX IV.............................................................................................................................................. 80
5
NRG ONCOLOGY
RTOG 1308
Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton
Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC
SCHEMA
Stage
1. II
2. IIIA
3. IIIB
R
S Both Arms:
A Arm 1: Photon dose—70 Gy*(RBE), at 2 Gy
T Consolidation
N (RBE) once daily plus platinum-based doublet
R Histology chemotherapy x 2
D chemotherapy**
A 1. Squamous cycles required for
O
T 2. Non-Squamous patients who
M Arm 2: Proton dose—70 Gy (RBE), at 2 Gy
I receive concurrent
I (RBE) once daily plus platinum-based doublet
F carboplatin and
Z chemotherapy**
Y Concurrent paclitaxel***
E
Chemotherapy
Doublet Type
1. Carboplatin/paclitaxel
2. Cisplatin/etoposide
*The total prescribed dose will be 70 Gy [Relative Biological Effectiveness (RBE)] without exceeding
tolerance dose-volume limits of all critical normal structures. (See Section 6.1.3 when 70 Gy (RBE)
is not achieved.)
**Chemotherapy delivered concurrently, cisplatin/ etoposide or carboplatin/paclitaxel doublets, is
required. The site/investigator must declare the chemotherapy regimen that the patient will receive prior
to the patient’s randomization. See Section 7.0 for details.
***If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of carboplatin and
paclitaxel consolidation chemotherapy are required. If cisplatin and etoposide is administered
concurrently with radiotherapy, consolidation chemotherapy is not allowed.
See Section 5.0 for pre-registration credentialing details.
Patient Population: (See Section 3.0 for Eligibility)

Untreated histologically or cytologically proven diagnosis of non-small cell lung cancer prior to
registration. Clinical AJCC (7th ed.) stage II-IIIB medically non-operable disease, or surgically
unresectable disease, or patients who refuse surgery; patients who present with N2 or N3 disease and an
undetectable NSCLC primary tumor also are eligible.
Required Sample Size: 560 patients
6
ELIGIBILITY CHECKLIST (10/23/14)
(page 1 of 4)
NRG Oncology Institution #
RTOG 1308
Case #
(Y) 1. Histologically or cytologically proven diagnosis of non-small cell lung cancer within 90
days of registration
(Y) 2. Clinical AJCC (AJCC, 7th ed.) II, IIIA or IIIB (with non-operable disease; non-operable
disease will be determined by a multi-disciplinary treatment team, involving evaluation by
at least 1 thoracic surgeon) within 60 days prior to registration; Note: For patients who
are clearly non-resectable, the case can be determined by the treating radiation
oncologist and a medical oncologist, or pulmonologist. Patients who refuse surgery are
also eligible. Patients who present with N2 or N3 disease and an undetectable NSCL
primary tumor also are eligible.
(Y) 3. Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:
 History/physical examination within 30 days prior to registration;
 FDG-PET/CT scan for staging within 60 days prior to registration.
 MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast
within 60 days prior to registration;
 FEV1 ≥ 1.0 Liter or ≥ 40% predicted with or without bronchodilator within 90 days
prior to registration.
o Patients who meet the criterion above without O2, but who need acute
(started within 10 days prior to registration) supplemental oxygen due to
tumor-caused obstruction/hypoxia are eligible, provided the amount of the O2
needed has been stable.
(Y) 4. Zubrod performance status 0-1 within 30 days prior to registration
(Y) 5. Age ≥ 18
(Y) 6. CBC/differential obtained within 30 days prior to registration, with adequate bone marrow
function defined as follows:
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
 Platelets ≥ 100,000 cells/mm3;
 Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve
Hgb ≥ 9.0 g/dl is acceptable.)
(Y) 7. SGOT or SGPT ≤ 1.5 upper limit of normal within 30 days prior to registration
(Y) 8. Total bilirubin ≤ 1.5 upper limit of normal within 30 days prior to registration
(Y) 9. Serum creatinine < 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/min within 30
days prior to registration estimated by the Cockcroft-Gault formula
Creatinine Clearance (male) = [(140 – age) x (wt in kg)]

[(Serum Creatinine mg/dl) x (72)]
Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male)
(Y) 10. Peripheral neuropathy ≤ grade 1 at the time of registration
7
(page 2 of 4)
RTOG 1308
Case #
(Y) 11. Patients with non malignant pleural effusion are eligible. If a pleural effusion is present,
the following criteria must be met to exclude malignant involvement:
 When pleural fluid is visible on both the CT scan and on a chest x-ray, a
pleuracentesis is required to confirm that the pleural fluid is cytologically negative.
 Exudative pleural effusions are excluded, regardless of cytology;
 Effusions that are minimal (ie, not visible on chest x-ray) and that are too small to
safely tap are eligible.
(Y) 12. Patients must have measurable or evaluable disease
(Y) 13. Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to registration.
(Y) 14. Women of childbearing potential and male participants must practice adequate
contraception.
(Y) 15. Patient must provide study-specific informed consent prior to study entry.
(N) 16. Prior invasive malignancy unless disease free for a minimum of 3 years. However, skin
cancer and in situ carcinomas of the breast, oral cavity, cervix, and other organs and are
permissible.
(N) 17. Patients with prior history of either small cell lung cancer or NSCLC regardless of the
treatment received.
(N) 18. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable. See Section 3.2.1.
(N) 19. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields.
(N) 20. Does the patient have any of the severe, active co-morbidity, defined as follows:
 Unstable angina and/or congestive heart failure requiring hospitalization within the
last 6 months;
 Transmural myocardial infarction within the last 6 months;
 Chronic obstructive pulmonary disease exacerbation or other respiratory illness other
than the diagnosed lung cancer requiring hospitalization or precluding study therapy
within 30 days before registration;
 Acquired immune deficiency syndrome (AIDS) based upon current CDC definition;
note, however, that HIV testing is not required for entry into this protocol. The need to
exclude patients with AIDS from this protocol is necessary because the treatments
involved in this protocol may be significantly immunosuppressive.
(N) 21. Unintentional weight loss > 10% within 90 days prior to registration.
(N) 22. Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly teratogenic.
8
(page 3 of 4)
RTOG 1308
Case #
The following questions will be asked at Study Registration:

See section 5 for 3DCRT, IMRT, Motion Management, Proton, Dry Run/Knowledge Assessment,
and IGRT CREDENTIALING REQUIRED BEFORE REGISTRATION
1. Institutional person randomizing case.
(Y) 2. Has the Eligibility Checklist been completed?
(Y) 3. In the opinion of the investigator, is the patient eligible?
4. Date informed consent signed
5. Patient’s Initials (Last First Middle)
6. Verifying Physician
7. Patient ID
8. Date of Birth
9. Race
10. Ethnicity
11. Gender
12. Country of Residence
13. Zip Code (U.S. Residents)
14. Method of Payment
15. Any care at a VA or Military Hospital?
16. Calendar Base Date
17. Randomization date
18. Medical oncologist’s name
(Y/N) 19. Have you obtained the patient's consent for his or her tissue to be kept for use in
research to learn about, prevent, treat, or cure cancer?
(Y/N) 20. Have you obtained the patient's consent for his or her blood to be kept for use in
research to learn about, prevent, treat, or cure cancer?
9
(page 4 of 4)
RTOG 1308
Case #
(Y/N) 21. Have you obtained the patient's consent for his or her tissue to be kept for use in
research about other health problems (for example: causes of diabetes,
Alzheimer's disease, and heart disease)?
(Y/N) 22. Have you obtained the patient's consent for his or her blood to be kept for use in
research about other health problems (for example: diabetes, Alzheimer's
disease, or heart disease).
(Y/N) 23. Have you obtained the patient's consent to allow someone from this institution to
contact him or her in the future to take part in more research?
(Y/N) 24. Did the patient agree to participate in the quality of life component?”
If no, please specify the reason from the following:

1. Patient refused due to illness
2. Patient refused for other reason: specify _____________
3. Not approved by institutional IRB
4. Tool not available in patient’s language
5. Other reason: specify_________________
(II/IIIA/IIIB) 25. Stage
(Squamous cell carcinoma or Non-squamous cell carcinoma) 26. Histology
(Cisplatin and Etoposide or Carboplatin and Paclitaxel) 27. Concurrent chemotherapy

doublet type
(N/Y) 28. Specify use of IMRT if you are randomized to the photon arm
_______(CTEP code) 29. CTEP code of site delivering photon therapy
_______(CTEP code) 30. CTEP code of site delivering proton therapy
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed,
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated
during an institutional NCI/NRG Oncology audit.
Completed by Date
10
1.0 INTRODUCTION
Lung cancer is the leading cause of cancer-related death. A total of 226,160 new cases and
160,340 deaths from lung cancer were estimated in 2012 in the U.S., and 80% to 85% were
NSCLC (American Cancer Society 2012). Radiation therapy is a critical component in both
curative and palliative treatment because most patients present with regional nodal disease that
cannot be cured with surgery.
During the past decade, significant advancements have taken place in radiation technology,
including the use of image guidance for both radiation planning and delivery, intensity-modulated
radiation therapy (IMRT), and tumor-motion management. These advances have translated to
improved treatment outcomes with reduced toxicity and improved survival (Yom 2007).
However, rates of local tumor failure of up to 50% remain a major problem after definitive
concurrent chemoradiation therapy (Dillman 1996, Sause 2000, Kong 2005).
Long-term survival has been shown to be better for patients without local-regional recurrence
than for those who develop local recurrence after lung cancer treatment (Auperin 2010), and
radiation doses of up to 69.6 Gy correlate with better tumor control and survival (Machtay 2012).
RTOG 1106/ACRIN 6697, a continuation of the effort to escalate tumor dose with functional
image guidance and adaptive re-planning, was recently activated. In this trial, with isotoxicity
used to guide treatment planning, the final total tumor dose will be escalated to as high as 85.5
Gy in 30 fractions.
However, intensification of the radiotherapy dose to the thorax, especially when concurrent
chemotherapy is administered, is often associated with severe toxicity, including treatment-
related pneumonitis and esophagitis. Three representative RTOG concurrent chemotherapy
and radiation dose intensification phase III trials for thoracic cancers (RTOG 0617 and RTOG
9410 for lung cancer and RTOG 94-05 for esophageal cancer) (Bradley2011, Minsky 2006,
Curran 2011) failed to demonstrate any benefit from high-dose radiation; indeed, the high-dose
arms had higher mortality. The phase III RTOG 0617 trial was originally designed to test
standard-dose (60 Gy) with high-dose radiation (74 Gy) with chemotherapy for stage III NSCLC.
However, the radiation dose-escalation component of this trial was closed in June 2011 when a
planned interim analysis showed that the 2 high-dose arms crossed a futility boundary. The
median survival times were 21.7 months for the control arms and 20 months for the high-dose
arms (Bradley 2011). In RTOG 94-10, a 3-arm study comparing induction versus concurrent
chemoradiation therapy at a standard dose of 60-63 Gy and at 69.6 Gy, the survival of the 69.6
Gy arm was worse than the 60 Gy arm; both were given with concurrent chemotherapy (Curran
2011). RTOG 94-05 was a phase III trial of combined modality therapy for esophageal cancer
comparing standard dose (50.4 Gy) with high-dose (64.8 Gy) radiation; the 2-year survival rates
in this study were 31% in the high-dose versus 40% in the standard-dose arms (Minsky 2006).
The reasons for the failure of the high-dose treatments to produce a survival difference in RTOG
94-10, RTOG 0617, and RTOG 94-05 remain to be determined, and treatment-related toxicity
might have contributed to the early deaths that occurred in these trials. Nonetheless, based on
the results of RTOG 0617, 74 Gy would not be considered an acceptable dose for photon
radiation, and therefore, 70 Gy (RBE) will be used in this study for both the photon and proton
arms. Furthermore, upon review by the study PIs, if normal tissue constraints cannot be met at
the 70 Gy (RBE) level, the dose will be decreased to as low as 60 Gy (RBE).
In terms of dosimetry, the use of protons as a source of therapeutic radiation provides a

substantial improvement over the dose distributions that can be achieved with conventional
sources of radiation such as high-energy x-rays. Because of the poor outcome of conventional
radiotherapy for most lung cancers and the high sensitivity of the adjacent normal tissues to
radiation, proton therapy has the potential for significant clinical gain owing to the unique
physical and dosimetric characteristics of protons, particularly the fact that large volumes of
critical organs at risk (OARs), such as the lung and heart, may receive greatly reduced or no
radiation dose. For example, this proton advantage can be exploited by reducing heart dose.
On multivariate analysis of RTOG 0617 for factors associated with overall survival between
11
standard dose and high dose radiation, lower heart V5 (heart V5= the volume of heart receiving
≥ 5 Gy) was associated with improved overall survival. Heart doses with proton beam therapy
are lower compared to the heart doses with IMRT. The Figure below shows the heart V5 value
for 103 patients on an ongoing trial. The mean value for Heart V5 is 14.6% (±13.6% SD) with
protons, and 44.3% (±33.3% SD) with IMRT. A t-test verifies a statistically significant (p<0.0001)
lower dose for protons than IMRT for Heart V5 values.
Heart V5
100
Relative Volume [%]
80
60
40
20
0
PSPT IMRT
Box-plot shows the maximum and minimum values (whisker) and 75th and 25th
percentile (box) and mean (center line) for 103 lung patients that were randomized
between passive scattering proton therapy (PSPT) or IMRT
Furthermore, in a previous study (Tucker and Liao 2012), investigators at MD Anderson

hypothesized that heart dose affects overall survival (OS) of patients with non-small cell lung
cancer (NSCLC) receiving definitive concurrent chemoradiotherapy. These investigators tested
this hypothesis by investigating the impact of mean heart dose (MHD) on OS in a retrospective
study including 532 patients with NSCLC treated with concurrent chemoradiation. The range of
radiation dose to tumor was 60 to 74.25 Gy, with most patients receiving 60, 63, 66, 69.6, 70, or
74 Gy. The techniques used for treatment delivery were 3-dimensional radiation (3DCRT, n=
332), intensity modulated radiation (IMRT, n=141), and passive scattering proton beam therapy
(PBT, n=59). Mean heart doses ranged from 0 to 55.4 Gy, with 25th, 50th, and 75th percentiles
corresponding to 9.9 Gy, 18.4 Gy, and 28.7 Gy, respectively. The median MHD was 22.3 Gy,
15.1 Gy and 6.5 Gy for 3DCRT, IMRT, and PBT, respectively. The median follow-up time was
18.6 months for the entire group and 36.1 months for surviving patients. By multivariate
analysis, mean heart doses above the 25% percentile were significantly associated with an
increased risk of death, with a hazard ratio (HR) of 1.4 compared to patients with MHD in the
lowest quartile (see Figure below). Other factors selected by the model as being independently
associated with survival were prescribed dose <63 Gy (HR=1.6), stage IV disease (HR=1.6),
and GTV, with a hazard ratio of 1.5 for tumors larger than the median GTV, and an additional
HR of 1.4 for tumors above the 75th percentile in size.
12
OS in patients with mean heart doses above or below the median per radiation dose
subgroups. There was a consistent trend for shorter survival with higher mean heart
doses in all 4 groups, and the difference in OS reached statistical significance in the
68-70 Gy group.
These investigators also noted that a bi-institutional prospective trial, “A Bayesian Randomized Trial
of Image-Guided Adaptive Conformal Photon (74 Gy) vs. Proton Therapy (74 Gy), with Concurrent
Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Radiation Pneumonitis and
Locoregional Recurrence” (MDACC 2008-0133, Clinicaltrials.gov identifier NCT00915005), currently
being conducted jointly by MD Anderson and Mass General, demonstrates the feasibility of multi-
institutional trials of proton therapy for patients with lung cancer. The investigators also compared
mean heart dose in 103 randomized patients between the proton and IMRT arms and found that the
mean heart dose has been consistently lower in the proton arm (see Figure below).
Mean heart dose between patients randomized to proton versus IMRT
13
Additional preliminary clinical studies have recently demonstrated that the 18-month overall
survival rate after concurrent chemoradiotherapy for NSCLC was strongly influenced by both
mean dose to heart (MHD) and lung V20 (Liao 2012), suggesting that the unwanted dose to heart
and lung during radiation therapy may contribute to the early death of patients with NSCLC
treated with concurrent chemoradiation. In the MD Anderson study, the potential association
between MHD and lung V20 and OS up to 18 months after start of radiotherapy was assessed
using a Cox proportional hazards analysis with forward stepwise selection of factors significant at
p<0.05. Patients surviving longer than 18 months were censored for OS at this time point. The
following factors also were considered for inclusion in the model to correct for their potential
effects on OS and/or their association with MHD and lung V20: tumor stage and histology, gross
tumor volume (GTV), patient’s Karnofsky status, treatment technique, and prescribed
radiotherapy dose. By multivariate analysis, the risk factors for survival included GTV, lung V20,
and MHD. Patients with GTV, MHD, and lung V20 above the median for each factor had 36%
survival at 18 months, whereas survival among patients with all three of these factors below the
median was 83%. Patients with one factor or two factors above the median had intermediate
survival levels at 18 months: 58% and 50% respectively (Figure below). Preliminary analysis of
RTOG 0617 further showed the heart V5 also to be associated with OS, supporting the
hypothesis of this concept that reduced dose to heart using proton beam therapy would improve
OS (Bradley 2011).
Association of OS and GTV, heart, and lung dose
Dosimetric treatment planning studies have shown that proton beam therapy can significantly
spare the critical organs in thorax, including normal lung, heart, esophagus, and spinal cord
(Chang 2006). Retrospective studies from MD Anderson and elsewhere seem to indicate that
chemotherapy given with proton beam therapy led to less severe treatment-related toxicity among
patients with locally advanced NSCLC relative to patients given chemotherapy plus photon RT.
Reductions in toxicity were observed for the lung, heart, esophagus, and bone marrow (Sejpal
2011).
Other retrospective studies from MD Anderson on stage II-IIB NSCLC also seem to indicate an
increase in OS rate from 20.3% to 35.1% (P=0.038) and an extension of median survival time
from 16.2 months with IMRT to 20.7 months with proton beam therapy, both given with
concurrent chemotherapy (Cox, personal communication, 2012).A study from Japan also
confirmed the advantage of high-dose proton beam therapy for NSCLC (Oshiro 2012).
14
A phase II single-arm prospective trial from MD Anderson confirmed the potential advantage
from high-dose proton therapy [74 cobalt Gray equivalents (CGE)] versus historical IMRT with
regard to treatment-related pneumonitis and OS: the median survival time in this study was 29.4
months (Chang 2011). The RTOG 1308 trial will keep the maximum tumor dose at 70 Gy
[relative biological effect (RBE)] based on the results of this phase II trial and the early results
from RTOG 0617. Based on pilot work at MD Anderson, an increase in median survival time
from 21 months in the photon arm to 28 months in the proton arm is expected. The proposed
study uses 28 months as the median survival time as the primary objective for 2 reasons: first,
because expecting a median survival time of 29.4 months for the proton arm would be quite
aggressive, especially in the less-tightly-controlled setting of a multicenter trial, and second,
because the highest dose will be 70 Gy (RBE), not 74 Gy (RBE). Furthermore, the normal
tissue constraints at 70 will be the same as those acceptable for 60 Gy (RBE).
Other evidence in support of proton beam therapy for locally advanced NSCLC comes from early
findings of an NCI-sponsored P01, “A Bayesian Randomized Trial of Image-Guided Adaptive
Conformal Photon vs. Proton Therapy, with Concurrent Chemotherapy, for Locally Advanced
Non-Small Cell Lung Carcinoma: Radiation Pneumonitis and Locoregional Recurrence” (MDACC
2008-1033, clinicaltrials.gov identifier NCT00915005), currently being conducted jointly by MD
Anderson and Massachusetts General. This trial is proceeding smoothly according to the trial
design. This trial mandates motion management with 4D CT simulation and, when appropriate,
gating. (RTOG 1308 will permit any type of motion management methods used by participating
institutions). The P01 trial requires the development of both IMRT and proton plans before
randomization. Patients are randomized only when both IMRT and proton plans can meet the
dose-volume constraints of OARs. All treatment plans are initially attempted at dose level of 74
Gy (RBE) for both IMRT and protons. If one of the plans cannot meet the normal tissue dose
constraints for ALL OARs, a second set of plans is attempted at the 66 Gy (RBE) level. Weekly
4D CT is acquired to access the need for adaptive re-planning, and PET scans are obtained at
mid-treatment as well. (In the RTOG 1308 study, mid-treatment PET will not be required).
This ongoing P01 trial has provided the investigators with invaluable insights for conducting a
randomized trial of proton therapy. These investigators have learned the following so far: 1) peer
review of all contours is critical; 2) image guidance with daily kV imaging and weekly CT scans is
very important; 3) modifications to treatment plans to adapt to changes in tumor or anatomy were
needed in 20% of the IMRT cases and 55% of the proton cases; 4) ~ 70% of all patients who
consented to this trial could be randomized, and among the randomized patients, 75% were at 74
Gy (RBE) and 25% at 66 Gy (RBE) dose levels; 5) five patients withdrew consent after having
been randomized to the IMRT arm (to date, no patients randomized to the proton arm have
withdrawn consent) and 9 patients were denied insurance coverage after having been
randomized to the proton arm; 6) among patients for whom the plan could not meet the
stipulated dose constraints, the modality that achieved higher target dose without violating dose-
volume constraints was used to deliver the treatment, and 7) the rate of treatment interruption or
incompletion has been extremely low. Of the 103 randomized patients, there have been 3 (2
disease progression, 1 esophagitis) patients who received less than 60 Gy due to treatment
interruption. Finally, early findings suggest that the outcomes in both the IMRT and proton groups
are better than those of historical controls.
With much discussion amongst the existing lung cancer experts at proton centers within the
U.S., this proposal differs from strategies used in RTOG 0617 in the following: a) This protocol
will allow the patient’s dose to be individualized to the highest achievable dose (within normal
tissue organs-at-risk [OAR] constraints) between 60-70 Gy; b) The protocol will maintain strict
organs-at-risk constraints for this trial; and c) The protocol will perform preliminary quality
assurance review as patients are entered on the trial to monitor dose prescriptions and
dose/contouring compliance.
The prescribed dose for this study is 70 Gy. The study is designed to allow lower doses in
situations for which critical structure constraints cannot be met. Before treatment can begin
15
using lower doses, a pre-treatment review of the case must be performed by one of the radiation
oncologist study chairs.
The rationale for testing proton therapy in stage III NSCLC in this trial is to determine if proton
therapy can improve overall survival by reducing the risk of severe toxicity to organs at risk
compared to photon-based IMRT.
Local tumor recurrence contributes to both morbidity and mortality in locally advanced NSCLC,
and increasing local control translates to survival benefits, especially in the era of effective
systemic therapy. Radiation therapy is a mainstay of treatment for locally advanced NSCLC, and
current therapy includes chemotherapy. Radiation dose escalation may improve local-regional
disease control and OS in patients with stage III NSCLC. Results from several groups (Kong
2005, Bradley 2002, Rengan 2004, Wang 2006) and a recent RTOG secondary analysis
(Machtay 2012) of more than 1,300 cases treated with chemoradiation in the dose range of 60-70
Gy have demonstrated that use of high-dose radiation is associated with improvements in both
these variables. However, these improvements come at the cost of increased treatment-related
toxicity (Curran 2011). Further improvements in OS for patients with NSCLC have been
challenging because of the difficulty in escalating radiation doses to the tumor further without
increasing the radiation dose to proximal critical organs.
Advancements in technology such as IGRT, IMRT, and in particular, proton beam therapy make it
possible to reduce the radiation dose and the volumes of OARs exposed and thus, to reduce
toxicity. Therefore, these advanced technologies and techniques have the potential to intensify
radiation doses without increasing side effects to unacceptable levels. The physical and
dosimetric characteristics of proton therapy make it an ideal radiation modality for lung cancer,
having the potential to reduce toxicity, improve patient quality of life (QOL), increase tumor dose,
and improve OS of patients with lung cancer. This potential has generated very high interest in
the use of proton beam therapy for cancer, and the number of proton facilities has increased
steadily worldwide. However, the lack of level I evidence of the effectiveness of proton therapy
and concerns regarding its cost and benefits have remained problematic. In April 2012, the NCI
issued “Guidelines for the Use of Proton Radiation Therapy in NCI-Sponsored Cooperative Group
Clinical Trials” http://atc.wustl.edu/credentialing/NCI_Proton_Guidelines_2012.pdf, which
provided some much-needed guidance for the radiation community. However, no standards or
guidelines have been established specifically for aspects of quality assurance, treatment
planning, and delivery of proton radiation therapy.
Given the rapid proliferation of new proton treatment facilities, it is a critical time to objectively and
scientifically assess the potential of protons versus photons for the treatment of lung cancer.
RTOG 1308, being a phase III randomized trial, will help to establish such evidence, which
clinicians can use to guide treatment recommendations. The results of this trial have the potential
to change the current standard of care for unresectable NSCLC.
On the basis of the published and preliminary information summarized in this section, the design
and radiation dose chosen for this trial is considered ethical, safe, and feasible.
1.1 Patient-Reported Outcome Study: Health-Related Quality of Life (HRQOL), Symptom

Burden, and Health Utility Analysis
As noted above, two key toxicities of concern from definitive chemoradiation for locally advanced
NSCLC are treatment-related pulmonary toxicity (ie, clinical pneumonitis and lung fibrosis) and
esophageal toxicity (ie, esophagitis). Thus, these two clinical toxicities will form the basis of the
main patient reported outcomes to be analyzed. Of these two main toxicities, the primary QOL
outcome of this study will focus on the pulmonary toxicity, as this is a typically a chronic effect of
treatment that can have long term negative effects on QOL. Esophagitis, on the other hand,
which will be followed as a secondary QOL outcome, is an acute/subacute effect which is largely
transient.
16
This randomized study aims to provide information on a clinically meaningful QOL benefit from
proton therapy over photon therapy in NSCLC patients. Our primary QOL hypothesis is that,
compared with patients receiving either 3DCRT or IMRT (Arm 1), patients on the proton arm (Arm
2) will have less-severe “shortness of breath” (as measured by the validate MDASI-Lung
instrument) 6 months after the end of concurrent chemoradiation therapy (representing late
adverse response to radiation), and that the differences in symptom ratings between Arms will be
clinically meaningful, after controlling for disease progression.
The second QOL hypothesis is that, compared with patients receiving either 3DCRT or IMRT
(Arm 1), patients in the proton arm (Arm 2) will have less severe “sore throat” (as measured by
the validated MDASI lung instrument) at the end of chemoradiation therapy (at 6 weeks of
therapy, representing acute response) and that the differences in symptom ratings between Arms
will be clinically meaningful.
Beyond analyzing the key patient reported outcomes related to shortness of breath and sore
throat, this study will also follow a variety of other QOL items and symptoms using the MDASI-
Lung and UCSD Shortness of Breath Questionnaire (SOBQ) instruments to better understand
the differences in QOL and breathing functioning between proton and photon therapy.
Time points and rationale are as follows:

1. Baseline: to serve as a control measurement for each patient.
2. 6 weeks during therapy: which is at the end of CXRT, as the peak of acute phase sore
throat symptoms related to esophagitis;
3. At the first follow-up visit (4-8 weeks) after CXRT: to document the initial change on lung
symptom burden related to acute adverse effects of therapy between arms.
4. 6 months post-CXRT document the difference in shortness of breath related to adverse
pulmonary effects of therapy between arms,
5. 12 months post-CXRT: document long-term difference in shortness of breath between
the two arms.
As noted above, dosimetric treatment planning studies have shown that proton beam therapy can
significantly spare the critical organs in thorax, particularly normal lung and esophagus (Chang
2006). Retrospective studies also suggest that chemotherapy given with proton beam therapy led
to less severe treatment-related toxicity among patients with locally advanced NSCLC relative to
patients given chemotherapy plus photon RT. Key reductions in toxicity were observed for the
lung and esophagus (Sejpal 2011).
Why is it important to collect prospective HRQOL data? Why not simply collect the NCI-CTC
toxicity information? More and more, studies are demonstrating a “disconnect” between physician
and patient reported outcome (PROs). This was evident from RTOG 98-01, a phase III trial of
amifostine, a radioprotector, in patients with stage III NSCLC receiving concurrent chemotherapy
and hyperfractionated radiation. Sarna et al (2008) found that patients receiving amifostine
reported significantly greater pain reduction after chemoradiation (34% vs. 21%), less difficulty
swallowing during chemoradiation, and less weight loss than patients not receiving amifostine.
However, physician-rated assessments of dysphagia were not significantly different by treatment
arm. This “disconnect” illustrates the critical role of patient reported outcomes (PRO) in this
setting.
1.1.1 MDASI-Lung
The lung cancer-specific module of the MDASI has also been validated (Mendoza 2011). In
addition to the key QOL endpoints of shortness of breath (the primary QOL endpoint) and sore
throat (the secondary QOL endpoint), this instrument also will capture patient reported outcomes
related to pain, fatigue, coughing, etc. In addition to collecting esophagitis-related symptoms, we
will add a “difficulty swallowing” item from a patient-reported symptom severity with the same 0-
10 scale. This item was validated under MDASI-GI (Wang et al, 2010). The radiation-induced
“difficulty swallowing” was documented as the second-worst symptom overtime of chemoradiation
therapy in esophagus cancer patients (Wang et al, 2012). A “clinically meaningful difference” will
17
be defined as an effect size greater than 0.5 standard deviation (SD) (Cohen 1988) on the
MDASI-Lung symptoms, as indicated by preliminary results from retrospective studies conducted
at MD Anderson (McLeod 2011).
The post-chemoradiation QOL effects of shortness of breath and difficulty swallowing are likely
related to the development of lung and esophagus tissue damage over time in response to
therapy. In an ongoing phase II longitudinal study in NSCLC patients treated by proton or photon
therapy at MD Anderson, investigators observed the following trends of symptom severity from 1
month to 6 months post-chemoradiation (N=96), see Table below. Of note, of these symptoms,
only the pulmonary symptoms (ie, shortness of breath and coughing) continually worsened over
time. The symptoms related to difficulty swallowing, sore throat, pain, and fatigue peaked at 1-3
months after treatment and then began to improve by 6 months. Moreover, the early pilot review
of shortness of breath at 6 months post-CXRT in a smaller sample (N=40) showed that mean
severity was lower for patients treated with protons (2.5) than for patients treated with for IMRT
(3).
MDASI Symptom Severity in NSCLC Patients undergoing Proton or Photon Therapy (N=96)
Shortness of Difficulty
Time Point_ Fatigue Breath Coughing Swallowing Pain Sore Throat
Pre CXRT Mean 2.87 2.22 1.88 .37 1.30 .36
SD 2.43 2.26 1.86 1.07 2.098 .95

1 month Mean 3.72 2.45 2.57 2.56 2.10 2.09
SD 2.57 2.31 1.97 2.67 2.292 2.51
3 months Mean 4.24 2.98 2.81 2.70 2.58 1.55
SD 2.65 2.52 2.59 2.87 2.562 2.35
6 months Mean 3.48 3.22 3.26 1.30 2.10 1.30
SD 2.58 2.69 2.82 2.31 2.646 2.04
Total Mean 3.64 2.74 2.66 1.87 2.08 1.42
SD 2.60 2.47 2.38 2.58 2.450 2.20
ANOVA, P-value .013 .044 .007 .000 .015 .000
On the basis of the pilot data, the critical time point for capturing acute adverse events, which will
be evidenced by ratings on the MDASI-Lung item “sore throat,” is 6 weeks after the initiation of
chemoradiation therapy (at the end of treatment); the optimal time point for capturing lung tissue
damage related late adverse events, which could be evidenced by ratings of the MDASI-Lung
symptom item “shortness of breath” and “coughing”, is 6 months after the end of chemoradiation
therapy
During the active component of the chemoradiation treatment course itself, Wang, et al. (2006)
found that esophagitis-related symptoms, including “sore throat” and “pain,” increased in a linear
fashion as the radiation dose accumulated (see left Figure below) and then began to decrease
Symptoms Steady increase during CXRT Non-randomized study: AUC, mean MDASI sore throat
3DCRT
18 IMRT
RTOG 1308; version

PROTON
date 10/23/14
Weeks from radiation start

AUC (3DCRT) = 148; AUC (IMRT) = 96; AUC (Proton) = 33.5
following completion of the chemoradiation. Interestingly, a previous non-randomized longitudinal
study of patients with NSCLC at MD Anderson (unpublished data) documented that the MDASI
sore throat scores differed significantly among 3 different radiation treatments (3DCRT, IMRT,
and proton) during the course of chemoradiation. The area under the curve (AUC) of mean sore
throat (right Figure below) depicts a symptom burden in the proton therapy patients that was
significantly lower than in patients receiving IMRT (effect size =.74) than in patients receiving 3D-
CRT (effect size =1.3). The end of CXRT time point presents the worst symptom burden related
to esophagitis.
In a pilot work in NSCLC patients with symptom measures pre and end of CXRT from a non-
randomized study (Wang 2013), the proton patients showed the lowest probability to report an
increase in esophagitis symptoms (pain and sore throat); see Figure below. Compared with
proton patients, a significantly higher percentage of 3DCRT patients reported any increase in
esophagitis symptoms (P<.0001). The probability of IMRT patients to report an increase in
esophagitis symptom was lower than 3DCRT patients (P=0.013) but higher than proton patients
(P=0.0001).
1.1.2 UCSD Shortness of Breath Questionnaire (SOBQ)

The SOBQ is a shortness of breath instrument (Eakin et al, 1998), which involves a 24 item
patient-reported outcome scale.. Item 22 is the symptom severity measure on 0-5. The other 23
items rate impaired functioning on 0 to 5, with 0 being “not at all” and 5 representing the
“maximally or unable to do because of breathlessness.” While the shortness of breath question
will be captured on MDASI as the primary outcome, we will also use SOBQ to more fully
understand the many related functional impairments secondary to shortness of breath.
Kupferberg (2005) reported the minimal clinical important difference for SOBQ and reported
moderate to large effect sizes between the SOBQ and SF-36 subscales (physical functioning,
role-physical, energy/fatigue and health change). Of note, this tool was also utilized in another
phase III NSCLC study (RTOG 1021).
1.2 Comparative Cost Effectiveness Analysis
We will calculate the area under the EuroQol (EQ-5D) utility curve from data points gathered at
treatment start (baseline), at week 6 after chemoradiation and at 3, 6, and 12 months after
chemoradiation to determine quality adjusted life years (QALYs) for photon beam and proton
beam radiotherapy. QALYs will be considered in the context of the differences in costs
associated with the interventions (i.e., incremental costs per QALY) to determine cost
effectiveness of each intervention.
1.2.1 Background
Lung cancer patients are sick, and it is estimated that it costs roughly 15 times more to care for
them than it does for healthy controls. The main costs associated with caring for lung cancer
patients in the initial treatment phase are inpatient hospitalizations (49%), outpatient office visits
(35%), and radiology and laboratory tests (13%) (Kutikova 2005). First-line treatment for patients
with inoperable, locally advanced NSCLC is generally considered very cost effective when
compared to best supportive care as an alternative treatment (Chouaid 2009). Three model-
19
based analyses done in Canada and Europe show that treatment with more intense multi-agent
chemotherapy, concurrent (as opposed to sequential) chemoradiotherapy, and hyperfractionated
(as compared to standard fractionated) radiotherapy are all cost-effective interventions from the
perspective of absolute dollars, dollars per life-year gained (LYG), and dollars per quality adjusted
life year (QALY), respectively (Evans 1997, Lievens 2005, Vergnenegre 2006). Among treatment
costs, radiotherapy is the most costly cancer treatment approach during the initial and terminal
care phases, responsible for 6 and 13% of total costs, respectively (Kutikova 2005).
Technological advances in radiotherapy delivery (e.g. IMRT) hold potential for improved cure
rates and reduction in acute and late treatment-related toxicity, as compared to their predecessor
technologies. Such technological advances almost always come with incremental increases in
monetary cost. In the case of IMRT for lung cancer treatment, single-institution series and small
clinical trials shown reduction in treatment-related toxicity when compared to historical controls
(Yom 2007); however, the rapid dissemination and adoption of this technology never allowed for
a prospective assessment of its cost effectiveness. IMRT has resulted in extreme increases in
the amount of money spent by the healthcare system overall on radiotherapy for cancer patients
(Nguyen 2011). The incremental costs of proton beam radiotherapy (PBT) (over IMRT) for the
treatment of localized prostate cancer is estimated to be approximately $14,000 for a standard
course of 44 radiation treatments; a similar increase is expected for the treatment of NSCLC
(ICER 2009).
To inform resource allocation decisions, differences in QALYs between PBT and IMRT must be
considered in the context of the differences in costs associated with the interventions (i.e.
incremental costs per QALY) (Drummond 2001).
1.2.2 EQ-5D
The EQ-5D is a method for obtaining valuations of health-related QOL, which also can be used
for quality-adjusted survival and cost-utility analyses (Glick 1999, Johnson 1998, Johnson 1998b,
Johnson 2000). It is a 2-part questionnaire that takes approximately 5 minutes to complete
(Schulz 2002). The first part of the EQ-5D consists of 5 items addressing 5 dimensions: mobility,
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be
graded on 3 or 5 levels whether one is utilizing the EQ-5D-3L vs. EQ-5D-5L. This modification of
the original instrument has been validated alongside the EQ-5D-3L for use in cancer patients and
shown to be have less ceiling effect and have greater ability to discriminate different levels of
health and changes in health than the EQ-5D-3L (Pickard 2007). For the sake of comparison, the
two versions of the instrument can be mapped one onto the other with the aide of the “crosswalk
index value calculator” which is available on the euroqol website (http://euroqol.org). For the
purpose of this study we plan on using the EQ-5D-5L.
The EQ-5D-5L response levels are: 1-no problems, 2-slight problems, 3-moderate problems, 4-a
lot of problems, and 5-extreme problems. Health states are defined by the combination of the
response levels for each of the 5 dimensions, generating 243 health states to which
unconsciousness and death are added (Badia 1998). The second part of the EQ-5D is a visual
analogue scale (VAS) valuing current health state, measured on a 20-cm 10-point-interval scale.
Worst imaginable health state is scored as 0 at the bottom of the scale, and best imaginable
health state is scored as 100 at the top. Both the 5-item index score and the VAS score are
transformed into a utility score between 0-“worst health state” and 1-“best health state.” Either the
index score or the VAS score can be used in the quality-adjusted survival analysis, or the cost-
utility equation can be entered, depending on the health state(s) of interest (Wu 2002). The area
under the EQ-5D curve yields predicted QALYs (Glick 2007). QALY differences of 0.03 are
considered important, and QALY differences of as little as 0.01 potentially meaningful and
important for several prevalent diseases, including cancer, diabetes, and heart disease (Samsa
1999; Walters 2003).
Although developed in Europe, the EQ-5D has been used in the United States and Canada (Glick
1999, Johnson 1998, Johnson 1998b, Johnson 2000). The EQ-5D web site,
http://www.euroqol.org/, lists multiple languages in which the instrument has been validated.
20
There have been few studies published reporting on the incorporation of the EQ-5D into the
evaluation of patients with NSCLC. Trippoli et al (2001) used the EQ-5D in the evaluation of 95
patients with NSCLC treated at 15 Italian hospitals. The mean utility score was 0.58 in the self-
classifier version and 0.58 in the VAS version. Both the self-classifier version and the VAS
version showed statistically significant correlation with each of the eight domains of the Short
Form-36 (SF-36).
1.3 Changes in Pulmonary Function After Concurrent Chemoradiation for NSCLC

Thoracic RT is associated with significant alterations in lung function as assessed by objective
pulmonary function tests (PFTs) [Cerfolio 2009, Kepka 2011, Semrau 2011, Theuws 1999,
Bishawi 2012]. The extent of residual lung function is a major determinant of a patient’s functional
status after treatment, particularly in patients with lung cancer who frequently have pretreatment
pulmonary compromise secondary to both malignancy and coexisting lung disease [Sundar
2011]. It is increasingly important to understand the relationship between thoracic RT and the
decline in lung function in the setting of aggressive concurrent chemoradiation. Studies by Gopal
2003 and others [Cerfolio 2009; Takeda 2006] have shown that the largest and most consistent
changes in PFT values after definitive radiation for NSCLC occur in diffusing capacity of the lung
for carbon monoxide (DLCO). Additionally, the decrease in DLCO after neoadjuvant
chemotherapy or chemoradiotherapy has been associated with an increased risk for
postoperative complication [Cerfolio 2009, Takeda 2006]. Lopez ( 2012) reported that 85%
patients were found to have decreased DLCO after RT with a median reduction of 20% in the
percent predicted value. Those patients who had grade 0, 1, 2 and 3 RP experienced a median
10.7, 13, 22.1, and 35.2% change in DLCO after treatment, respectively (P = 0.0004; Figure
below
Comparison between radiation-induced pneumonitis grades and the median of percent

reductions in diffusing capacity of the lung for carbon monoxide tests. The 25th and 75th
percentile range is represented by the thin line of the lung for carbon monoxide tests. The
25th and 75th percentile range is represented by the thin line.
There was a significant association between the percentage reduction in DLCO and grade ≤ 1 vs.
grade ≥ 2 RP (P = 0.0004; correlation coefficient, 0.30). Similar results were observed for the
DLCO change in patients with a pre-RT FEV1 < 60% of predicted with a median DLCO reduction
of 10.8% for those cases with RP grade ≤ 1 and 24.2% if the patients experienced grade ≥ 2 RP
(P = 0. 051). Additionally, when patients with V20 and MLD below the median values were
evaluated for the change of DLCO according to RP grade, again a higher DLCO reduction was
observed in the symptomatic cases (10% vs 20%; P = 0.11 for both V20 < 30% and MLD < 17Gy
cases).
21
RTOG 1308 provides a unique opportunity to further explore the utilization of PFT as a functional
endpoint as a measure of patient QOL and the possibility of using PFT as an objective
measurement for treatment-related lung toxicities.
1.4 Physics and Technological Considerations

Relative to photons, the physical characteristics of proton beams are appealing for cancer
therapy. The technology associated with proton delivery is still evolving, and there are many
practical challenges associated with the planning and delivery of this treatment modality. [Martijn
2013] With the introduction of intensity-modulated photon delivery and the use of a drastically
increased number of beam angles, the dose deposition advantage of standard proton therapy is
not so obvious. [Seco 2012] The distal penumbra of protons is much sharper than the lateral
penumbra, especially when using uniform scanning. As a consequence of range uncertainties,
the sharp finite range of proton beams can change from a major advantage to a significant risk of
inaccurate delivery. [Lu 2011] There are many factors contributing to delivery inaccuracies: the
cumulative uncertainty in treatment planning and treatment delivery associated with changes in
patient geometries. It is essential to investigate the physics aspects of proton therapy and photon
therapy to determine the most appropriate and clinically relevant technological parameters, to
ensure quality and effectiveness throughout radiation therapy processes, including imaging,
simulation, patient immobilization, target and critical structure definition, treatment planning,
image guidance and delivery. [Nitin 2013] This would ensure collection of quality technical data
and a meaningful clinical trial outcome.
2.0 OBJECTIVES
2.1 Primary Objective
To compare the overall survival (OS) in patients with stage II-IIIB NSCLC after image guided,
motion-managed photon radiotherapy (Arm 1) or after image guided, motion-managed proton
radiotherapy (Arm 2) both given with concurrent platinum- based chemotherapy.
2.2 Secondary Objectives

2.2.1 To compare 2-year progression-free survival (PFS) between the 2 arms;
2.2.2 To compare the development of grade 3 or higher adverse events definitely, probably, or possibly
related to treatment (see Section 13.2 for specific adverse events).
2.2.3 To compare differences between the two arms in QOL based primarily on the development of
shortness of breath at 6 months and secondarily on the development of sore throat at the end of
chemoRT (as measured by the lung cancer module of the MD Anderson Symptom Inventory
[MDASI-Lung]), as well as breathing related functioning impairments as measured by the
Shortness Breath Questionnaire [SOBQ];
2.2.4 To compare cost-effectiveness outcomes between the 2 arms;
2.2.5 To compare pulmonary function changes by treatment arms and response;
2.2.6 To explore the most appropriate and clinically relevant technological parameters to ensure quality
and effectiveness throughout radiation therapy processes, including imaging, simulation, patient
immobilization, target and critical structure definition, treatment planning, image guidance and
delivery.
3.0 PATIENT SELECTION

NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED
3.1 Conditions for Patient Eligibility

For questions concerning eligibility, please contact the study data manager.
3.1.1 Histologically or cytologically proven diagnosis of non-small cell lung cancer

3.1.2 Clinical AJCC (AJCC, 7th ed.) II, IIIA or IIIB (with non-operable disease; non-operable disease will
be determined by a multi-disciplinary treatment team within 60 days prior to registration; Note:
For patients who are clearly nonresectable, the case can be determined by the treating radiation
oncologist and/or a medical oncologist or pulmonologist.
22
 Patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor are
eligible.
 Patients who refuse surgery are eligible.
3.1.3 Appropriate stage for protocol entry, including no distant metastases, based upon the following
minimum diagnostic workup:
 History/physical examination within 30 days prior to registration;
 FDG-PET/CT scan for staging within 60 days prior to registration.
 MRI scan with contrast of the brain (preferred) or CT scan of the brain with contrast within 60
days prior to registration;
 FEV1 ≥ 1.0 Liter or ≥ 40% predicted with or without bronchodilator within 90 days prior to
registration.
o Patients who meet the criterion above without O2, but who need acute (started within
10 days prior to registration) supplemental oxygen due to tumor-caused
obstruction/hypoxia are eligible, provided the amount of the O2 needed has been
stable.
3.1.4 Zubrod performance status 0-1 within 30 days prior to registration;
3.1.5 Age ≥ 18
3.1.6 CBC/differential obtained within 30 days prior to registration, with adequate bone marrow function
defined as follows:
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
 Platelets ≥ 100,000 cells/mm3;
 Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥
9.0 g/dl is acceptable.);
3.1.7 SGOT or SGPT ≤ 1.5 upper limit of normal within 30 days prior to registration
3.1.8 Total bilirubin ≤ 1.5 upper limit of normal within 30 days prior to registration
3.1.9 Serum creatinine < 1.5 mg/dL or calculated creatinine clearance ≥ 50 mL/min within 30 days prior
to registration estimated by the Cockcroft-Gault formula:
Creatinine Clearance (male) = [(140 – age) x (wt in kg)]
[(Serum Creatinine mg/dl) x (72)]
Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male)
3.1.10 Peripheral neuropathy ≤ grade 1 at the time of registration
3.1.11 Patients with non malignant pleural effusion are eligible.
 If a pleural effusion is present, the following criteria must be met to exclude malignant
involvement:
o When pleural fluid is visible on both the CT scan and on a chest x-ray, a
pleuracentesis is required to confirm that the pleural fluid is cytologically negative.
o Exudative pleural effusions are excluded, regardless of cytology;
o Effusions that are minimal (ie, not visible on chest x-ray) that are too small to safely
tap are eligible.
3.1.12 Patients must have measurable or evaluable disease.
3.1.13 Women of childbearing potential must have a negative serum pregnancy test within 14 days prior
to registration.
3.1.14 Women of childbearing potential and male participants must practice adequate contraception.
3.1.15 Patient must provide study-specific informed consent prior to study entry.
3.2 Conditions for Patient Ineligibility

3.2.1 Prior invasive malignancy unless disease free for a minimum of 3 years. However, skin cancer
and in situ carcinomas of the breast, oral cavity, cervix, and other organs and are permissible..
3.2.2 Patients with prior history of either small cell lung cancer or NSCLC regardless of the treatment
received.
3.2.3 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different
cancer is allowable. See Section 3.2.1.
3.2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation
therapy fields;
3.2.5 Severe, active co-morbidity, defined as follows:
23
 Unstable angina and/or congestive heart failure requiring hospitalization within the last 6
months;
 Transmural myocardial infarction within the last 6 months;
 Chronic obstructive pulmonary disease exacerbation or other respiratory illness other than
the diagnosed lung cancer requiring hospitalization or precluding study therapy within 30
days before registration;
 Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note,
however, that HIV testing is not required for entry into this protocol. The need to exclude
patients with AIDS from this protocol is necessary because the treatments involved in this
protocol may be significantly immunosuppressive.
3.2.6 Unintentional weight loss > 10% within 90 days prior to registration.
3.2.7 Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is necessary
because the treatment involved in this study may be significantly teratogenic.
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT

NOTE: This section lists baseline evaluations needed before the initiation of protocol
treatment that do not affect eligibility.
4.1 Required Pretreatment Evaluations/Management (NOTE: See Sections 3.1 and 3.2 for
evaluations required for eligibility)
 Glucose, electrolytes, LDH, aspartate alkaline phosphatase, total protein, albumin, calcium,
blood urea nitrogen (BUN), and serum magnesium level within 30 days before concurrent
chemotherapy start date.
 Serum creatinine and CBC with differential within 10 days before concurrent chemotherapy
start date.
 DLCO within 90 days of treatment start.
4.2 Highly Recommended Evaluations/Management

Note that these evaluations/interventions are highly recommended as part of good clinical care of
patients on this trial but are not required
 MRIs of the thorax 90 days before treatment start, if there is a medical justification, especially
for superior sulcus tumors
 CT or MRI scans of the abdomen, with or without contrast within 90 days before treatment
start if medically indicated
 Cardiac Single-Photon Emission CT (SPECT) for patients with lower lung tumor when
medically indicated as determined by the treating radiation oncologist within 90 days before
treatment start
 Quantitative lung ventilation/perfusion scan +/- CT scan if FEV1 ≤ 1.4 liters within 90 days
before treatment start
 Bone scan within 90 days before treatment start if there is a medical justification;
 Comprehensive pulmonologist consultation within 90 days before treatment start;
 EKG and/or echocardiogram within 90 days before treatment start
 Nutritional assessment, including evaluation of the need for prophylactic gastrostomy tube
placement (if the patient is ≥ 10% below ideal body weight) within 90 days before treatment
start
5.0 REGISTRATION PROCEDURES (10/23/14)

Access requirements for OPEN, Medidata Rave, and TRIAD:
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and
Access Management (IAM) account. This is the same account (user id and password) used for
the CTSU members' web site. To obtain an active CTEP-IAM account, go to https://eapps-
ctep.nci.nih.gov/iam.
24
NOTE: All sites must submit a Letter of Intent (LOI) to NRG Oncology Regulatory to receive
approval to participate in this trial. For more details see the regulatory tab on the NRG
Oncology/RTOG website next to the RTOG 1308 protocol link.
The RT treatment modalities are either photon (3DCRT and/or IMRT) or proton therapy. Image-
Guided Radiotherapy (IGRT) is required for all patients enrolled on this trial. In order to be eligible
to enroll patients onto this trial, centers must be credentialed for photons (3D-CRT and/or IMRT)
AND protons in addition to Lung image-guided radiotherapy (IGRT).
Institutions not having credentialed for IMRT/3D-CRT and proton treatment must credential for
each of the modalities being used for this protocol. Credentialing for IMRT allows the institution
to also use 3D-CRT. As part of this credentialing, institutions intending to use gating or tracking
for motion management must be credentialed using the IROC Houston phantom placed on a
moving table supplied by the IROC Houston. If this credentialing has not been obtained
previously as part of IMRT or 3D-CRT credentialing, the process must be repeated.
There is a required knowledge assessment for both photons and protons for this protocol, which
is in addition to the Facility Questionnaire and the credentialing requirements. This must be
successfully completed prior to the enrollment of the first patient. Details for the knowledge
assessment can be found on the IROC Houston website at http://rpc.mdanderson.org/rpc/
5.1 RT-Specific Pre-Registration Requirements
For detailed information on the specific technology requirement required for this study, please
refer to the table below and utilize the web link provided for detailed instructions. The check
marks under the treatment modality columns indicate whether that specific credentialing
requirement is required for this study. Specific credentialing components may require you to work
with various QA centers. However, the NRG Oncology will be the entity to notify your institution
when all credentialing requirements have been met and the institution is RT credentialed to enter
patients onto this study.
Proton centers wishing to participate in this study must comply with the NCI proton guidelines for
the Use of Proton Radiation Therapy in NCI Sponsored Cooperative Group Clinical Trials, which
are available on the IROC Houston website (http://rpc.mdanderson.org). These requirements
include, but are not limited to, completion of a proton facility questionnaire, a successful IROC
Houston site visit, which identifies the proton technique(s) which can be used, annual monitoring
of the proton beam calibration, e.g. IROC Houston’s monitoring program, and successful digital
data submission to the TRIAD. Once these requirements are successfully met, the proton center
is approved to use proton therapy in NCI sponsored clinical trials. Each trial may require
additional proton therapy credentialing steps prior to being allowed to enter a patient treated with
protons onto a specific study. The IROC Houston QA Center will coordinate the completion of the
proton therapy use approval process in conjunction with the appropriate other Quality Assurance
Offices for any additional protocol specific credentialing requirements. See the table below for
the credentialing requirements of this study.
25
Web Link for Procedures and Instructions: http://rpc.mdanderson.org/rpc/
RT Treatment Modality
Credentialing
Requirements Photons Key Information
Protons If questionnaire was previously completed for another trial,

Facility
Questionnaire
X X update Section 2A of the existing questionnaire to add this trial
number.
Knowledge The Knowledge Assessment Form will be available on the
Assessment
X X IROC Houston website at http://rpc.mdanderson.org/rpc/
See Section 5.0 above describing phantom irradiation
Phantom
Irradiation
X X requirements for specific motion management techniques.
Questions may be directed to IROC Houston.
IGRT For details, see the RTOG website at
Verification X X http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.as
Study px?study=1308
5.2 Digital RT Data Submission to RTOG Using TRIAD

TRIAD is the American College of Radiology’s (ACR) image exchange application and it is used
by NRG Oncology. TRIAD provides sites participating in NRG Oncology clinical trials a secure
method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the images
as they are transferred.
TRIAD Access Requirements:

 Site physics staff who will submit images through TRIAD will need to be registered with
The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP
Identity and Access Management (IAM) account. Please refer to Section 5.0 of the
protocol for instructions on how to request a CTEP-IAM account.
 To submit images, the site physics user must have been assigned the 'TRIAD site user'
role on the relevant Group or CTSU roster. NRG Oncology users should contact your site
Lead RA to be added to your site roster. Users from other cooperative groups should
follow their procedures for assignment of roster roles.
 RAs are able to submit standard of care imaging through the same method.
TRIAD Installations:
When a user applies for a CTEP-IAM account with proper user role, he/she will
need to have the TRIAD application installed on his/her workstation to be able to
submit images. TRIAD installation documentation can be found on the NRG
Oncology/RTOG website Core lab tab.
This process can be done in parallel to obtaining your CTEP-IAM account username and
password.
If you have any questions regarding this information, please send an e-mail to the TRIAD
Support mailbox at TRIAD-Support@acr.org.
26
5.3 Dry Run and Knowledge Assessment
There is a required dry-run and knowledge assessment for both photons and protons for this
protocol, which is in addition to the Facility Questionnaire and the credentialing requirements.
This must be successfully completed prior to the enrollment of the first patient. Details for this
dry-run/knowledge assessment can be found on the IROC Houston website at
http://rpc.mdanderson.org/rpc/
5.4 Regulatory Pre-Registration Requirements

5.4.1 This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Prior to the recruitment of a patient for this study, investigators must be registered members of a
lead protocol organization. Each investigator must have an NCI investigator number and must
maintain an “active” investigator registration status through the annual submission of a complete
investigator registration packet (FDA Form 1572 with original signature, current CV,
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original
signature) to the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI. These forms
are available on the CTSU registered member web site:
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm . For questions, please
contact the CTEP Investigator Registration Help Desk by e-mail at pmbregpend@ctep.nci.nih.gov
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM)
application is a web-based application intended for use by both Investigators (i.e., all physicians
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in
the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to
register (both initial registration and annual re-registration) with CTEP and to obtain a user
account. Investigators will use the CTEP-IAM application to obtain a user account only. (See
CTEP Investigator Registration Procedures above for information on registering with CTEP as an
Investigator, which must be completed before a CTEP-IAM account can be requested.) An active
CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support
Unit) websites and applications, including the CTSU members‘ web site. Additional information
can be found on the CTEP web site at
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. For questions, please contact
the CTEP Associate Registration Help Desk by email at ctepreghelp@ctep.nci.nih.gov.
IRB Approval
Each investigator or group of investigators at a clinical site must obtain IRB approval for this
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office
before they can enroll patients. Study centers can check the status of their registration packets by
querying the Regulatory Support System (RSS) site registration status page of the CTSU
member web site by entering credentials at https://www.ctsu.org. For sites under the CIRB
initiative, IRB data will automatically load to RSS.
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study are not
required to submit separate IRB approval documentation to the CTSU Regulatory Office for initial,
continuing or amendment review. This information will be provided to the CTSU Regulatory
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB approval. The
Signatory site may be contacted by the CTSU Regulatory Office or asked to complete information
verifying the participating institutions on the study. Other site registration requirements (i.e.,
laboratory certifications, protocol-specific training certifications, or modality credentialing) must be
submitted to the CTSU Regulatory Office or compliance communicated per protocol instructions.
Site registration forms may be downloaded from the RTOG-1308 protocol page located on the
CTSU members‘ web site. Go to https://www.ctsu.org and log in to the members‘ area using your
CTEP-IAM username and password
 Click on the Protocols tab in the upper left of your screen
 Click on the (state organization type e.g. P2C, CITN, NCTN Groupname) link to expand,
then select trial protocol, RTOG-1308
27
 Click on the Site Registration Documents link
Requirements for RTOG 1308 site registration:

 CTSU IRB Certification (for sites not participating via the NCI CIRB)
 CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the
NCI CIRB)
 CTSU RT Facilities Inventory Form (if applicable)
NOTE: Per NCI policy all institutions that participate on protocols with a radiation therapy
component must participate in the Radiological Physics Center (RPC) monitoring program. For
non-lead group institutions an RT Facilities Inventory Form must be on file with CTSU. If this
form has been previously submitted to CTSU it does not need to be resubmitted unless updates
have occurred at the RT facility.
 IRB/REB approval letter (for sites not participating via the NCI CIRB)
 IRB/REB approved consent
 IRB/REB assurance number renewal information as appropriate.
Submitting Regulatory Documents:

Submit completed forms along with a copy of your IRB Approval and Informed Consent to the
CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS.
CTSU Regulatory Office
1818 Market Street, Suite 1100
Philadelphia, PA 19103
Phone: 1-866-651-2878
Fax: 215-569-0206
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only)
Checking Your Site’s Registration Status:

Check the status of your site’s registration packets by querying the RSS site registration status
page of the members’ section of the CTSU website. (Note: Sites will not receive formal
notification of regulatory approval from the CTSU Regulatory Office.)
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM
username and password
 Click on the Regulatory tab at the top of your screen
 Click on the Site Registration tab
 Enter your 5-character CTEP Institution Code and click on Go
5.5 Registration
OPEN Registration Instructions
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have
been met, and the study site is listed as ‘approved’ in the CTSU RSS. Patients must have signed
and dated all applicable consents and authorization forms.
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site
user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating
organization roster. All site staff will use OPEN to enroll patients to this study. It is integrated with
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes the
patient position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the
OPEN tab on the CTSU members’ web site https://www.ctsu.org.
Prior to accessing OPEN site staff should verify the following:
28
 All eligibility criteria have been met within the protocol stated timeframes. Site staff should
use the registration forms provided on the group or CTSU web site as a tool to verify
eligibility.
All patients have signed an appropriate consent form and HIPPA authorization form (if
applicable).
The OPEN system will provide the site with a printable confirmation of registration and treatment
information. Please print this confirmation for your records.
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the
CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.
In the event that the OPEN system is not accessible, participating sites can contact web support
for assistance with web registration: websupport@acr.org or call the Registration Desk at (215)
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax
in the eligibility checklist and will need the registering individual’s e-mail address and/or return fax
number. This information is required to assure that mechanisms usually triggered by the OPEN
web registration system (e.g. drug shipment and confirmation of registration) will occur.
6.0 RADIATION THERAPY (10/23/14)

Notes: Both Intensity Modulated RT (IMRT) and 3D-Conformal Radiation (3DCRT) are allowed
for photon planned cases. The proton centers should use their standard proton planning and
delivery techniques in the respective center for proton treatment.
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior
to enrolling patients.
Protocol treatment must begin within 30 calendar days after registration and within 21
calendar days after simulation.
Proton dose will be reported in Gy (relative biological effectiveness, RBE), where 1 Gy (RBE) =
proton dose Gy x RBE , RBE = 1.1.
Radiation doses shall be prescribed using the protocol specified definitions for iGTV, ITV, and
PTV.
Proton treatment plans will be based upon scans obtained with a CT scanner for which the
institution has defined an imaging protocol for protons which establishes the relationship between
the CT number and the stopping power ratios.
The pre-treatment PET or PET/CT study will be used to assist the treatment planning process. It
is highly recommended that institution perform follow-up PET or PET/CT studies at 3 months after
the completion of chemoradiation treatment. It is recommended that these studies be performed
on the same equipment used for the pre-treatment study. These studies will not be collected.
Institutions should archive this information for possible future collection.
6.1 Dose Specifications

6.1.1 Dose Prescription
 Patients in both proton and photon arms will receive treatments 5 days per week using 2 Gy
(RBE) per fraction. RBE used will be 1.1 for protons and 1 for photons. The total prescribed
dose will be 70 Gy (RBE) without exceeding tolerance dose-volume limits of all critical
normal structures. (See Section 6.1.3 when 70 Gy (RBE) is not achieved.)
 Dose distribution will be normalized to cover 95% of the PTV with the prescription dose.
 A volume of no more than 0.03 cc inside PTV should exceed 120% of the prescribed dose.
29
 100% of the ITV (motion-incorporated CTV) must be covered by the prescription dose.
6.1.2 Acceptable Variations and Unacceptable Deviations From the Prescription Dose
Per Protocol: See Section 6.1.1.
Variation Acceptable: Deviations of this magnitude are not desirable but are acceptable for
situations where a patient’s geometry (target and critical structure positions within the body)
makes treatment planning more challenging. .
o ≥95% of the PTV is covered by ≥95% of the prescription dose,
o A volume of no more than 0.03 cc inside the PTV exceeds 120% but not 125% of the
prescribed dose;
o The minimum PTV dose to a volume of 0.03 cc falls below 85% but not below 75% of
the prescription dose;
o Less than 100% of the ITV (motion incorporated CTV) is covered by the prescription
dose but no less than 99% is covered.
Deviation Unacceptable: Dose distributions falling in this region are not acceptable, and plan
modifications should be attempted to improve results. A Deviation Unacceptable occurs when
any of the Variation Acceptable dose limits stated above are not met.
6.1.3 Failure To Achieve 70 Gy (RBE)
If the prescription dose of 70 Gy (RBE) cannot be achieved within the normal tissue constraints,
the treatment plan must be submitted for pre-treatment review (See Section 6.8).
6.1.4 Failure To Achieve 60 Gy (RBE)
If the prescription dose of at least 60 Gy (RBE) cannot be achieved within the normal tissue
constraints, the treatment will be deemed Deviation Unacceptable.
6.2 Technical Factors [Equipment, Energies]

 Photon beam energies of 6-10 MV may be used. IMRT or 3DCRT may be used, but IMRT is
strongly preferred. IMRT may be delivered using multiple fixed fields employing dynamic
multi-leaf collimator, helical arc therapy or volumetric modulated arc therapy using any of the
commercially available delivery systems.
 Proton therapy may be delivered using passively scattered protons or using scanning beam.
o Selected proton energies should be high enough to adequately provide target
coverage. Range shifters may be used to make fine adjustment to the maximum
proton range.
o Both passive scattering and scanning beams may employ apertures and/or
compensators, as appropriate, to shape the fields laterally and distally.
6.3 Simulation, Immobilization, Motion Assessment, and Motion Management

6.3.1 Simulation
Motion assessment must be performed on all patients to determine the motion management
technique (see Section 6.3.3) and the appropriate type of treatment planning CT required.
A motion management technique-specific treatment planning CT (e.g., 4D, breath-hold, with ABC
device, etc.) will be required during simulation to define gross tumor volume (GTV), clinical target
volume (CTV), and planning target volume (PTV) (see definitions in Section 6.4). Contiguous CT
slices, having no more than 3 mm thickness are to be obtained starting from the level of the
cricoid cartilage and extending inferiorly through the entire liver volume. The field of view must be
large enough so that none of the patient’s anatomy along the path of the treatment beams is cut
off.
A CT scanner unit calibrated for proton treatments with the appropriate proton relative linear
stopping power (RLSP) vs. HU conversion function shall be used for simulation of patients
randomized to the proton arm.
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the patient in the treatment
position is encouraged for treatment planning. In the case where the PET/CT is obtained in the
treatment position, the CT from this study may be used as the planning CT scan.
30
Intravenous contrast during the planning CT is optional provided a diagnostic chest CT was done
with contrast to delineate the major blood vessels. If not, intravenous contrast should be given
during the planning CT. If contrast is used, the densities should be over-ridden or the contrast
scan must be registered to a non-contrast scan for planning purposes.
6.3.2 Immobilization
Patients will be positioned in a stable position capable of allowing accurate reproducibility of the
target position. Positions uncomfortable for the patient should be avoided so as to prevent
uncontrolled movement during treatments.
A variety of immobilization systems customized to the participating institutions standard of

practice may be used, including using an alpha-cradle or vac-bag. Stereotactic frames that
surround the patient on 3 sides and large rigid pillows (conforming to patients’ external contours)
may be used as indicated.
6.3.3 Motion Assessment and Motion Management

 Motion assessment is mandatory for this protocol. As a first step, it is required that each site
quantify the specific target motion for each patient, so as to determine if management
strategies are needed (motion management strategies are not needed for patients with end-
to-end target motion ≤ 10 mm). Instead, an ITV (see Section 6.4.1) can be developed for
treatment planning and DVH analysis. Options for motion assessment include real time
fluoroscopy (using either the treatment unit table when an IGRT system with fluoroscopy
capability is available or a conventional simulator with fluoroscopy), or 4-D CT scanning.
 Examples of acceptable methods of accounting for tumor motion include: design of the target
volume to cover the excursion of the lung primary cancer and nodes during breathing (the
“ITV approach”), active breathing control (e.g. Elekta ABC device), abdominal compression,
active breath hold, free-breathing gating (e.g. with Varian RPM system), or gated breath
hold.
 If the necessity of special respiratory management with a specific technique (e.g., ABC) is
obvious to the treating physician, simulation CT specific to that technique must be acquired.
 The impact of motion and need for motion management will be assessed with 4D CT
simulation combined with initial dose calculation for at least end inhale and end exhale
phases.
 If dose constraints are met with the ITV approach (Section 6.4.1), no further motion
management is needed. If dose constraints are not met, then one of the volume-reduction
motion management approaches mentioned above must be employed before reducing the
dose below 70 Gy.
Note: If end-to-end tumor motion is > 10 mm (+/-5 mm relative to the mean position), the use of
ITV approach is discouraged.
6.4 Target Definitions, Target Delineation, and Normal Anatomy Delineation

6.4.1 Target Definition
 GTV: Gross tumor volume is all known gross disease as demonstrated on the single phase
planning CT, and modified as deemed necessary based on PET and other imaging studies.
 iGTV: GTV plus margin for tumor motion, which isthe union of the GTVs on all respiratory
correlated images, or the gross tumor volume contoured directly on maximum intensity
projection (MIP) images.. 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. (If a breath-hold technique is used, iGTV is the union of
the GTVs on 3 breath hold scans - see table below
 CTV: Clinical target volume is the subclinical involvement around the GTV. The CTV is the
GTV plus an 8-mm margin for micro extensions of the tumor (CTV=GTV+8 mm) without
extending into uninvolved organs, such as the esophagus, heart, or bone.
31
 ITV: ITV=iGTV+8mm Internal target volume is the union of the CTV plus motion or iGTV plus
8 mm CTV. The ITV may equivalently be created in one of two ways: (1) by expanding the
iGTV by 8 mm to include subclinical microscopic disease without extending into uninvolved
organs, such as the esophagus, heart, or bone; or (2) by combining all CTVs in all respiratory
phases. This volume will be reviewed and edited according to patient’s anatomy by the
treating radiation oncologist, according to the prevailing 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 isotropically by 5 mm
to generate the PTV. The PTV, defined in this manner, is relevant to photon planning and for
plan evaluation for both protons and photons. For proton planning, the PTVs are beam
specific and defined differently (see Section 6.5.3).
6.4.2 Target Delineation
 The simulation CT scan images will be used for target delineation and treatment planning.
The proper lung window should be used for target delineation in the lung parenchyma, and
proper soft tissue window should be used to delineate the nodal disease.
 iGTV should be contoured on the maximum intensity projection (MIP) images when 4D CT
simulation is done. Or, the iGTV should be created by combining the GTV contours
delineated in inhale and exhale scans.
 Pretreatment PET/CT and/or contrast CT images should be fused with the simulation images
to help target delineation.
6.4.3 Normal Anatomy Delineation
(See http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx)
 The normal anatomy to be outlined on each CT image will include both right and left lungs,
heart, brachial plexus for upper lobe tumors, esophagus and spinal cord. Liver and kidneys
will also be contoured if these organs will be in the beam path.
 Lungs should be contoured on the average image of the 4D CT scans for free-breathing
based treatments or the mid position of gated planning CTs for gated treatments, or on the
selected breath-hold CT for breath-hold treatments.
 The heart should be contoured from its base to apex, beginning at the CT slice where the
ascending aorta originates.
 The esophagus should be contoured from the bottom of the cricoid to the gastro-esophageal
junction.
 The spinal cord should be contoured on each CT slice..
6.4.4 Required Structures – Standard Names for Digital RT Submission
Note: All required structures must be labeled as listed in the table below for digital RT data
submission. Resubmission of data may be required if labeling of structures does not
conform to the standard DICOM name listed.
The following table outlines the naming/definition of the various target volumes. iGTV/ITV/PTV
are for the motion management scenarios as specified in the table below:
Motion Management Scans Scan to be used for Images from
dose calculation which the target
volume
contours are to
be generated
4-D CT simulation with free 1 free breathing scan, 1 AVG of all phases MIP or union of
breathing 4D scan (10 imaging data the GTVs of all
sets) phases used to
generate gross
tumor plus tumor
motion=iGTV,
iGTV+ CTV
(8mm)=ITV
ITV+5mm =PTV
4-D CT simulation with free 1 free breathing scan, 1 AVG of the beam-on Union of GTVs
32
breathing gating 4D scan (10 imaging data phases (e.g. 40 – contoured at
sets) 60%) each breathing
phase while the
beam will be on
(e.g. 40-60%)
=iGTV
iGTV+ CTV
(8mm)=ITV
ITV+5mm =PTV
4D CT simulation with breath hold Repeat breath hold scan 3 Select one scan for Union of GTVs
(with or without ABC) times to assess dose calculation contoured at
reproducibility of the each breath hold
breath hold. scan =iGTV
iGTV+ CTV
(8mm)=ITV
ITV+5mm =PTV
The following table outlines the naming of the various normal and critical structures for
submission to TRIAD. All structures must be submitted and labeled according to the
specifications in the table below or resubmission will be required. This includes capitalization,
spacing, etc.
Please note: For Tumor Volumes, select the three appropriate tumor volumes required for
your motion management technique selected for your patient as described in Section 6.1
and the above table 6.4.4
For Arms 1 and Arm 2

Structure DICOM Standard Name
Gross Tumor Volume GTV

GTV plus margin for tumor motion IGTV
Clinical Target Volume CTV
Internal Target Volume ITV
Planning Target Volume PTV
Spinal Cord SpinalCord
Right + Left Lung minus GTV (or iGTV) Lungs
Right Lung Lung_R
Left Lung Lung_L
Esophagus Esophagus
Brachial Plexus BrachialPlexus Required for upper lobe
tumors
Heart Heart
Liver Liver *Required if in the beam
path
Right Kidney Kidney_R *Required if in the beam
Left Kidney Kidney_L path
*Required if in the beam
path
6.5 Treatment Planning and Quality Assurance
6.5.1 Target Contour Quality
All contours and treatment plans for the first 3 proton cases and the first 3 photon cases from
each participating institution will have pretreatment review by the protocol PIs or a radiation
33
oncologist designee. Additional reviews for the first 3 cases for which adaptive replanning is
necessary are required as well.
6.5.2 Planning Procedures – Photons
 For IMRT (multiple fixed fields or arc therapy, see Section 6.2) or 3DCRT planning, the PTV
will be treated with any combination of coplanar, non-coplanar, or dynamically arcing fields.
Please refer to Section 5 above for credentialing requirements.
 For 3DCRT plans, forward planning with optimized beam orientation and shaping is
expected.
 Margins to be used are stated in Section 6.4.1.
For protons, average of all scans used will be employed for dose calculations, compensator and
aperture design and plan evaluation. However, individual phases may also be used for
evaluating dose distributions.
6.5.3 Planning Procedures – Protons
 Passively scattered proton therapy (PSPT) or scanned proton beams will be used for patients
enrolled in the proton arm.
 For proton planning, each beam has an individual and unique PTV expansion from the ITV. In
the plane perpendicular to the proton beam axis, the PTV expansion from the ITV is
according to the method used for photons. However, along the direction parallel to the proton
beam axis, the distal and proximal margins to expand the ITV will be computed using
established algorithms based on range uncertainty of the beam. For multiple ITVs, the most
distal edge of the collection of ITVs is assigned range uncertainty margin.
 To compensate for the perturbation of the proton dose distribution due to misalignment of the
compensator and the anatomy, the compensator is smeared. The smearing radius will be
calculated using the algorithms established at each participating institution (Moyers 2001).
The compensator may be smoothed to reduce hot spots.
 A block margin must be assigned depending on the penumbra specific to the proton beam
being used. Note that proton beam penumbra is a function of proton energy and the distance
between aperture + compensator and patient’s anatomy. It may vary significantly from one
clinical situation to another.
 Note: While the treatment planning parameters, including distal and proximal margins, block
margin and the smearing radius may be calculated based on published formulae, (Moyers
2001) they may be modified for the local machine characteristics and practice. Variation of
magnitudes in these parameters from one institution to another is acceptable; however, the
parameters selected must ensure specified target coverage and normal tissue sparing in the
face of range and set up uncertainties.
6.5.4 Critical Structures Constraints
 Dose volume constraints for normal critical structures are given in the Table below. These
dose values can be used as guidelines for constraining the optimization process during
treatment planning, and they are also used for scoring each case for protocol compliance
(see Section 6.6).
 For superior sulcus tumor or upper lobe tumors where the brachial plexus is part of the target
volume, the volume receiving 70 Gy (V70) can be as large as 10 cc with significant areas
within receiving doses as high as 74 Gy.
 If any portion of cardiac structure is part of the planning target volume (PTV), respiratory
gating or another technique to separate cardiac structures from the PTV and allowing the full
prescription dose to be delivered should be the first stepDoses exceeding the limits of
variation acceptable listed in the Table below will be considered a deviation unacceptable.
Critical Structure Dose Constraints and Compliance Criteria
Note: Must label structures per DICOM Standard Name as listed above. See Table in Section 6.4.4
Per Protocol Variation Acceptable*
Normal lung (right lung + left V20 ≤ 37%; MLD ≤ 20 Gy (RBE); V20 ≤ 40 % or MLD ≤ 22 Gy (RBE);
lung minus GTV) lung V5 ≤ 60% lung V5 ≤ 65%
34
Esophagus Max dose: 74 Gy (RBE) ≤ 1cc of Max dose: 74 Gy (RBE) ≤ 1.5 cc of
partial circumference partial circumference
Brachial Plexus** V70 ≤ 3.0 cc V75 ≥ 0.5 cc
V74 ≤ 1.0 cc
V75 ≤ 0.5 cc
Spinal Cord*** V50 < 0.03 cc V52 < 0.03 cc

Heart V30 ≤ 50% V30 ≤ 55%
V45 ≤ 35% V45 ≤ 40%
* Doses not meeting the Variation Acceptable limits will be classified as Deviation Unacceptable.
** See first bullet in the list just above the Table for exception to the values for this critical structure.
*** See the last bullet in the list just above the Table for exception to the values for this critical structure.
**** When this value cannot be achieved, treatment plans must be modified to move dose distribution
hotspots away from the heart to avoid having the case scored as a Deviation Unacceptable. Also refer to
the 3rd bullet in Section 6.5.4.
6.5.5 Dose Distribution Calculations

Dose matrix grid size must be 3 mm x 3 mm x 3 mm or smaller.
6.5.6 Plan Review and Evaluation
 For IMRT, traditional DVHs and dose distribution displays will be used for plan review and
evaluation. DVHs will also be used for retrospective outcomes analyses.
 For proton planning, additional plan review procedures are required to ensure adequacy of
dose distributions.
o At a minimum, beam-by-beam review of dose distributions is required to ensure that
CTV plus the lateral, distal and proximal margins are covered. For the ITV approach,
adequacy of coverage in both end-inhale and end-exhale phases must be reviewed.
o While it is understood that DVHs derived from composite dose distribution of all
beams have limitations, they are to be used for plan evaluation for comparison of
competing plans.
o Robustness of dose distributions should be evaluated to ensure that the target and
critical normal tissue constraints are not violated in the face of set-up and range
uncertainties and breathing motion.
6.6 Compliance Criteria

 Compliance criteria for targets can be found in Section 6.1.2.
 Compliance criteria for critical structures are found in the Table in Section 6.5.4.
 Target doses not meeting either the Per Protocol or the Variation Acceptable criteria are
classified as Deviation Unacceptable and are considered non-compliant.
 Any of the critical normal tissue dose and dose-volume indices that are not Per Protocol or
classified as Variation Acceptable will be considered non-compliant.
6.6.1 Missed Treatment Days/Elapsed Days
Per Protocol: No missed treatments (other than holidays) .
Variation Acceptable: Total consecutive missed or interrupted treatments (not including holidays)
≤5 total days. Total elapsed time exceeding 7 weeks but less than 9 weeks will be considered
Variation Acceptable.
Deviation Unacceptable: Treatment break or missed treatments (other than holidays, weekends)
>5 total days. Total elapsed time exceeding 9 weeks.
6.6.2 Temporary Unavailability of Proton Machine
Patients randomized to the proton therapy arm may receive up to 5 fractions with photons in the
event the proton machine is not available.
35
6.7 Treatment Delivery
6.7.1 Image Guided Treatment
 Image-guided radiation therapy (IGRT), consisting of images and appropriate image
alignment software tool, is required for both photon and proton treatments on this protocol. It
is expected that investigators will be familiar with those concepts presented in the ASTRO
IGRT White paper (Jaffray in press).
 Patients will be treated only on units with image guidance capabilities. Such units include
ones with on-board imaging, CT-on-rails, or other dedicated imaging system for patient
positioning. At a minimum, these units must include orthogonal x-ray imaging systems for
patient positioning and employ software tools for image registration.
 To achieve compliance with the PTV expansions stated in the protocol, daily imaging is
required.
 Image Guidance for IGRT (see Section 5.2.2): Daily image guidance of IGRT may be
achieved using any one or more of the following techniques:
o Orthogonal kilovoltage (KV) images, e.g. ExacTrac; on-board imagers (OBI) or similar
systems;
o Linear-accelerator mounted kV and MV conebeam CT images;
o Linear-accelerator mounted MV CT images (e.g., Tomotherapy);
 The institution’s procedure to register treatment day image dataset with the reference dataset
should comply with the following recommendations:
o Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high
dose PTV and adjacent vertebral bodies. (Note: The same strategy should be used for
repeat CT scans required for verification, QA or replanning.)
o If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac),
treatment room objects seen on in-room X-rays should be excluded from the registration.
o Automatic (e.g., based on mutual information bone or soft tissue fusion) types of
registration should be used; the result of the fusion must be visually checked for
alignment of the target or bony structures, such as vertebral bodies when appropriate.
Manual adjustments (using drag-and-drop capabilities) should be made when necessary.
 Following the registration, the translational and (if the appropriate technology is available)
rotational corrections should be applied to the treatment couch. If all the variances are less
than 3 mm, the treatment can proceed without correction. If one or more corrections are 3-5
mm, adjustment is necessary prior to treatment; however, re-imaging is not recommended. If
one or more of the corrections are larger than 5 mm, the imaging can be repeated in addition
to performing table/positioning adjustments.
 If orthogonal projection imaging is used for setup, this fact should be communicated to the
therapists (i.e. bony anatomy or fiducial). The relationship between the image surrogate of
internal anatomy and the soft tissue targets shall be verified, at a minimum, as part of the
repeat CTs done for QA, verification or replanning..
 If in room CT is available but orthogonal projection X-ray imaging is used for daily setup,
weekly verification of soft tissue with setup surrogate is recommended.
 If in-room CT is used for daily setup, the setup surrogate needs to be communicated to the
therapists (i.e. bony anatomy, GTV, or other). If, due to changing anatomy, a compromise
must be made between multiple target structures, the therapists shall be guided by the
treating physician as to the best compromise.
6.7.2 Mid-Course Repeat CT Scans to Adapt Radiotherapy to Anatomic Changes

Repeat CT acquisition
 In addition to the CT datasets obtained for planning of treatments, repeat CT scans will be
performed to assess whether a patient requires modifications to their treatment plan. The
initial simulation planning scan should be scheduled to occur as close as possible to the
starting date and no more than 21 days prior to the estimated treatment start date. If the
starting date is 14 days or more from the simulation date, a pre-treatment verification CT
scan is strongly recommended. Additional repeating studies must occur during the time the
dose delivered is between 20-24 Gy and between 46-50Gy.
36
 Repeat CTs will be of the same type (4D, breath-hold, etc.) as the initial planning CT
depending upon the motion management strategy being used.
Determination of the need for replanning
 The repeat CT scan will undergo a rigid fusion with planning-CT and the targets from the
original simulation scan and OARs will be transferred to the repeat CT scan. The same
fusion technique used for daily IGRT (bone matching, soft tissue matching, drag-and-drop)
will be used for image registration of the repeat CT scans. Rotational changes to the fusion
should only be done if the institution has the equipment needed to implement this type of
adjustment as part of its daily IGRT system.
 The GTV or iGTV, spinal cord, lungs and other OARs will be reviewed by a physician and will
be modified as needed. Any modifications to an OAR must be denoted by the structure
name (see Table in Section 6.4.4) followed by the sequence number of the scan (1 or 2,
depending on which of the three repeat scans is currently being evaluated). GTV or iGTV do
not require modifications, unless they lie > 3mm outside the originally contoured GTV or
iGTV. GTV or iGTV should be re-contoured if tumor regression develops within the
previously contoured region, but the CTV (or ITV) and PTV should remain the same. Re-
contouring may also be necessary if the GTV shifts relative to other anatomy or deforms. In
this case the CTV should be adjusted to the new iGTV/GTV + margin, and a new PTV should
be created.
Important note: Even though the GTV may shrink substantially during the course of
radiotherapy, the CTV is assumed to retain its volume. Therefore, the CTV (or ITV) should
not be reduced even if the GTV or iGTV has regressed in the repeat CT scans. The
assumption is that there is likely to be microscopic disease present where GTV or iGTV was.
The CTV (or ITV) shape may change depending on changes in the surrounding anatomy.
 The beam configuration (beam directions, energies, SOBPs, weights, compensators,
apertures, etc.) from the previously approved treatment plan will be transferred to the repeat
CT, the dose distribution will then be recalculated, and a new set of DVHs will be created for
the OARs and target structures.
Verification plan and replanning (adaptive planning)

A verification plan is a plan with dose distribution computed using the new repeat image and the
original (or the current beam) configuration to verify whether the dose distribution is still
acceptable. An adaptive plan is a new plan designed to meet the specified criteria. It will very
likely have a different beam configuration.
The treating physician should evaluate the verification plan and decide on the need of replanning.
When there is an unfavorable change in dose distribution to an OAR or target in the verification
plan, every effort is made to restore the DVH for that structure to the previous/original plan's
DVH. At times this is not achievable, but that is the goal of replanning.
 The following steps should be taken to evaluate verification plans and create the adaptive
plans:
o Use the original plan on the original scan to full prescription dose as reference
o Create the dose distribution from the original plan with the full prescription dose on
the replanning scan. This is done to evaluate if there is any change in DVH on the
replanning scan if the original plan is delivered in full.
o If replan is indicated, create an adaptive plan on the new scan with the remaining
dose and this will be used to deliver the rest of the treatment or until another replan is
indicated.
 Target coverage: Replanning of a treatment plan based on under coverage of the target
must be performed if the target coverage shows deviation unacceptable in verification plan.
 OAR overdose: Replanning of a treatment plan based on higher doses to the OARs must be
performed if the spinal cord Dmax(0.03cc)>52 Gy, lung V20>40%, or mean lung dose >22Gy.
 Inferior dose distribution compared with the original plan: Replanning of a treatment plan
should be done when the verification plan is inferior to the original plan. For example, MLD 17
Gy in the verification plan when MLD was 12 Gy in the original plan in the event that the
37
tumor becomes cavitary or had significant reduction causing overshooting into the normal
lung. Another example would be proton overshoot to heart due to tumor regression.
 For other, less critical tissues, if the dose calculated with the original beam configuration to
the new image indicates unacceptable deviation based on criteria specified in the Table in
Section 6.5.4, replanning will be at the discretion of the treating physician.
 Dose distributions displayed on each of the modified plans are used for evaluation and
delivery of the remainder of the treatments. The dose delivered to date is not considered in
the design and optimization of the new plan. The new plan, on its own, should meet the
specified target coverage and normal tissue criteria.
 For patients requiring adaptive plans, the following procedure is to be used to estimate the
summed dose distributions. Beam configurations for the original and the adaptive replans
used for treatments will be applied to the CT image of week 5, assumed to represent an
average anatomy over the course of radiotherapy. The dose distributions computed for each
of the configurations will be summed weighted according to the number of fractions each
distribution was used.
 All plans developed and used for treatments and the corresponding CT images will be
submitted to IROC Philadelphia-RT Core Lab. The RTOG will not collect repeat CT study
information when a replan is not necessary.
6.7.3 Management of IGRT and Repeat CT Radiation Dose to the Patient
According to the IGRT literature, estimates of patient dose per imaging study for different imaging
systems vary considerably. The doses are in the range of 1 mGy for Cyberknife’s and BrainLab’s
ExacTrac planar kV-systems and can be considered negligible compared with doses from MV
portal imaging and kV and MV CT. The doses from helical MV cone-beam CT scan on a
tomotherapy unit are estimated to be in range of 1 to 3 cGy for head and neck studies, similar to
doses reported for kV cone beam CT on Elekta Synergy machine. The doses for MV cone beam
CT are reported to be in range from 10 cGy for a pelvis study to 6 cGy for a head and neck study.
Thus, the doses for 3D imaging systems are in the range from 1 to 6 cGy for head and neck
imaging and can contribute from 0.5 to 3% to the daily dose of 2.0 Gy. These are small enough
dose contributions that if there is only one imaging study done per treatment session, the dose
does not need to be incorporated into treatment planning and is not expected to have any clinical
relevance to the patient. However, the imaging dose to the patient may become significant if
repeated studies are done for patients with severe set up problems (e.g., requiring frequent
corrections of more than 5 mm). It is recommended that patients demonstrating severe set up
problems during the first week of treatment be moved to a treatment with larger margins.
6.8 R.T. Quality Assurance Reviews

6.8.1 Pre-Treatment Review
Pre-treatment reviews will be performed for the first 3 cases of proton treatment as well as the
first 3 cases of photon treatment from each participating institution. Pre-treatment reviews will
also be performed for the first 3 adaptive replans. When a facility partners with one or more
outside facilities to provide the treatment modality not available at the enrolling institution, this
facility will be required to submit their first 3 cases for pre-treatment review on behalf of the
enrolling site. These reviews will be performed by the PI of the protocol (Zhongxing Liao, MD) or
a radiation oncology co-chair.
If the prescribed dose of 70 Gy (RBE) is not achievable

If the prescription dose of 70 Gy (RBE) cannot be achieved within the stated normal tissue
constraints, the treatment plan must be submitted for pre-treatment review.
6.8.2 Post-Treatment Review
For cases not requiring pre-treatment review, the Radiation Oncology Co-Chairs, will perform an
RT Quality Assurance Review after complete data for the first 20 cases enrolled has been
received at NRG Oncology. The Radiation Oncology Co-Chairs will perform the next review after
complete data for the next 20 cases enrolled has been received at NRG Oncology. The final
cases will be reviewed within 3 months after this study has reached the target accrual or as soon
as complete data for all cases enrolled has been received at NRG Oncology, whichever occurs
38
first. These reviews will be ongoing and performed remotely or at the NRG Oncology semi-annual
meetings as needed.
6.9 Radiation Therapy Adverse Events

All radiation therapy adverse events will be graded according to CTCAE, v. 4.0 (see Section 7).
Treatment-related acute adverse event is defined as any side effect occurring within 90 days from
the start of treatment. Treatment-related late toxicity is defined as any side effect occurring after
or persisting beyond 90 days from the start of treatment. Radiation pneumonitis will be evaluated
for 12 months after the start of radiation treatment. Also see Section 7.6 for treatment
modifications for hematologic and non-hematologic toxicity.
6.9.1 Potential Adverse Events
Reversible or permanent alopecia, bone marrow toxicity, skin reactions, pneumonitis, pleural
effusion, fibrosis of the AORs in the path or radiation, esophagitis, odynophagia, dysphagia, and
sometimes esophageal stricture are expected side effects of radiation therapy. Radiation-induced
myocarditis or transverse myelitis rarely occurs at doses lower than 50 Gy.
6.9.2 Acute Esophageal Toxicities (AET)
Acute esophageal toxicities include esophagitis, odynophagia, dysphagia. Esophageal
complaints are common with combined modality therapy. AET does not constitute a reason to
interrupt or delay radiotherapy or chemotherapy provided oral intake is sufficient to maintain
hydration. Patients should be advised to avoid alcoholic, acidic, or spicy foods or beverages.
Viscous Xylocaine, Carafate, or other medications should be used for symptomatic relief. Quite
often, narcotics may be required. Acute esophagitis may persist for 4-6 weeks. If grade 4
esophagitis occurs, all treatments including chemotherapy and radiation therapy should be put on
hold until patient is stable enough to continue with the same or modified treatment.
Esophagitis Grading System

Please refer to CTCAE v.4 for the diagnosis and grading of esophagitis.
Treatment should be interrupted for grade 4 or greater dysphagia or odynophagia. Acute

esophageal toxicity, which typically can occur within 2 weeks of the initiation of treatment and
manifests as dysphagia, odynophagia, reflux symptoms, etc. should be pharmacologically
managed with the following approach and should be initiated at the first signs or symptoms of
esophageal toxicity.
Suggested Management of Radiation Esophagitis

1. Ketoconazole 200 mg PO q day OR Fluconazole 100 mg PO q day until the completion of
radiation;
2. Mixture of 2% viscous lidocaine: 60 cc; Mylanta: 30 cc; sucralfate (1 gm/cc): 10 cc. Take 15-
30 cc PO q3-4 hrs prn. (Contraindications: patients taking Dilantin, Cipro, Digoxin);
3. Ranitidine 150 mg PO BID (or other H2 blocker or a proton pump inhibitor such as
omeprazole) until the completion of radiation;
4. Grade 4 esophagitis: hold RT + chemotherapy until grade 2 or less.
A significant portion of patients is expected to experience grade 2 esophagitis. Treatment of

esophagitis varies with the severity of the patient’s symptoms; for example, diet adjustment and
narcotic management may be sufficient for grade 2 esophagitis. Nutritional support via gastric
tube or jejunostomy tube may be initiated upon development of grade 3-4 esophagitis, per mutual
preference of the treating physician and patient.
Severe acute esophageal toxicity is defined as persistent grade 3 or higher esophageal toxicity
occurring within 3 months of the start of radiation therapy, defined as severe dysphagia or
odynophagia with dehydration or weight loss > 15% from treatment baseline, requiring a feeding
tube, intravenous fluids for more than 3 consecutive days, or hyperalimentation. Grade 4 is
defined as esophagitis causing life-threatening consequences, such as perforation, obstruction,
or fistula formation. Grade 5 is severe esophagitis directly contributing to death. Persistent grade
39
3 esophageal toxicity is defined as esophageal toxicity dependent on a feeding tube, intravenous
fluids, or hyperalimentation longer than 6 weeks after the completion of radiation therapy.
6.9.3 Changes in Pulmonary Function Tests
Patients enrolled to this study are allowed to have some degree of impaired pulmonary function
as measured by pulmonary function tests (PFTs), including Forced Expiratory Volume in 1
second (FEV1), Forced Vital Capacity (FVC), and Diffusing Capacity for Carbon Monoxide
(DLCO). The Common Toxicity Criteria (CTCAE), v. 4 includes specified criteria for grading
adverse events related to these PFT parameters under the system organ class of Investigations.
The grading criteria for these PFT changes use the “percent predicted” values from 0-100%
which are recorded on the patient’s PFT report. A percent predicted of 90% conveys that the
patient is able to perform the PFT test to a result that is 90% of what would be expected for the
normal general population of the same height, age, and sex. The CTCAE version 4 specified
grading criteria for PFTs assumes that all patients have normal baseline pulmonary function.
This assumption is not appropriate for this protocol enrolling patients with abnormal baseline
function.
As a remedy to monitor treatment effects on PFTs, we will define a protocol specific toxicity
classification for PFTs that adjusts for baseline abnormalities. Changes that occur after therapy
will be referenced to the baseline for a given patient, which will be abnormal for most patients.
We have defined a proportional decline from the baseline. Grade 1 toxicity will be a decline from
baseline to a level 0.90 times the baseline, grade 2 will be a decline to a level 0.75 of baseline,
grade 3 will be a decline to a level 0.5 of baseline, grade 4 will be a decline to a level 0.25 of
baseline, and grade 5 will be death. This scheme is depicted in the Table below and graphically
represented in the Figure below.
As an example, a patient who enters the study with a percent predicted DLCO of 55% who
experiences a post-treatment decline to a percent predicted DLCO of 40% would have a grade 3
event in the original CTCAE, v. 4 criteria; however, under this modified PFT toxicity classification
for patients with abnormal baseline, his decline would constitute a decrease to 0.72 of the
baseline value which is between 0.75 and 0.5 or a grade 2 event.
40
Pulmonary Toxicity Scale
Grade
Adverse Event 1 2 3 4 5
FEV-1 Decline 0.90-0.75 <0.75-0.50 <0.50-0.25 <0.25 times Death
times the times the times the the patient’s
patient’s patient’s patient’s baseline
baseline baseline baseline value
value value value
Forced Vital 0.90-0.75 <0.75-0.50 <0.50-0.25 <0.25 times Death

Capacity times the times the times the the patient’s
Decline patient’s patient’s patient’s baseline
value value value
DLCO Decline 0.90-0.75 <0.75-0.50 <0.50-0.25 <0.25 times Death

times the times the times the the patient’s
patient’s patient’s patient’s baseline
value value value
PFT(FEV-1, FVC, DLCO) Decline
100 Baseline
Percent Predicted
Grade 1
75 Grade 2
Grade 3
Grade 4
50
25
6.10 Radiation Therapy Adverse Event Reporting (See Section 7.8)
7.0 DRUG THERAPY

Institutional participation in chemotherapy studies must be in accordance with the Medical
Oncology Quality Control guidelines stated in the RTOG Procedures Manual.
Concurrent chemotherapy treatment must begin within 24 hours of radiation therapy start.
7.1 Treatment
7.1.1 Concurrent Chemotherapy
41
Concurrent chemotherapy is one treatment course during the 7 weeks of radiotherapy. A single
platinum-based doublet chemotherapy regimen is to be administered during radiotherapy. The
choice of the chemotherapy regimen is at the discretion of the treating physician. One of the
following recognized standard, protocol-allowed regimens must be given with radiation therapy:
 Paclitaxel (50 mg/m2) intravenous over 1 hour followed by

Carboplatin AUC = 2 mg/min/mL intravenous weekly (every 7 days) during radiotherapy
(Belani 2005, NCCN 2012)
Standard premedications with steroids, diphenhydramine, H2 receptor antagonist, and 5-
HT3 receptor antagonist antiemetics must be administered per individual institutional
guidelines.
OR
 Etoposide (50 mg/m2/d) intravenous on days 1 to 5 and days 29 to 33
Cisplatin (50 mg/m2/d) intravenous on days 1, 8, 29, and 36
(Albain 2002, NCCN 2012)
Standard premedications with steroids and 5-HT3 receptor antagonist antiemetics must
be administered per individual institutional guidelines. Standard intravenous hydration (≥
1.5 liters) must be administered in conjunction with cisplatin.
Filgrastim and pegfilgrastim may not be used during concurrent chemoradiotherapy.

Erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may not be used during
concurrent chemoradiotherapy.
Chemotherapy dosing for all patients will be based on actual body weight, in accordance with
ASCO guidelines (Griggs 2012).
Chemotherapy scheduling modifications of +/- 48 hours are allowed due to weekends and
holidays.
7.1.2 Consolidation Chemotherapy

The treating physician will administer 2 cycles of consolidation chemotherapy 4-6 weeks after
concurrent chemoradiotherapy has ended, only if patients receive concurrent carboplatin and
paclitaxel with radiotherapy. Each cycle length is 21 days. The consolidation chemotherapy
regimen is carboplatin and paclitaxel.
 Paclitaxel (200 mg/m2) intravenous over 3 hours on day 1

Carboplatin at an area under the plasma concentration time curve (AUC) = 6 mg/min/mL
intravenous on day 1
A second cycle of paclitaxel and carboplatin will be administered on day 22.
Standard premedications with steroids, diphenhydramine, H2 receptor antagonist and 5-
HT3 receptor antagonist antiemetics must be administered per individual institutional
guidelines.
Patients who receive concurrent cisplatin and etoposide with radiotherapy are not allowed to
receive consolidation chemotherapy.
Filgrastim and pegfilgrastim may be used in accordance with ASCO guidelines during
consolidation chemotherapy (Smith 2006).
Erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa) may be used in accordance
with ASCO guidelines during consolidation chemotherapy (Rizzo 2010).
Chemotherapy scheduling modifications of +/- 48 hours is allowed due to weekends, holidays,

and other scheduling constraints.
42
7.2 Cisplatin Agent Information
Refer to package insert for detailed pharmacologic and safety information.
7.2.1 Formulation
Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and
hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH
range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous
solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH.
Cisplatin also is available in vials containing 50mL or 100mL of a 1mg/mL solution.
7.2.2 Storage and Stability
Reconstituted solution of cisplatin is stable for 20 hours when stored at 25°C and should be
protected from light if not used within 6 hours. The vials and injection should not be refrigerated.
Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30
minutes. Therefore, needles or intravenous sets containing aluminum parts that may come in
contact with the drug must not be used for the preparation or administration of cisplatin.
7.2.3 Adverse Events
Human toxicity includes nausea, vomiting, anaphylaxis, neuropathies, ocular disturbances, renal
toxicity (with an elevation of BUN and creatinine and impairment of endogenous creatinine
clearance, as well as renal tubular damage, which appears to be transient), ototoxicity (with
hearing loss that initially is in the high-frequency range, as well as tinnitus), and hyperuricemia.
Much more severe and prolonged toxicity has been observed in patients with abnormal or
obstructed urinary excretory tracts. Myelosuppression, often with delayed erythrosuppression, is
expected.
7.2.4 Supply
Commercially available.
The use of drug(s) or combination of drugs in this protocol meet the criteria described under Title
21 CFR 312.2(b) for IND exemption.
7.3 Etoposide Agent Information


Store the unopened vials under refrigeration 2º to 8º C (36º-46º F). Retain in original package to
protect from light.
Hematologic: Myelosuppression is dose related and dose limiting with granulocyte nadirs
occurring 7 to 14 days after drug administration and platelet nadirs occurring 9 to 16 days after
drug administration. Bone marrow recovery is usually complete by day 20. Acute myeloid
leukemia has been reported in rare instances.
Gastrointestinal: Nausea and vomiting are the major gastrointestinal toxicities. Nausea and
vomiting can usually be controlled with standard antiemetic therapy.
Hypotension: Transient hypotension following rapid intravenous administration has been reported
in 1% to 2% of patients. It has not been associated with cardiac toxicity or electrocardiographic
changes. No delayed hypotension has been noted.
Allergic Reactions: Anaphylactic-like reactions characterized by chills, fever, tachycardia,
bronchospasm, dyspnea and hypotension have been reported to occur in less than 1% of the
patients treated with the oral capsules. These reactions have usually responded promptly to the
cessation of the drug and to the administration of pressor agents, corticosteroids, antihistamines
or volume expanders as appropriate. One fatal acute reaction associated with bronchospasm
has been reported.
Alopecia: Reversible alopecia, sometimes progressing to total baldness was observed in up to
66% of patients.
Other: The following adverse reactions have been infrequently reported: aftertaste, hypertension,
rash, fever, pigmentation, pruritus, abdominal pain, constipation, dysphagia, transient cortical
blindness, and a single report of radiation recall dermatitis
43
7.3.3 Supply
7.4 Carboplatin Agent Information

Refer to the package insert for additional information.

7.4.1 Formulation
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150
mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and
mannitol. Carboplatin also is available as a 10 mg/mL solution in 50, 150, and 450 mg vials.
7.4.2 Preparation
When available, prediluted vials of carboplatin should be utilized. Otherwise, the preparation of
carboplatin should proceed as described below:
Immediately before use, the contents of a carboplatin vial must be reconstituted with either sterile
water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. The
following shows the proper diluent volumes to be used to obtain a carboplatin concentration of 10
mg/mL:
Vial size Diluent volume

50 mg 5mL
150 mg 15 mL
450 mg 45 mL
Carboplatin reacts with aluminum to form a precipitate and cause a loss of potency. Therefore,
needles or intravenous sets containing aluminum parts that may come in contact with the drug
must not be used for the preparation or administration of carboplatin.
Intact vials of carboplatin are stable for the period indicated on the package when stored at room
temperature (15-30˚C or 59-86˚F) and protected from light. When prepared as described above,
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The
solution should be discarded after 8 hours since no antibacterial preservative is contained in the
formulation.
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia,
neutropenia, leucopenia, and anemia are common but typically resolve by day 28 when
carboplatin is given as a single agent.
Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of patients receiving
the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and
hypotension. The reactions can be successfully managed with standard epinephrine,
corticosteroid, and antihistamine therapy. Desensitization per the allergy team is allowed.
Neurologic: Peripheral neuropathies have been observed in 4% of patients receiving carboplatin
with mild paresthesia being the most common.
Gastrointestinal: Nausea and vomiting are the most common gastrointestinal events; both usually
resolve within 24 hours and respond to antiemetics. Other gastrointestinal events include
diarrhea, weight loss, constipation, and gastrointestinal pain.
Hepatic: Elevated alkaline phosphatase, total bilirubin, and SGOT have been reported.
Other: Pain and asthenia are the most common miscellaneous adverse events. Alopecia has
been reported in 3% of the patients taking carboplatin.
7.4.5 Supply
44
7.5 Paclitaxel Agent Information

7.5.1 Preparation
Paclitaxel injection is a sterile solution concentrate, 6 mg/ml in 5, 16.7, and 50 ml vials (30, 100,
and 300 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol,
USP, 50%. Paclitaxel will be diluted to a final concentration of 0.3 to 1.2 mg/ml in D5W, NS, or
D5NS , in glass or polyolefin containers due to leaching of diethylhexphthalate (DEHP) plasticizer
from polyvinyl chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which
paclitaxel is solubilized. Each bag/bottle should be prepared immediately before administration.
NOTE: Formation of a small number of fibers in solution (NOTE: acceptable limits established by
the USP Particular Matter Test for LVPs) have been observed after preparation of paclitaxel.
Therefore, in-line filtration is necessary for administration of paclitaxel solutions. In-line filtration
should be accomplished by incorporating a hydrophilic, microporous filter of pore size not greater
than 0.22 microns (e.g.: Millex-GV Millipore Products) into the intravenous fluid pathway distal to
the infusion pump. Although particulate formation does not indicate loss of drug potency,
solutions exhibiting excessive particulate matter formation should not be used.
Paclitaxel vials should be stored between 20-25C (68°-77°F). When prepared as suggested
(0.3 – 1.2 mg/ml), the solution is stable for 27 hours.
7.5.3 Adverse Effects
Hematologic: Myelosuppression;
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain;
Heart: Arrhythmias, heart block, hypertension;
Neurological: Sensory and peripheral neuropathy;
Allergy: Severe anaphylactic reactions;
Other: Alopecia, fatigue, arthralgia, myopathy, myalgia, infiltration (erythema, induration,
tenderness, rarely ulceration), hypotension, irritation to the injection site, mucositis
7.5.4 Supply
7.6 Dose Modifications

7.6.1 Dose Modifications During Concurrent Chemoradiotherapy With Weekly Carboplatin and
Paclitaxel
Hematologic Toxicity
Absolute neutrophil count (ANC) and platelet count (plt) must be obtained within 72 hours prior to
each dose of carboplatin and paclitaxel, except for on day 1, as specified in Appendix I.
If ANC < 1000 or plt < 75,000, omit weekly carboplatin and paclitaxel. Restart weekly carboplatin
and paclitaxel at same dose if ANC > 1000 and plt > 75,000. Doses that are omitted are not made
up.
Dysphagia/Radiation Esophagitis
If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold weekly
carboplatin and paclitaxel. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis
and radiation is to be restarted, it is the investigator’s decision whether or not to restart
chemotherapy. If the decision is made to restart chemotherapy in this setting, weekly carboplatin
and paclitaxel must be dose reduced to 50%. If radiation is interrupted for grade 4 dysphagia or
radiation esophagitis, do not restart chemotherapy even if radiation is restarted.
45
Neurologic Toxicity
Carboplatin and paclitaxel doses will be modified for neurologic toxicity:
 If grade 1 neurologic toxicity, no dose modification
 If grade 2 neurologic toxicity, reduce dose to 75%.
 If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to
grade ≤ 2, then either reduce dose to 50% or discontinue chemotherapy, at the
physician’s discretion.
Renal Toxicity
Carboplatin dose will be modified for renal toxicity. Serum creatinine must be obtained within 72
hours prior to each dose of weekly carboplatin, except for day 1. Serum creatinine is required
within 10 days prior to day 1 carboplatin, as specified in Appendix I.
 If serum creatinine ≤1.5 mg/d, give full carboplatin dose.
 If serum creatinine > 1.5 mg/d, calculate creatinine clearance (Cockcroft-Gault formula).
If calculated creatinine clearance is ≥ 50 ml/min give full carboplatin dose.
 If serum creatinine > 1.5 mg/d and calculated creatinine clearance is 25-50 ml/min,
reduce carboplatin dose to 50%.
 If serum creatinine > 1.5 mg/d and calculated creatinine clearance is ≤ 25 ml/min hold
carboplatin dose. Reassess creatinine and creatinine clearance weekly. If creatinine
clearance improves to > 25 mL/min, restart carboplatin at a dose of 50%.
Neutropenic Fever [defined as temperature ≥ 38.3 C (101 F) and ANC < 500]
 If neutropenic fever occurs and the patient subsequently meets criteria for further
chemotherapy, the doses are reduced to 75%
Other Toxicities Not Defined Above

 If toxicities ≤ grade 2, then manage symptomatically, if possible, and retreat without dose
reduction.
 If toxicities ≥ grade 3, the suspected drug should be withheld until resolution to grade 1 or
baseline, if baseline was > grade 1, then reinstitute if medically appropriate and reduce
dose to 50%.
If carboplatin or paclitaxel doses are reduced, all future weekly doses are reduced.
7.6.2 Dose Modifications During Concurrent Chemoradiotherapy With Cisplatin and Etoposide
As specified in Appendix I: ANC and plt must be obtained within 72 hours prior to day 29
chemotherapy.
For day 1 and day 29 cisplatin and etoposide:
 If ANC ≥ 1250 and plt ≥ 100,000, give full dose
 If ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1 week.
 If after a 1 week delay ANC ≥ 1250 and plt ≥100,000, give full dose. If after a 1-week
delay ANC < 1250 or plt < 100,000, hold chemotherapy and recheck ANC and plt in 1
more week (total of a 2-week delay). If after a 2-week delay ANC ≥ 1250 and plt ≥
100,000, reduce dose of chemotherapy by 25%. If after a 2-week delay ANC < 1250 or
plt < 100,000, omit chemotherapy.
For day 8 and day 36 cisplatin:

ANC and plt must be obtained within 72 hours prior to day 8 and 36 chemotherapy, as specified
in Appendix I.
 If ANC ≥ 1000 and plt ≥ 75,000, give full dose
 If ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in 1 week.
 If after a 1-week delay ANC ≥ 1000 and plt ≥ 75,000, give full-dose cisplatin. If after a 1-
week delay ANC < 1000 or plt < 75,000, hold chemotherapy and recheck ANC and plt in
1 more week (total of a 2-week delay). If after a 2-week delay ANC ≥ 1000 and plt ≥
46
75,000, reduce dose of cisplatin to 75%. If after a 2-week delay ANC < 1000 or plt <
75,000, omit the dose of cisplatin.
Dysphagia/Radiation Esophagitis
If radiation is interrupted for grade 3 or 4 dysphagia or radiation esophagitis, hold cisplatin and
etoposide. If radiation is interrupted for grade 3 dysphagia or radiation esophagitis and radiation
is to be restarted, it is the investigator’s decision whether or not to restart chemotherapy. If the
decision is made to restart chemotherapy in this setting, cisplatin and etoposide doses must be
reduced to 50%. If radiation is interrupted for grade 4 dysphagia or radiation esophagitis, do not
restart chemotherapy even if radiation is restarted.
Neurologic Toxicity
Cisplatin dose will be modified for neurologic toxicity:
 If grade > 2 neurologic toxicity, hold cisplatin until neurologic toxicity improves to grade ≤
2, then either reduce dose to 50% or discontinue cisplatin, at the physician’s discretion
Renal Toxicity
Cisplatin dose will be modified for renal toxicity.
Serum creatinine must be obtained within 72 hours prior to each dose of cisplatin, except for day
1. Serum creatinine is required within 10 days prior to day 1 cisplatin. See Appendix I.
 If serum creatinine ≤ 1.5 mg/d, give full cisplatin dose.

 If serum creatinine 1.5-2.0 mg/d, calculate creatinine clearance. If calculated creatinine
clearance is ≥ 50 ml/min give full cisplatin dose.
 If serum creatinine 1.5-2.0 mg/d and calculated creatinine clearance is < 50 ml/min, omit
cisplatin dose and recheck serum creatinine at next scheduled cisplatin dose. If
creatinine is < 2.0 and creatinine clearance has improved to ≥ 50 mL/min, reduce
cisplatin dose to 75% .
 If serum creatinine > 2.0 mg/d , omit cisplatin dose, and recheck serum creatinine at next
scheduled cisplatin dose. If creatinine is < 2.0 and creatinine clearance ≥ 50 mL/min,
reduce dose to 50%; otherwise continue to omit cisplatin dose, recheck serum creatinine
again at next scheduled cisplatin dose, and follow the same guidelines.
If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy,
the doses are reduced by 25%.

reduction.
baseline; if baseline was > grade 1, then reinstitute if medically appropriate and reduce
dose by 50%.
If cisplatin or etoposide doses are reduced, all future doses are reduced.
7.6.3 Dose Modifications for Consolidation Chemotherapy With A Carboplatin and Paclitaxel Regimen
ANC and plt must be obtained within 72 hours prior to each dose of carboplatin and paclitaxel , as
specified in Appendix I.
 If ANC ≥ 1500 and plt ≥100,000, give full dose
 If ANC < 1500 or plt < 100,000, hold chemotherapy and repeat ANC and plt in 1 week. If
ANC ≥ 1500 and plt ≥100,000, give full dose. If ANC < 1500 or plt < 100,000, hold
47
chemotherapy again and repeat ANC and plt in 1 week (total of a 2-week delay). If ANC
≥ 1500 and plt ≥ 100,000, give full dose; otherwise omit chemotherapy dose.
Neurologic Toxicity
Carboplatin and paclitaxel doses will be modified for neurologic toxicity:
 If grade > 2 neurologic toxicity, hold chemotherapy until neurologic toxicity improves to
grade ≤ 2, then either reduce dose to 50% or discontinue chemotherapy, at the
physician’s discretion.
Renal Toxicity
Carboplatin dose will be modified for renal toxicity.
Serum creatinine must be obtained within 72 hours prior to each dose of carboplatin, as specified
in Appendix I.
 If serum creatinine ≤ 1.5 mg/d, give full carboplatin dose.
 If serum creatinine > 1.5 mg/d, calculate creatinine clearance. If calculated creatinine
clearance is ≥ 50 ml/min give full carboplatin dose.
 If serum creatinine > 1.5 mg/d and calculated creatinine clearance is 25-50 ml/min,
reduce carboplatin dose to 50%.
 If serum creatinine > 1.5 mg/d and calculated creatinine clearance is ≤ 25 ml/min hold
carboplatin dose. Reassess creatinine and creatinine clearance weekly. If creatinine
clearance improves to > 25 mL/min within 14 days, restart carboplatin at a dose of 50%.
If neutropenic fever occurs and the patient subsequently meets criteria for further chemotherapy,
the doses are reduced to 75%.

reduction.
baseline; if baseline was > grade 1, then reinstitute if medically appropriate and reduce
dose to 50%.
If carboplatin or paclitaxel doses are reduced, all future doses are reduced.
7.7 Modality Review

The Medical Oncology Co-Chair, Charles Lu, M.D., will perform a Chemotherapy Assurance
Review of all patients who receive or are to receive chemotherapy in this trial. The goal of the
review is to evaluate protocol compliance. The review process is contingent on timely submission
of chemotherapy treatment data as specified in Section 12.1. The scoring mechanism is: Per
Protocol/Acceptable Variation, Unacceptable Deviation, and Not Evaluable. A report is sent
to each institution once per year to notify the institution about compliance for each case reviewed
in that year. Failure to deliver consolidative chemotherapy will be considered an acceptable
variation.
Dr. Lu will perform a Quality Assurance Review after complete data for the first 20 cases enrolled
has been received at NRG Oncology. Dr. Lu will perform the next review after complete data for
the next 20 cases enrolled has been received at NRG Oncology. The final cases will be reviewed
within 3 months after this study has reached the target accrual or as soon as complete data for all
cases enrolled has been received at NRG Oncology, whichever occurs first.
48
7.8 Adverse Events
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version
4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate
treatment areas should have access to a copy of the CTCAE version 4.0.
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via
the CTEP web site at https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to
1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is
restored, an AE report submitted by phone must be entered electronically into CTEP-AERS.
NRG Oncology is responsible for adverse event reporting to the FDA.
7.8.1 Adverse Events (AEs)

Definition of an AE: Any untoward medical occurrence associated with the use of a drug in
humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational) product, whether or not considered related
to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or
definite). (International Conference on Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines:
Adverse Event Reporting Requirements. February 29, 2012;
http://ctep.cancer.gov/reporting/adeers.html]
7.8.2 Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited
reporting criteria defined in the table in section 7.9 will be reported via CTEP-AERS. SAEs that
require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section
7.9. Contact the CTEP-AERS Help Desk if assistance is required.
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in
any of the following outcomes:
 Death;
 A life-threatening adverse drug experience;
 Inpatient hospitalization or prolongation of existing hospitalization;
 A persistent or significant disability/incapacity;
 A congenital anomaly/birth defect;
 Important medical events that may not result in death, be life threatening, or require
hospitalization may be considered an SAE, when, based upon medical judgment, they may
jeopardize the patient and may require medical or surgical intervention to prevent one of the
outcomes listed in the definition.
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy
of a study participant must be reported via CTEP-AERS in an expedited manner.
7.8.3 Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERSwithin 30
days of AML/MDS diagnosis.
Secondary Malignancy
49
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g.,
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary
malignancy is not considered a metastasis of the initial neoplasm.
Three options are available to describe the event:
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])

 Myelodysplastic syndrome (MDS)
 Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be
reported via the routine reporting mechanisms outlined in each protocol.
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via
CDUS unless otherwise specified.
7.9 CTEP-AERS Expedited Reporting Requirements

All serious adverse events that meet expedited reporting criteria defined in the reporting table
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed
via the CTEP web site, https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 .
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG
Oncology requirements for expedited adverse event reporting.
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only
pathway.
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to
NRG Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet
connectivity is restored, an AE report submitted by phone must be entered electronically into
CTEP-AERS.
 CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is

electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS
24-hour notification must be followed by an CTEP-AERS 5 Calendar Day Report. Serious
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited
reporting table below.
 Supporting source document is not mandatory. However, if the CTEP-AERS report indicates
in the Additional Information section that source documentation will be provided, then it is
expected. If supporting source documentation accompanies an AdEERS report, include the
protocol number, patient ID number, and CTEP-AERS ticket number on each page, and fax
supporting documentation to the NRG Oncology dedicated SAE FAX, 215-717-0990.
 A serious adverse event that meets expedited reporting criteria outlined in the following table
but is assessed by the CTEP-AERS System as “expedited reporting NOT required” must still
be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT
Required” assessment; the CTEP-AERS System allows submission of all reports regardless
of the results of the assessment.
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE
section of the appropriate case report form (see Section 12.1).
50
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events
that Occur on Studies Utilizing Commercial Drug within 30 Days of the Last Administration
of the Commercial Drug 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death
2) A life-threatening adverse event
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization
for ≥ 24 hours
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life
functions
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon medical judgment, they may
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI
via CTEP-AERS within the timeframes detailed in the table below.
Grade 1 Grade 2 Grade 3 Grade 4 & 5
Hospitalization Timeframes Timeframes Timeframes Timeframes
Resulting in
Hospitalization 10 Calendar Days
≥ 24 hrs 24-Hour 5 Calendar
Not resulting in Days
Hospitalization Not required 10 Calendar Days
≥ 24 hrs
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24
hours of learning of the AE, followed by a complete expedited report within 5 calendar days
of the initial 24-hour report.
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10
calendar days of learning of the AE.
1
Serious adverse events that occur more than 30 days after the last administration of
investigational agent/intervention and have an attribution of possible, probable, or definite require
reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
 All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
 Grade 3 adverse events
2
For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive
half lives, rounded UP to the nearest whole day, after the agent/intervention was last
administered. Footnote “1” above applies after this reporting period.
Effective Date: May 5, 2011
51
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements
The following are protocol specific exceptions to expedited reporting via CTEP-AERS. Report the
following AEs in an expedited manner only if they exceed the grade in parentheses next to the
AE: esophagitis (gr 2); dysphagia (gr 2); nausea (gr 3); vomiting (gr 3); dehydration (gr
3). Routine adverse event reporting on the case report form fulfills safety reporting requirements
for these events at the aforementioned grades.
8.0 SURGERY
Not applicable to this trial.
9.0 OTHER THERAPY

9.1 Permitted Supportive Therapy
All supportive therapy for optimal medical care will be given during the study period at the
discretion of the attending physician(s) within the parameters of the protocol and documented on
each site’s source documents as concomitant medication.
9.1.1 Filgrastim, pegfilgrastim, and erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa)
may be used in accordance with ASCO guidelines during consolidation chemotherapy (Smith
2006; Rizzo 2010). Per Section 9.2.1 below, they are not permitted during concurrent
chemoradiotherapy.
9.1.2 See Sections 7.1.1 and7.1.2, for premedication regimens for chemotherapy administration.
9.2 Non-Permitted Supportive Therapy

9.2.1 Filgrastim, pegfilgrastim and erythropoiesis-stimulating agents (epoetin alfa, darbepoietin alfa)
may not be used during concurrent chemoradiotherapy.
10.0 TISSUE/SPECIMEN SUBMISSION (10/23/14)

NOTE: Patients must be offered the opportunity to participate in the correlative
components of the study, such as tissue/specimen submission.
 If the patient consents to participate in the tissue/specimen component of the study, the
site is required to submit the patient’s specimens as specified in Section 10.0 of the
protocol. Note: Sites are not permitted to delete the tissue/specimen component from the
protocol or from the sample consent.
10.1 Tissue/Specimen Submission
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved
through careful block storage and processing. NRG Oncology encourages participants in protocol
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides
tissue specimens to investigators for translational research studies. Translational research
studies integrate the newest research findings into current protocols to investigate important
biologic questions.
In this study, it is strongly encouraged that tumor tissue and blood will be submitted to the NRG
Oncology Biospecimen Bank for the purpose of specimen banking for future research.
10.2 Tissue Collection for Banking for Future Research

(optional but strongly encouraged)
The following must be provided in order for the case to be evaluable for the NRG Oncology
Biospecimen Bank:
10.2.1 One H&E stained slide per positive biopsy site (slide can be a duplicate cut stained H&E of the
diagnostic slide (block); it does not have to be the diagnostic slide itself).
10.2.2 A corresponding paraffin-embedded tissue block of the tumor (preferred; the block must match
the H&E being submitted) or a 2-mm diameter core of tumor tissue, punched from the tissue
52
block containing the tumor with a punch tool and submitted in a plastic tube labeled with the
surgical pathology number; or 10 unstained sections on adherent slides. Note: A kit with the
punch, tube, and instructions can be obtained free of charge from the NRG Oncology
Biospecimen Bank. Block or core must be clearly labeled with the pathology identification number
and block number that corresponds to the Pathology Report.
 The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the
submitted material is reviewed and is not tumor, the site may be assessed a protocol
violation.
10.2.3 A Pathology Report documenting that the submitted block or core contains tumor. The report
must include the NRG Oncology and patient’s case number. The patient’s name and/or other
identifying information should be removed from the report. The surgical pathology numbers and
information must NOT be removed from the report.
10.2.4 A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG Oncology
Biospecimen Bank; if for translational research, this should be stated on the form. The form must
include the NRG Oncology protocol number and patient’s case number.
10.3 Serum, Plasma, and Whole Blood for DNA Collection for Banking for Future Research
(optional but strongly encouraged)
10.3.1 The following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen
Transmittal Form documenting the date of collection of the biospecimen; the NRG Oncology
protocol number, the patient’s case number, time point of study, and method of storage, for
example, stored at -80 C, must be included.
10.3.2 Specimens will be collected per Section 10.5.
10.4 Storage Conditions for All Specimens

Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not
available:
 Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to
one week (please ship out Monday-Wednesday only).
OR:
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out
Monday-Wednesday only).
OR:
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored.
53
10.5 Specimen Collection Summary
Specimens for Banking for Future Research (optional but strongly encouraged)
Specimens taken from Collected when: Submitted as: Shipped:
patient:
Representative H&E Pre-treatment H&E stained slide Slide shipped ambient
stained slides of the Pre-treatment
primary tumor
A paraffin-embedded tissue Pre-treatment Paraffin-embedded Block or punch shipped
block of the primary tumor tissue block or punch ambient. Include a cold
taken before initiation of biopsy (must match the pack during warm
treatment or a 2 mm H&E slide being weather.
diameter core of tissue, submitted). If site cannot
punched from the tissue provide block then 10
block with a punch tool unstained slides are
permitted as an
alternative.
SERUM: 5-10 mL of whole 1) Pre-treatment; Frozen serum samples Serum sent frozen on dry
blood in 1 red-top tube and 2) During treatment: at 4 containing a minimum of ice via overnight carrier
centrifuge weeks after initiation of 0.5 mL per aliquot in 1
treatment; mL cryovials (five to ten)
3) Post-treatment: at
first follow-up visit after
completion of concurrent
chemoradiotherapy
PLASMA: 5-10 mL of 1) Pre-treatment; Frozen plasma samples Plasma sent frozen on
anticoagulated whole blood 2) During treatment: at 4 containing a minimum of dry ice via overnight
in EDTA tube #1 (purple/ weeks after initiation of 0.5 mL per aliquot in 1 carrier
lavender top) and treatment; mL cryovials (five to ten)
centrifuge 3) Post-treatment: at
first follow-up visit after
completion of concurrent
chemoradiotherapy
Whole blood for DNA: 5-10 Pre-treatment Frozen whole blood Whole blood sent frozen
mL of anticoagulated whole samples containing a on dry ice via overnight
blood in EDTA tube #2 Note: If site missed this minimum of 1 mL per carrier
(purple/lavender top) and collection time point they aliquot in 1ml cryovials
mix may collect whole blood for (three to five)
DNA at a later time point
instead but must note this
on the ST Form.
10.6 Submit materials for Banking as follows:

U. S. Postal Service Mailing Address: For Non-frozen Specimens Only
NRG Oncology Biospecimen Bank
University of California San Francisco
UCSF Box 1800
2340 Sutter Street, Room S341
San Francisco, CA 94143-1800
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen and
Trackable Specimens
San Francisco, CA 94115
Questions: 415-476-7864/FAX 415-476-5271; RTOG@ucsf.edu
54
10.7 Reimbursement
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program,
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per
the requirements/methods specified by the new NCTN Program. This information will be made
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN)
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from
the NCI-sponsored Cooperative Group Clinical Trials Program.
10.8 Confidentiality/Storage
(See the RTOG Patient Tissue Consent Frequently Asked Questions,
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for
further details.)
10.8.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s
case number only. The NRG Oncology Biospecimen Bank database only includes the following
information: the number of specimens received, the date the specimens were received,
documentation of material sent to a qualified investigator, type of material sent, and the date the
specimens were sent to the investigator. No clinical information is kept in the database.
10.8.2 Specimens for banking will be stored for an indefinite period of time. If at any time the patient
withdraws consent to store and use specimens, the material will be returned to the institution that
submitted
11.0 PATIENT ASSESSMENTS

11.1 Study Parameters
See Appendix I
11.2 Quality of Life/Cost-Effectiveness

NOTE: Patients must be offered the opportunity to participate in the correlative
components of the study, such as quality of life assessment.
If the patient consents to participate in the quality of life (QOL) component of the study, sites are
required to administer the baseline QOL and functional assessments prior to the start of protocol
treatment, during treatment, and in follow-up per the Appendix I schedule.
11.2.1 Instructions for Administration of the Instruments
Patients will be given the 4 instruments (MDASI-Lung, SOBQ, EQ-5D, and Medical Service Use
Survey) to be completed in the clinic at specified visits per Appendix I. A research assistant will
be available to answer any questions that the patients have and review the questionnaire for
completeness. If the questionnaires are not complete, patients will be asked if they left out
answering the question by mistake or because they did not wish to answer the question. If the
former, patients will be asked to answer those questions; if the latter, patients would not be asked
anything further. If a patient does not come in to clinic (and/or if requested), the questionnaires
will be mailed to the patient. If the questionnaires have not been received in 2 weeks after the due
date, another set will be sent to the patients, reminding them to complete the questionnaire. If the
patient prefers, he or she will be interviewed by the research assistant over the telephone at that
time.
11.3 Response Assessment (RECIST Criteria) Measurement of Response Prior to Study Entry
Response will be evaluated in this study using the revised RECIST guideline, v. 1.1 [European
Journal of Cancer. 45: 228-247, 2009]. See
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf for further details.
Response Criteria: Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions; Any pathological lymph
nodes (whether target or non-target) must have reduction in
short axis to <10 mm.
55
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target
lesions, taking as reference the baseline sum diameters
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this
includes the baseline sum if that is the smallest on study). In
addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5
mm. (Note: the appearance of one or more new lesions is
also considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest
sum diameters while on study
11.4 Criteria for Discontinuation of Protocol Treatment

 Progression of disease (Further treatment will be given at the discretion of the treating
physician);
 Pregnancy;
 Protocol-specified adverse event that precludes continuation of treatment;
 Any clinical adverse event, laboratory abnormality, or intercurrent illness that, in the opinion
of the Investigator, indicates that continued treatment with all study therapy is not in the best
interest of the patient;
 A delay in protocol treatment of greater than 21 days during the concurrent phase and more
than 6 weeks in the consolidation chemotherapy phase; and
 Unacceptable toxicity; see Section 6.0 and Section 7.0 for further information.
If protocol treatment is discontinued, follow up and data collection will continue as specified in the
protocol.
12.0 DATA COLLECTION (10/23/14)

This study will utilize Medidata Rave® for remote data capture (RDC) of all data. Access to the
trial in Rave is granted through the iMedidata application to all persons with the appropriate roles
in RSS. To access iMedidata/Rave, see Section 5.0 of the protocol.
Each person responsible for data entry must be on the NRG Oncology roster in order to receive
access to Medidata Rave®.
Upon initial site registration approval for the study in RSS (Regulatory Support System), all
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail
from iMedidata (iMedidata-Notification@mdsol.com) to activate their account. To accept the
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner
of the iMedidata page. Once an account is activated, eLearning modules will be available for
Rave RDC instructions. Please note, site users will not be able to access the study in Rave until
all required Medidata and study specific trainings are completed. Trainings will be listed in the
upper right pane of the iMedidata screen.
Users that have not previously activated their iMedidata/Rave accounts will also receive a
separate invitation from iMedidata to activate their account. Account activation instructions are
located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account
Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is
available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.
12.1 Summary of Data Submission (11/26/13)

Adverse event data collection and reporting, which are required as part of every clinical trial, are
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in
56
future studies using similar agents. Adverse events are reported in a routine manner at scheduled
times during the trial using Medidata Rave. Additionally, certain adverse events must be reported
in an expedited manner for more timely monitoring of patient safety and care. The following
sections provide information about expedited reporting. For this trial the Adverse Events Form is
used for routine AE reporting in Rave.
For reporting of secondary cancers or other report forms available in Rave:

Folder Form/Item
Registration via the OPEN System  Subject Enrollment
Enrollment  Eligibility Checklist
When pushed into RAVE there will be  Step Information
4 forms representing registration  Treatment Assignment
 Demography
Baseline  Baseline Labs

 Diagnostic Staging
 Exclusion Criteria
 Lymph Node Assessment
 Pathology Report
 Patient History (formerly known as the A5)
 Work Up
RT Plan Upload  Digital Data-(Upload of e-mail confirmation

from TRIAD submission required)
Concomitant Medications  Concomitant Medication (only required if
patient is taking concomitant medications)
Concurrent Treatment  RT Administration
 RT Treatment-if was radiation therapy
given = ‘yes’
 Protocol Specific RT Questions
 Any Adverse Events?
 Adverse Events – if any adverse events? =
‘yes’
 Carboplatin (if selected during registration)
 Paclitaxel (if selected during registration)
 Cisplatin (if selected during registration)
 Etoposide (if selected during registration)
 On Treatment Labs 01 (up to 11 additional
weeks may be added by user if needed)
End of Chemo/RT  End of Chemo/RT (this form should be

completed for all patients after their final day
of concurrent Chemo/RT)
Consolidation Treatment*  Any Adverse Events?
 Adverse Events – if any adverse events? =
*Only appears if paclitaxel and carboplatin
‘yes’
are selected during registration
 Carboplatin (consolidation)
 Paclitaxel (consolidation)
 On Treatment Labs 01 (up to 11 additional
weeks may be added by user if needed)
Year 1-2  Any Adverse Events?
4-8 Week Follow-Up  Adverse Events – if any adverse events? =
57
3 Month Follow-Up ‘yes’
6 Month Follow-Up  Patient Contacted
9 Month Follow-Up  Follow-up - if Patient able to be Contacted
1 Year Follow-Up = ’yes’
18 Month Follow-Up  Disease Assessment- if Documented
2 Year Follow-Up clinical assessment = ‘yes’
 New Primary Cancer- If New Primary
Years 3-10 Cancer= ‘yes’
3 Year Follow-Up  Non-Protocol Treatment- if non-protocol
4 Year Follow-Up cancer therapy= ‘yes’
5 Year Follow-Up  Pulmonary Function Tests – if PFTs
6 Year Follow-Up performed = ‘yes’
7 Year Follow-Up  Primary Cause of Death – If Vital Status =
8 Year Follow-Up ‘dead’
9 Year Follow-Up
10 Year Follow-Up
CTEP-AERS  CTEP-AERS Upload Form – used by HQ to

upload CTEP-AERS reports, sites have read
only access to this folder/form
Source Documentation Upload  Source Documentation Upload – used by
sites in the event that source documentation
needs to be uploaded to HQ
Quality of Life Coversheets will  Difficulty Swallowing Coversheet
appear in the following folders if the  Difficulty Swallowing*
patient has consented to the  EQ-5D Coversheet
Quality of Life component:  EQ-5D*
 Baseline  MDASI-LC Coversheet
 Concurrent Treatment  MDASI-LC*
 4-8 Week Follow-Up  Medical Service Use Coversheet
 6 Month Follow-Up  Medical Service Use Survey*
 12 Month Follow-Up  UCSD SOB Coversheet
 UCSD Shortness of Breath Form*
*These quality of life forms only appear if the corresponding

coversheet is submitted and “was the patient questionnaire
completed” was answered as YES.
12.2 Summary of Dosimetry Digital Data Submission (10/23/14)

(Submit to TRIAD; see Section 5.2 for account access and installation instructions))
Item Due
Dosimetry Information
ALL DIGITAL RT DATA REQUIRED IN DICOM format via TRIAD
 Each adaptive plan(s) used for treatment must be submitted Pre-Treatment Cases:
Must submit prior to
 Simple sums of target and critical normal tissue doses for all beginning RT for first 3
sub-courses must also be submitted. cases of each modality,
including Initial, Adaptive
 All plans developed and used for treatments and the and Composite planning
corresponding CT images will be submitted . data
58
CT Files (NOTE: Per Section 6.7.2 do not submit repeat CT study
information when a re-plan is not necessary) Post-Treatment Cases:
Within one week of RT
RT Dose Files, including composites end
RT Plan Files
RT Structure Files (must be labeled exactly as shown in Table
in Section 6.4.4 or resubmission will be required)
 Digital DVH data for all required tumor volumes and critical
normal structures
 RTOG 1308 Datasheet, located on the RTOG website at
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.as
px?study=1308 (submit via TRIAD with Digital RT Data listed
above)
Upon submission of any digital data via TRIAD, complete an

online digital data submission form (DDSI) located on the NRG
Oncology/RTOG web site at
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?stu
dy=1308
Final Dosimetry Information Within 1 week of RT end

Radiotherapy Form
Protocol Specific Form
Daily Treatment Chart Upload
NOTE: ALL SIMULATION AND PORTAL IMAGES WILL BE STORED BY THE INSTITUTION AND
ONLY SUBMITTED UPON REQUEST.
13.0 STATISTICAL CONSIDERATIONS

13.1 Primary Endpoint
Overall survival (OS); failure defined as death due to any cause
13.2 Secondary Endpoints

13.2.1 2-year progression-free survival (PFS); failure defined as occurrence of local or regional
progression, distant metastases or death from any cause, whichever occurs first;
13.2.2 The development of grade 3 or higher adverse events definitely, probably, or possibly related to
treatment for the following adverse events within 1 year of concurrent chemoradiation therapy
completion:
 Grade 3-5 Cardiac Disorders
o Acute coronary syndrome
o Atrial fibrillation
o Atrial flutter
o Conduction disorder
o Pericardial effusion
o Pericarditis
o Restrictive cardiomyopathy
 Grade 4-5 Gastrointestinal Disorders
o Dysphagia
o Esophagitis
59
o Esophageal fistula
o Esophageal obstruction
o Esophageal perforation
o Esophageal stenosis
o Esophageal ulcer
o Esophageal hemorrhage
 Grade 3-5 Injury, Poisoning, and Procedural Complications
o Dermatitis radiation
o Fracture (to be limited to rib fractures only)
 Grade 3-5 Nervous System Disorders
o Brachial plexopathy
o Recurrent laryngeal nerve palsy
o Myelitis
 Respiratory, Thoracic, and Mediastinal Disorders, Grade 3-5, except as noted below
o Atelectasis (grade 4-5 only)
o Bronchopulmonary hemorrhage
o Mediastinal hemorrhage
o Pleural hemorrhage
o Tracheal hemorrhage
o Bronchial fistula
o Pulmonary fistula
o Bronchopleural fistula
o Tracheal fistula
o Hypoxia (provided grade 3 is worse than baseline)
o Bronchial obstruction
o Tracheal obstruction
o Pleural effusion
o Pneumonitis
o Pulmonary fibrosis
 Grade 3-5 Skin and Subcutaneous Disorders
o Skin ulceration (thorax only)
 Changes in Pulmonary Function Tests per the RTOG Pulmonary Toxicity Scale (see Section
6.9.3), Grade 3-5
o FEV1 decline
o Forced Vital Capacity decline
o DLCO decline
 Any Grade 5 Adverse Event Attributed to Treatment
13.2.3 To compare the development of symptom burden and quality of life (QOL) as measured by the
single esophagitis and shortness of breath items and the entire lung cancer module of the MD
Anderson Symptom Inventory (MDASI-Lung), and the SOBQ, and the EuroQol (EQ-5D)–derived
health utility score;
13.2.4 To compare cost-effectiveness outcomes between the 2 arms;
13.2.5 To compare pulmonary function changes by treatment arms and response;
13.2.6 To explore the most appropriate and clinically relevant technological parameters to ensure quality
and effectiveness throughout radiation therapy processes, including imaging, simulation, patient
immobilization, target and critical structure definition, treatment planning, image guidance and
delivery.
13.3 Sample Size and Power Justification

13.3.1 Treatment Comparison
The sample size calculation will address the primary hypothesis that proton therapy will improve
OS in stage II-IIIB NSCLC patients. The survival times are exponentially distributed with (at least
approximately) constant hazards in both treatment arms. The proposed design is based on the
primary hypothesis that the median OS will be improved from 21 months (monthly hazard
60
λ=0.0330) with photon therapy, 60-70 Gy (RBE), (Arm 1) to 28 months (monthly hazard
λ=0.0248) with proton therapy, 60-70 (RBE), (Arm 2), i.e., hazard ratio (HR) equals to 0.75, which
translates to a 25% relative hazard reduction. The statistical power is set as 80% and the
significance level is 0.025 (1-sided). Using a group sequential design, a total of 390 deaths is
required to detect a 25% relative hazard reduction. Three interim analyses will be performed
when 25%, 50%, and 75% cumulative information for OS is available. A total of 504 analyzable
patients are required to be accrued uniformly with 10 patients per monthly accrual and an
additional 24 months of follow-up is needed to meet the required number of deaths. Guarding
against up to a 10% ineligibility and lost to follow-up rate, the final targeted accrual for this
study will be 560 cases.
Given the potential impacts of treatment crossovers such as patient preferences or insurance
denial, the rate of treatment crossovers will be closely monitored. The table below shows the
impact for 5% and 10% crossover rates. The adjusted type 1 error, power, and additional accrual
time are derived by assuming the other original design parameters remain the same. NRG
Oncology will discuss with NCI possible protocol amendments and feasibility of continuing the
trial if the treatment crossover truly becomes an issue.
Impacts of Crossover
Crossover Rate Adjusted Hazard Adjusted Adjusted Type Adjusted Add. Accrual
Arm 2 to 1 Arm 1 to 2 Arm 1 Arm 2 HR 1 Error Power Time (month)
0% 0% 0.0330 0.0248 0.75 0.025 80% 0
5% 5% 0.0326 0.0252 0.772 0.048 71% 8.5
5% 10% 0.0326 0.0256 0.785 0.066 67% 16
10% 5% 0.0322 0.0252 0.782 0.062 67% 15
10% 10% 0.0322 0.0256 0.795 0.085 61% 24
13.3.2 Statistical Power for Quality of Life (QOL) Endpoint

Our primary QOL hypothesis is that, compared with patients receiving photon therapy (Arm 1),
patients on the proton arm (Arm 2) will have less severe shortness of breath 6 months after the
end of concurrent chemoradiation therapy (representing late adverse response to therapy), and
that the differences in symptom ratings (based on MDASI shortness of breath item) between
arms will be clinically meaningful. Patients are strongly encouraged to provide PRO/QOL
assessments regardless of disease status (e.g., progression or stable). However, the primary
QOL analysis of MDASI shortness of breath item will include patients only if they have provided
symptom-assessment data at both baseline and 6 months post concurrent chemoradiation
therapy without local or regional disease progression, as local or regional progression may
confound the evaluation of shortness of breath and the corresponding comparison.
Based on preliminary results from retrospective studies conducted at MDACC, as well as Cohen’s
widely used rules of thumb for interpreting the magnitude of difference (Cohen 1988), an effect
size greater than 0.4 standard deviation (SD) in the MDASI-lung shortness of breath symptom is
considered as clinically meaningful. This discussion is also very applicable to the MDASI-lung
and specific symptom items as well as the UCSD SOBQ. Based on past RTOG trials, we expect
about 70% patients (176 per arm) to consent to PRO-QOL data collection. Depending on the
proportion of patients who become ineligible for QOL analysis (ineligible due to insufficient
measurements, drop-out, disease progression, death etc.), the following table summarizes the
powers to detect different effect sizes. Briefly, with sample sizes of 106, 123, and 144
(corresponding to 60%, 70%, and 80% evaluable (with both pre- and post-treatment
assessments) rate among patients consenting to QOL) per treatment arm, we will have 82%,
87%, and 91% power to detect an effect difference of 0.4 between the two treatment groups at
the significance level of 0.05 (2-sided) in the MDASI-lung shortness of breath item. Other
comparisons in scores/subscales of the MDASI-Lung, as well as the UCSD SOBQ, may be
evaluated similarly. These treatment comparisons will be considered exploratory for planning in
nature, and no effort will be made to control for the overall significance level.
61
Power of the Treatment Comparison at a Significance Level 0.05 (2-sided)
Effect size detection in Proportion of randomized patients with MDASI-Lung SOBQ
standard deviation (corresponding number of eligible patients per treatment arm)
60% (106) 70% (123) 80% (141)
0.5 0.95 0.97 0.98
0.4 0.82 0.87 0.91
0.3 0.58 0.64 0.70
13.4 Randomization
Patients will be enrolled and randomized 1:1 to either photon therapy (Arm 1) or proton therapy
(Arm 2). The treatment allocation scheme described by Zelen (1974) will be used, as it balances
patient factors other than institution. The following factors will be stratified
 Tumor stage (II, IIIA, IIIB);
 Histology (squamous, non-squamous);
 Concurrent chemotherapy doublet type (carboplatin/paclitaxel, cisplatin/etoposide).
13.5 Patient Accrual

RTOG 0617 (phase III trial for stage IIIA/B NSCLC) accrued approximately 130 patients per year,
or 11 patients per month. With the increasing interests and number of proton centers available in
United States, the monthly accrual rate is projected to be 10 patients and the trial is projected to
accrue uniformly in 56 months. During the first 6 months following activation, little accrual is
anticipated while the trial is being approved by institutional review boards (IRBs). If the total
accrual during months 13 through 18 of the study is ≤ 20% of the targeted accrual (≤ 2 cases per
month) the protocol will be discontinued per NCI-CTEP accrual guidelines for phase III studies. If
the total accrual is between 21% and 49%, the protocol will continue to accrue subject to approval
of the NRG Oncology Data Monitoring Committee (DMC) and NCI-CTEP. If the trial remains
open to accrual, the study must accrue at least 50% of targeted accrual (> 5 cases per month)
during months 22 through 24 to remain open beyond 2 years.
13.6 Statistical Analysis Plan

13.6.1 Overall Survival
The primary analysis will be performed on an intent-to-treat basis, such that all eligible cases will
be included in the treatment arm to which they were randomized regardless of what treatment the
patients actually received. Patients who cannot receive 60 Gy will be included, while ineligible
patients or patients who withdrew consent to participate before receiving any protocol treatment
will be excluded. OS will be measured from the date of randomization to the date of death or the
last follow-up date on which the patient was reported alive. OS rates will be estimated using the
Kaplan-Meier method (1958), and the differences between arms will be tested using a stratified
log-rank test by adjusting for stratification factors (Mantel 1966). A multivariate analysis with the
Cox proportional hazard model (1972) for OS will be performed with the stratification variables as
fixed variables to assess the treatment effect adjusting for patient-specific risk factors.
Proportional hazard assumptions will be checked using different graphical or time-varying
coefficients testing methods (Kalbfleisch 2002). If the data clearly do not support the proportional
hazard assumption, other statistical models will be used to fit the data if applicable. A step-down
procedure that consists of dropping the least significant covariates, one at a time, will be used to
obtain a more parsimonious model.
13.6.2 Progression-Free Survival (PFS)
PFS is defined as the time from randomization to disease progression or death of any cause,
whichever occurs first. A rigorous definition of disease progression is provided in Section 11.3.
Due to the limitations of PFS in solid tumors (Bhattacharya 2009), efforts will be made to
minimize any potential bias introduced in assessment during study conduct, and appropriate
sensitivity analyses (FDA 2007) may be conducted accordingly to assure the robustness of
analysis results.
As both OS and PFS can be considered as time-to-event endpoints, the distribution of PFS will
be similarly summarized using the product limit estimator developed by Kaplan and Meier (1958)
62
by treatment arm. From the product limit estimates, median PFS, 2-year PFS as well as their 95%
confidence intervals will be estimated. Comparisons between arms will be conducted using a log
rank test. The Cox proportional hazards model will be used to estimate the hazard ratio and its
95% confidence interval of Arm 2 relative to Arm 1. Appropriate methods for competing risks will
also be applied on other progression-related endpoints (e.g., distant metastasis, local-regional
failure) when applicable; specifically, cumulative incidence functions (Kalbfleisch 2002) for
estimation of cumulative cause-specific event probabilities with associated testing for differences
(Gray 1988) as well as regression methods for cause-specific hazards (Kalbfleisch 1978) and
subdistribution hazards underlying cumulative incidence functions (Fine 1999) may be applied
accordingly for exploratory purposes.
13.6.3 Toxicity Endpoints
The analysis for reporting the initial results of treatment will be undertaken when each patient has
been potentially followed for a minimum of 1 year from the end of concurrent chemoradiation
therapy.
Only patients that meet the eligibility requirements of this protocol and start protocol treatment will
be included. Analyzable patients are defined as eligible patients who received any protocol
treatment.
The rate of treatment-related adverse events using NCI Common Terminology Criteria for
Adverse Events (CTCAE, v. 4) and RTOG Pulmonary Toxicity Scale (see Section 6.9.3) will be
reported with the frequency and severity (e.g., type, grade, and attribution) by arm. The analysis
will be performed at the time of primary endpoint analysis. Logistic regression (Agresti 1990) will
be used to model the distribution of adverse events with and without adjustment for covariates.
Both unadjusted and adjusted odds ratios and the respective 95% confidence intervals will be
computed and tested at a significance level of 0.05 (2-sided).
13.6.4 Statistical Methods for Symptoms and Quality of Life
The mean severity score changes for the MDASI-Lung item “shortness of breath” will be
calculated. Comparisons between arms [photon (3DCRT/IMRT) versus proton] at 6 months after
the end of chemoradiation will be made using the two-sample t-test. If the parametric
assumptions are not met, the Mann-Whitney test will be used. Effect size will be calculated
through dividing the difference between arms in mean score changes by the pooled standard
deviation of the pretreatment score means.
The mean score changes from different tools, including MDASI-lung scores and SOBQ, will be
similarly calculated at baseline and key subsequent assessment time points, for the proton arm
and photon arm separately. Among these tools and subscales, mean score changes of MDASI-
lung item “sore throat” at end of chemoradiation, as well as local symptoms (coughing, difficulty
swallowing, pain) and systemic symptoms (fatigue, total symptom interference) at subsequent
key time points, may also be examined and compared between the 2 arms (among the
therapies). In addition, the relationship between high symptom burden and specific toxicities
could be explored. Due to the exploratory nature, no multiplicity adjustment will be applied. For
MDASI Shortness of Breath item and SOBQ, cases with local or regional progression are
excluded for analysis purposes to avoid any potential confounding.
Symptom worsening will be calculated as the difference of before and after CXRT (week 0 vs.
week 6 for pain and sore throat, baseline vs. 6 months for lung symptoms) and the significance of
the differences will be tested between the 2 arms using a paired t-test. The cumulative proportion
of patients reporting symptom worsening in each chemoradiation technique will be plotted and
compared among the 2 arms using the Kolmogorov–Smirnov test (McLeod et al, 2011).
A longitudinal analysis will also be conducted with a focus on the patterns of scores over time
points (baseline, 6 weeks, 6 months, 12 months) of PRO instruments (MDASI-Lung and SOBQ).
Following the descriptive statistics on assessments, repeated measures for analysis of
covariance (ANCOVA) will be used on scores/subscales for the assessment measures, where
63
time points are considered the within-patient factor and treatment groups is considered the
between-patient factor (Diggle 1994). While scales for the individual instrument questions are
quantitative, they represent ordinal values on a bounded range rather than continuous quantities.
Nonetheless, in aggregate these approximate continuous distributions and appropriate
transformations will be applied to improve consistency with model assumptions. The hierarchical
analytic approach described below permits tests of omnibus hypotheses that control for multiple
comparisons among time points and treatment groups. The analysis will be conducted as follows:
(1) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that
there is a common mean score across time points within the treatment groups: H0: it =
i., where i = treatment group 1 or 2, t = time point (baseline and subsequent time
points) and it is the mean score in treatment group i at time t.
(2) If the hypothesis in (1) is rejected, individual comparisons of the post-radiation and
subsequent scores will be conducted within treatment groups. Additional modeling and
graphical methods to determine trends or patterns of change in scores over time points
will be conducted.
(3) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that
there is a common mean score at each time point among the treatments: H0: it = .t,
where again it is the mean score in treatment group i at time t.
(4) Assuming the result of the hypothesis test in (3) is significant (H0 rejected), individual
tests will be carried out to determine differences between treatment groups at specific
time points. If there are no significant treatment differences identified in (3), an overall
test of trend in scores can be aggregated over treatment groups. Additional modeling to
characterize patterns of change over time will be conducted.
Following the above analysis, the linear mixed model will also be used to analyze the symptom
outcomes collected over time, taking into account potential confounding factors in addition to
treatment groups and time. This analysis could be done when all time points of PRO data have
been collected in a desired study period, either in the acute phase or in long-term follow-up.
Patient participation in the QOL component is not mandatory in this study, but sites must offer all
patients the opportunity to participate. If patients agree to participate in this component, patients’
adherence to the component assessment schedule will be encouraged through reminders sent to
the patient from participating institutions. Completion of all scheduled assessments is part of the
routine delinquency assessment for institutions with patients participating. The Statistics and Data
Management Center staff will monitor the proportions of missing quality of life information in each
treatment arm at different assessment points. In spite of these efforts, missing data is to a certain
extent expected. The information from patients with missing data will be reviewed to determine
whether the data analyses will be biased. Patients with missing data will be reviewed for the
distributions of treatment arms and patient characteristics (patient exclusion is not considered as
missingness). Mean scores by assessment time for cohorts stratified by baseline score quartile
will also be compared to investigate if the missingness is consistent with an ignorable missing
data process (missing at random). If a missing-at-random (MAR) mechanism is reasonable, the
data will be analyzed with appropriate likelihood-based analysis methods such as linear mixed
effect models. If a missing-at-random (MAR) mechanism is suspected, multiple imputations for
missing values and sensitivity analyses will be conducted to control for the potential bias. The
possible strategies for imputation and analyses will depend on the severity of the missing data
problem and may include: worse-case scenario, use of mean response for individuals who
withdraw from the trial from either all or similar (matched) patients remaining in the trial, last
observation carried forward, or multiple imputations. The data can also be analyzed using pattern
mixture models to estimate separate estimates for the outcome within strata based on the
missing data pattern, and then combining estimates in a specialized way to yield an appropriate
64
overall effect estimate (Little 2002). Sensitivity analyses based on the varying assumptions about
the missing data mechanisms will also be conducted.
Quality-adjusted survival can be defined by the weighted sum of different time episodes added up
to a total quality-adjusted life-year [U= sum of quality (qi) of health states K times the duration (si)
spent in each health state] (Glasziou 1990):
K
U   qisi
i 1
The area under the EQ-5D curve yields predicted Quality-Adjusted Life Years (QALYs) (Glick
2007). QALY differences of 0.03 are considered important, and QALY differences of as little as
0.01 are considered potentially meaningful and important for several prevalent diseases,
including cancer, diabetes, and heart disease (Samsa 1999; Walters 2003). We will use
Glasziou’s multiple health-state (Q-TwiST) models to use the repeated measures of EQ-5D.
Because Glasziou’s method incorporates longitudinal QOL data into an analysis of quality-
adjusted survival, the health state model must be constructed on the following assumptions:
A1) QOL is independent from treatment.

A2) A health state is independent from previous states.
A3) Proportionality of quality-adjusted duration and duration of the actual state of health
Assumption A1 can be checked by plotting QOL scores over time according to treatment, and the
t-test can be used to compare the mean QOL scores of each treatment arm. Assumption A2 can
be checked by comparing the QOL scores for patient groups in a given health state where the
groups are defined by duration of previous health state experience using a regression model. A
suitable check for assumption A3 at a minimum would be a simple plot. If data do not support
these assumptions, we will use a method that uses the longitudinal QOL data directly. We will use
the 5-item utility score in EQ-5D for the cost-utility analysis. We will use the Z-test to test the
hypothesis that the cost-utility in the 2 treatment arms is the same at 1 year after initiation of
treatment with a significance level of 0.05 (2-sided). The remaining time points at which the EQ-
5D is collected will also be assessed using similar longitudinal analysis techniques as described
for the other QOL endpoints.
13.6.5 Statistical Methods for Cost-Effectiveness Analysis
Only direct medical costs will be estimated. These fall into 3 categories: 1) initial therapy costs; 2)
costs of managing the most common side effects as determined by this study; and 3) costs of
managing recurrence. Costs for external beam radiotherapy will be determined using CPT coding
and Medicare reimbursement rates. Cost of common management strategies of the most
common side effects documented in this study will be estimated from regional costs per unit.
Costs for managing recurrence will assume the following salvage therapies: second-line
chemotherapy or biological therapy in selected patients, radiotherapy for cancer recurrence (e.g.
whole-brain radiation for central nervous system recurrence), or hospice/supportive care
depending on individual patient preference.
We will make an attempt to estimate other medical costs including that of emergency
room/inpatient admissions, radiology and laboratory tests, and subsequent medical management
of treatment-related toxicity including medications (and RedBook costs) by polling patients at the
same time points as above (pre-treatment, at 6 weeks, and at 3, 6, and 12 months post-
treatment) regarding medical service use by utilizing a modification of the “Medical Service Use
Form” being used to collect similar data in an active Massachusetts General/University of
Pennsylvania trial of proton versus IMRT for localized prostate cancer that is being used
(http://clinicaltrials.gov/ct2/show/NCT01617161). The form is used to document utilization of
specific medical services including inpatient hospitalizations, specialist physician visits,
radiology/laboratory services, and homecare.
65
As part of this analysis we will formulate a Markov model of cost-utility. We will take the societal
perspective to assess the comparative effectiveness of photon versus proton radiation therapy in
this randomized trial. Model cycles will be 3 or 6 months long, to coincide with the primary clinical
trial’s follow-up scheme. The model’s primary outcome will be incremental cost-utilities
expressed in dollars per quality-adjusted life year (QALY).
We will run the primary model as a Monte Carlo probabilistic sensitivity analysis, in which each
parameter (e.g., cost of treatment, cost of additional medical services utilized, probability of
survival/death) is modeled based on its characteristics in the trial population. This modeling
allows simultaneous variation in all model parameters and allows us to determine the confidence
intervals around our model’s results, expressed as an incremental cost utilities ratio (cost/QALY).
Acceptability curves will then be performed to determine, at a specified willingness to pay ICUR
level, the percentage of simulations in which photon or proton radiation therapy is considered
cost-effective for treating patients with inoperable stage II-III NSCLC.
13.6.6 PFT Change
The descriptive statistics of changes in FEV1 and diffusion capacity before and after treatment
will be reported by treatment arm and by response categories (complete response; partial
response; stable disease; progressive disease). Linear regression will be used to model PFT
changes with adjustment for treatment arms and possibly other baseline covariates, if applicable.
The Grade 3-5 NRG Oncology Pulmonary Toxicity Scale (see Section 6.9.3) for PFT changes will
be reported with the frequency and grade by arm. Logistic regression (Agresti 1990) will be used
to model the distribution of the NRG Oncology Pulmonary Toxicity Scale by arms with and without
adjustment for covariates. Both unadjusted and adjusted odds ratios between arms and the
respective 95% confidence interval will be computed and tested at a significance level of 0.05.
Adherence to the PFT assessment schedule will be required, and reminders from participating
institutions will be sent to patients to facilitate adherence. Similar to the QOL component,
completion of all scheduled assessments is part of the routine delinquency assessment for
participating institutions. The Statistics and Data Management Center staff will monitor the
proportions of missing PFT information in each treatment arm at different assessment points. In
spite of these efforts, missing data is to a certain extent expected. The information from patients
with missing data will be reviewed to determine whether the data analyses will be biased.
Patients with missing data will be reviewed for the distributions of treatment arms and patient
characteristics. As described in Section 13.6.5, a missing data mechanism will be appropriately
evaluated, and methods for assessing and adjusting the impacts of missing data will be adopted
accordingly.
13.7 Interim and Final Analysis

13.7.1 Special Interim Toxicity Analysis
Treatment-related adverse events (AEs) experienced by patients on both arms will be closely
monitored throughout the study. The following grade 3-5 (CTCAE, v. 4) treatment-related AEs
occurring within 90 days after the start of chemoradiation defined as possibly, probably, or
definitely related to treatment are of particular interest: Pneumonitis, esophagitis, dysphagia,
esophageal ulcer, dermatitis radiation, pericarditis, pericardial effusion, brachial plexopathy,
myelitis, recurrent laryngeal nerve palsy.
An interim analysis of AEs is planned after 30 evaluable patients have been accrued and
randomized to each arm and have been followed for a minimum of 90 days after the start of
chemoradiation. Patients will be considered evaluable if they are eligible and receive at least 1
fraction of radiation. The interim analysis will include all of the specified unacceptable treatment-
related AEs reported at the time of the interim analysis, and the interim analysis results for each
arm will be discussed with the study chairs and CTEP accordingly to assure patient safety.
13.7.2 Special Interim Analysis for Treatment Completion
Similarly, treatment completion rates of both arms will be closely monitored throughout the trial.
An interim analysis of treatment completion rates is planned after 50 evaluable patients have
66
been accrued and randomized to each arm. The interim analysis results will be discussed with
the study chairs and CTEP accordingly to assure that treatment completion rates are balanced.
13.7.3 Interim Analysis for Early Termination and Reporting
Interim treatment comparisons will be performed when we observe 25% (98 deaths), 50% (195
deaths), and 75% (292 deaths) of the 390 required maximum number of deaths. The 3 analyses
will be done on an intent-to-treat analysis basis, with all eligible cases included in the treatment
arm to which they were randomized regardless of what treatment the patients actually received.
The primary endpoint, OS, will be tested in each interim analysis. A conservative upper
superiority bound, based on a Lan-DeMets approximation to the O’Brien-Fleming boundary
(DeMets 1994; O'Brien 1979) provides test critical values used in the sequential analyses and
preserves an overall alpha level of 0.025 (1-sided) for the study.
An interim futility analysis will be based on the rule of Freidlin (2010), with a Linear 20% Inefficacy
Boundary (LIB20). This rule provides the opportunity to terminate early for evidence that the
experimental arm will not prove superior, but protects against aggressive early termination for
treatment effect sizes smaller than planned.
The following Table summarizes the interim efficacy/futility monitoring schedule with respect to
the primary endpoint:
Interim and Final Analysis for OS
Analysis Projected Percent Number Efficacy boundary Futility boundary

Time Information of Events Z> P< Z< P>
(month)
Interim 1 31 25% 98 4.333 0.00001 -1.645* 0.05*
Interim 2 47 50% 195 2.963 0.0015 0.008 0.497
Interim 3 60 75% 292 2.359 0.009 0.248 0.402
Final 80 100% 390 2.014 0.022 - -
Early look for detriment in experimental arm, left-tail p<0.05 will prompt stopping.
At each protocol-planned interim analysis, the results from the test assessing the treatment
efficacy and futility will be reported to the NRG Oncology Data Monitoring Committee (DMC).
The responsible senior statistician may recommend early reporting of the results and/or stopping
accrual (if applicable) of the trial if the critical value exceeds the specified boundary in a
sequential design for either efficacy or futility. The accrual rate, treatment compliance, treatment
safety, and the importance of the study are also considered in making such a recommendation.
The results will be reported to the NRG Oncology DMC with the treatment blinded. The DMC will
then make a recommendation about the trial to the NRG Oncology Group Chair.
13.7.4 Significance Testing for Final Analysis

The major analysis will occur after at least 390 deaths have been observed, unless an early
stopping rule is satisfied. It will include:
 Tabulation of all cases entered and those excluded from the analyses with the reasons
for exclusion given;
 Distributions of important prognostic baseline variables;
 The frequencies and severity of AEs by treatment arms;
 Compliance rate of treatment delivery;
 Observed results with respect to the primary and secondary endpoints.
All eligible patients randomized will be included in the comparison and will be grouped by
assigned treatment in the analysis. The primary hypothesis of treatment benefit will be tested
using the stratified log-rank statistic with a significance level of 0.025 (1-sided), given that the 3
interim analyses will have been carried out. Additional analyses of treatment effect will be
performed using the Cox proportional hazards model with the stratification factors included as
fixed covariates, as well as any factors that show an imbalance between the arms.
67
13.7.5 Interim Analysis to Monitor Study Progress
Phase III trials are required by NCI National Clinical Trials Network (NCTN) Guidelines to be
reviewed by a data and safety monitoring committee. This study will be reviewed by the NRG
Oncology Data Monitoring Committee (DMC) on a semi-annual basis, and an interim study
summary report will be prepared twice per year accordingly until the initial study results have
been presented to the scientific community. In general, the interim reports will contain information
about the patient accrual rate, a projected completion date for the accrual phase, patient
exclusion rates and reasons following registration, compliance rate of treatment delivery,
distributions of pretreatment characteristics and important prognostic baseline variables, and the
frequencies and severity of treatment-related adverse events. The interim reports will not contain
the results from the treatment comparisons with respect to the efficacy endpoints.
In general, the interim reports will contain the following information:

 Patient accrual rate with a projected completion date (while the study is still accruing);
 Total patients accrued;
 Distributions of important pretreatment and prognostic baseline variables;
 The frequencies and severity of AEs by treatment arms;
 Compliance rates of treatment delivery.
13.7.6 CDUS Reporting
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative
CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April
30, July 31, and October 31.
13.8 Gender and Minorities
Projected Distribution of Gender and Minorities

Gender
Ethnic Category Females Males Total
Hispanic or Latino 14 20 34
Not Hispanic or Latino 221 305 526
Ethnic Category: Total of all subjects 235 325 560
Gender
Racial Category Females Males Total
American Indian or Alaskan Native 1 2 3
Asian 6 8 14
Black or African American 23 33 56
Native Hawaiian or other Pacific Islander 1 1 2
White 204 281 485
Racial Category: Total of all subjects 235 325 560
68
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Wu AW, Jacobson KL, Frick KD, et al. Validity and responsiveness of the EuroQOL as a measure of
health-related quality of life in people enrolled in an AIDS clinical trial. Qual Life Res. 2002;11:273-82.
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.
73
APPENDIX I
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS
Assessments ≤90 d prior to ≤30 d prior to ≤14 d prior to ≤90 d prior to ≤10 d prior to
registration registration registration treatment start treatment start
Histologically/ cytologically X
proven NSCLC diagnosis
AJCC staging ≤60 days
Physical examination/ X
performance status
FDG-PET/CT ≤60 days
MRI (preferred) or CT of ≤60 days
brain w/ contrast
FEV1 X
DLCO X
CBC/differential including X X
ANC, platelets, Hgb
SGOT or SGPT X
Total bilirubin X
Serum creatinine or X X
calculated creatinine
clearance
Serum pregnancy test X
Glucose, electrolytes, 30 d
LDH, alkaline
phosphatase, total protein,
albumin, calcium, BUN,
serum magnesium
MRI of thorax Recommended*
CT or MRI of abdomen, w/ Recommended*
or w/o contrast
Cardiac SPECT Recommended
for pts w/ lower
lung tumor
when medically
indicated*
Quantitative lung Recommended
ventilation/perfusion scan if FEV1 ≤ 1.4
+/- CT scan liters
Bone scan Recommended*
Pulmonary consultation Recommended*
EKG and/or Recommended*
echocardiogram
Nutritional assessment Recommended
if ≥ 10% below
ideal body
weight*
HRQOL/Cost- X
Effectiveness Analysis (for
consenting pts): MDASI-
Lung, SOBQ, EQ-5D,
Medical Service Use
Survey
Blood collection (for Taken pre-treatment
consenting pts)
Paraffin-embedded Taken pre-treatment
tissue/slides collection (for
consenting pts)
*See Section 4.2. for details.
74
APPENDIX I (continued)
STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT
During Concurrent Chemoradiotherapy During Consolidation
Chemotherapy
(for pts receiving
carboplatin/paclitaxel)
Physical examination Wkly Within 72 hours prior to day 1
of each cycle of chemotherapy
Toxicity assessment Wkly Wkly
CBC with differential Within 72 hours prior to each dose of Within 72 hours prior to day 1
(including ANC, hgb, plt) carboplatin and paclitaxel or each dose of of each cycle of
cisplatin, except for day 1 chemotherapy. chemotherapy.
Glucose, electrolytes, LDH, Within 72 hours prior to day 1

aspartate aminotransferase of each cycle of
(AST), alanine chemotherapy.
aminotransferase (ALT),
alkaline phosphatase, total
bilirubin, total protein,
albumin, calcium, BUN,
serum magnesium
Serum creatinine:
 Pts receiving Within 72 hours prior to each dose of Within 72 hours prior to each
carboplatin/paclitaxel carboplatin, except for day 1 carboplatin. dose of carboplatin .
Serum creatinine is required within 10
days prior to day 1 carboplatin.
 Pts receiving Within 72 hours prior to each dose of Not applicable
cisplatin/etoposide cisplatin except for day 1 cisplatin. Serum
creatinine is required within 10 days prior
to day 1 cisplatin.
CT scan Day 13-15 (+/- 2 days), Day 29-32 (+/- 2
days)
Blood collection (for Wk 4
consenting pts)
HRQOL/Cost-Effectiveness At 6 wks after initiation of treatment

Analysis (for consenting
pts): MDASI-Lung, SOBQ,
EQ-5D, Medical Service Use
Survey
75
APPENDIX I (continued)
STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW-UP
Assessments At 4-8 weeks post- Every 3 months post-
st
chemo/RT end chemo/RT end for 1 year,
every 6 months for 2nd
year, then annually
Physical examination X X
Toxicity assessment X X
FDG-PET/CT At 3 months (Recommended
*please see section 6.0 for
further details)
CT Chest, upper abd with contrast or To 2nd year
PET/CT
FEV1 and DLCO At 6 and 12 months
Blood collection (for consenting pts) X

HRQOL/Cost-Effectiveness Analysis (for X At 6 and 12 months
consenting pts): MDASI-Lung, SOBQ, EQ-
5D, Medical Service Use Survey
76
APPENDIX II
ZUBROD PERFORMANCE SCALE
0 Fully active, able to carry on all predisease activities without restriction
1 Restricted in physically strenuous activity but ambulatory and able to

carry work of a light or sedentary nature. For example, light
housework, office work
2 Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair 50% or more

of waking hours
4 Completely disabled. Cannot carry on self-care. Totally confined to bed
5 Death
77
APPENDIX III: AJCC STAGING SYSTEM
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
LUNG
Primary Tumor (T)

TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in
sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0 No evidence of primary tumor.
Tis Carcinoma in situ
T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the
main bronchus)*
T1a Tumor 2 cm or less in greatest dimension
T1b Tumor more than 2 cm but 3 cm or less in greatest dimension
T2 Tumor more than 3 cm but 7 cm or less with any of the following features (T2 tumors with
these features are classified T2a if 5 cm or less): Involves main bronchus, 2 cm or more
distal to the carina; Invades the visceral pleura PL1 or PL2); Associated with atelectasis
or obstructive pneumonitis that extends to the hilar region but does not involve the entire
lung
T2a Tumor more than 3 cm but 5 cm or less in greatest dimension
T2b Tumor more than 5 but 7 cm or less in greatest dimension
T3 Tumor more than 7 cm or one that directly invades any of the following: parietal (PL3),
chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal
pleura, parietal pericardium; or tumor in the main bronchus (less than 2 cm distal to the
carina* but without involvement of the carina; or associated atelectasis or obstructive
pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels,
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor
nodules in a different ipsilateral lobe
*The uncommon superficial spreading tumor of any size with its invasive component limited to the
bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessed
N0 No regional lymph nodes metastasis
N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and
intrapulmonary nodes including involvement by direct extension
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral
scalene, or supraclavicular lymph node(s)
78
APPENDIX III (Continued)
AJCC STAGING SYSTEM

Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
LUNG
Distant Metastasis (M)

M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumor nodule(s) in a contralateral lobe tumor with pleural nodules or malignant
pleural (or pericardial) effusion*
M1b Distant metastasis
* Most pleural (and pericardial effusions with lung cancer are due to tumor. In a few patients, however,
multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is
nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is
not related to the tumor, the effusion should be excluded as a staging element, and the patient should be
classified as M0.
STAGE GROUPING
Occult Carcinoma TX, N0, M0
Stage 0 Tis, N0, M0
Stage IA T1a-b, N0, M0
Stage IB T2a, N0, M0
Stage IIA T2b, N0, M0
T1a-b, N1, M0
T2a, N1, M0
Stage IIB T2b, N1, M0
T3, N0, M0
Stage IIIA T1a-b, N2, M0
T2a-b, N2, M0
T3, N1-2, M0
T4, N0-1, M0
Stage IIIB T1a-b, N3, M0
T2a-b, N3, M0
T3, N3, M0
T4, N2-3, M0
Stage IV Any T, Any N, M1a-b
79
APPENDIX IV
Appendices for NRG Oncology Biospecimen Collection
NRG Oncology FFPE Specimen Plug Kit Collection

NRG ONcology Blood Collection Kit Instructions
Shipping Instructions:
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only
UCSF Box 1800
Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens
 Include all NRG Oncology paperwork in pocket of biohazard bag.

 Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.
 Check that all samples are labeled with the NRG Oncology study and case number, and include
date of collection as well as collection time point (e.g., pretreatment, post-treatment).
 FFPE Specimens:
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top
of the container. If you can hear the slides shaking it is likely that they will break during
shipping.
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you
shake the container the blocks are not shaking. If you can hear the block shaking it might break
during shipping.
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address
(94115). Do NOT ship on Dry Ice.
 Frozen Specimens:
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate
bag and clearly identified. If possible keep Serum, Plasma, and Whole Blood submissions in
separate bags.
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two
separate boxes. Any Styrofoam box can be used, as long as it is big enough.
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and
the site will be notified.
o Send frozen specimens on dry ice via overnight courier to the address above. Specimens
should only be shipped Monday through Wednesday to prevent thawing due to delivery delays.
Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -80° C
until ready to ship.
 For Questions regarding collection/shipping please contact the NRG Oncology

Biospecimen Bank by e-mail: RTOG@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-
5271.
80
NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen
Bank. The plug kit contains a shipping tube and a punch tool.
Step 1
If the block is stored cold, allow it to equilibrate for 30 minutes at
room temperature. Place the punch tool on the paraffin block over
the selected tumor area. (Ask a pathologist to select area with
tumor.) Push the punch into the paraffin block. Twist the punch tool
once around to separate the plug from the block. Then pull the
punch tool out of the block. The punch should be filled with tissue
sample.
Step 2
Label the punch tool with the study #, case #, pathology accession
number and block ID. DON’T remove specimen from the punch.
Use a separate punch tool for every specimen. Call or e-mail us if

you have any questions or need additional specimen plug kits.
Step 3
Once punch tool is labeled, place in shipping tube and mail to
address below. Please do not mix specimens in the same tube.
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID.
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block
and return the remaining block to your facility. Please indicate on the submission form the request to
perform the plug procedure and return of the block.
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact
the NRG Oncology Biospecimen Bank by e-mail: RTOG@ucsf.edu or call 415-476-7864/Fax 415-
476-5271.
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only
UCSF Box 1800
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable shipments
81
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as
specified by the protocol):
Kit contents:
 One Red Top tube for serum (A)
 One Purple Top EDTA tube for plasma (B)
 One Purple Top EDTA tube for Whole Blood (C)
 Twenty-five (25) 1 ml cryovials
 Biohazard bags (3) and Absorbent shipping material (3)
 Styrofoam container (inner) and Cardboard shipping (outer) box
 UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers
 Specimen Transmittal (ST) Form and Kit Instructions
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD:

(A) Serum (if requested): Red Top Tube
 Label as many 1ml cryovials (5 to 10) as necessary for the serum collected. Label them with
the NRG Oncology study and case number, collection date, time, and time point, and clearly
mark cryovials “serum”.
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4°C (preferred). If sites
are unable to process samples at 4°C then spinning at room temperature is acceptable if
done within 2 hours of draw but must be noted on the ST Form.
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to
10) labeled with NRG Oncology study and case numbers, collection date/time, protocol time-
point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”.
Indicate the volume on the vials if less than 0.5 ml. It is more important to have 0.5 ml per
tube than ten tubes with variable amounts.
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen
until ready to ship. See below for storage conditions.
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on
the ST Form.
(B) Plasma (If requested): Purple Top EDTA tube #1

 Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with
the NRG Oncology study and case number, collection date, time, and time point, and clearly
mark cryovials “plasma”.
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA.
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4 C then
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted
on the ST Form..
3. If the interval between specimen collection and processing is anticipated to be more than one
hour, keep specimen on ice until centrifuging is performed.
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the
plasma collected (5 to 10) labeled with NRG Oncology study and case numbers, collection
date/time, time point collected and clearly mark specimen as “plasma”. Avoid pipetting up the
buffy coat layer. Indicate the volume on the vials if less than 0.5 ml. It is more important to have
0.5 ml per tube than ten tubes with variable amounts.
(continued on next page)
82
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued)
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C.
6. Store frozen plasma until ready to ship on dry ice.
7. See below for storage conditions.
the STF.
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2
 Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with
the RTOG study and case number, collection date/time, and time point, and clearly mark
cryovials “blood”.
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can
also be mixed for 5 minutes on a mixer at room temperature.
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the
blood collected (3 to 5) labeled with RTOG study and case numbers, collection date/time,
time point collected and clearly mark specimen as “blood”. Indicate the volume on the vials if
less than 1.0 ml. It is more important to have 1.0 ml per tube than five tubes with variable
amounts.
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.
4. Store blood samples frozen until ready to ship on dry ice.
5. See below for storage conditions.
ST Form.
(continued on next page)
83
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued)
Freezing and Storage:
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.
 Store at –80C (-70C to -90C) until ready to ship.
If a -80C Freezer is not available,
 Samples can be stored short term in a -20C freezer (non-frost free preferred) for
up to one week (please ship out Monday-Wednesday only).
OR:
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily
(please ship out on Monday-Wednesday only).
OR:
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only).
 Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
Shipping/Mailing:
 Ship specimens on Dry Ice overnight Monday-Wednesday to prevent thawing due to delivery
delays. Saturday and holiday deliveries cannot be accepted.
 Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the
Styrofoam box.
 Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods
together) in absorbent shipping material and place each specimen type in a separate biohazard
bag. Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg
minimum). Add padding to avoid the dry ice from breaking the tubes.
 Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and
UN1895 stickers to outer cardboard box.
 Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from
breaking the tubes.
 For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail RTOG@ucsf.edu or call (415) 476-7864.
Shipping Address:
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens
For questions, call 415-476-7864 or e-mail: RTOG@ucsf.edu
84

NRG Oncology: RTOG 1308

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NRG ONCOLOGY

Radiation Oncology Co-Chairs Bradford Hoppe, MD, MPH

Study chairs continued on next page

Medical Physics Co-Chairs Outcomes Co-Chair

Radhe Mohan, PhD Comparative Cost Effectiveness Co-Chairs

ELIGIBILITY CHECKLIST ........................................................................................................................... 10

1.0 INTRODUCTION............................................................................................................................. 11

2.0 OBJECTIVES .................................................................................................................................. 22

3.0 PATIENT SELECTION.................................................................................................................... 22

4.0 PRETREATMENT EVALUATIONS/MANAGEMENT ..................................................................... 24

5.0 REGISTRATION PROCEDURES................................................................................................... 24

6.0 RADIATION THERAPY................................................................................................................... 29

7.0 DRUG THERAPY............................................................................................................................ 41

8.0 SURGERY ...................................................................................................................................... 52

10.0 TISSUE/SPECIMEN SUBMISSION................................................................................................ 52

11.0 PATIENT ASSESSMENTS ............................................................................................................. 55

12.0 DATA COLLECTION....................................................................................................................... 56

13.0 STATISTICAL CONSIDERATIONS ................................................................................................ 59

REFERENCES ............................................................................................................................................ 69

APPENDIX I ................................................................................................................................................ 74

APPENDIX II ............................................................................................................................................... 77

APPENDIX III .............................................................................................................................................. 78

APPENDIX IV.............................................................................................................................................. 80

See Section 5.0 for pre-registration credentialing details.

Patient Population: (See Section 3.0 for Eligibility)

Required Sample Size: 560 patients

(Y) 4. Zubrod performance status 0-1 within 30 days prior to registration

Creatinine Clearance (male) = [(140 – age) x (wt in kg)]

(Y) 10. Peripheral neuropathy ≤ grade 1 at the time of registration

(Y) 12. Patients must have measurable or evaluable disease

The following questions will be asked at Study Registration:

1. Institutional person randomizing case.

(Y) 2. Has the Eligibility Checklist been completed?

(Y) 3. In the opinion of the investigator, is the patient eligible?

4. Date informed consent signed

5. Patient’s Initials (Last First Middle)

12. Country of Residence

13. Zip Code (U.S. Residents)

14. Method of Payment

15. Any care at a VA or Military Hospital?

16. Calendar Base Date

17. Randomization date

18. Medical oncologist’s name

If no, please specify the reason from the following:

(II/IIIA/IIIB) 25. Stage

(Squamous cell carcinoma or Non-squamous cell carcinoma) 26. Histology

(Cisplatin and Etoposide or Carboplatin and Paclitaxel) 27. Concurrent chemotherapy

_______(CTEP code) 29. CTEP code of site delivering photon therapy

_______(CTEP code) 30. CTEP code of site delivering proton therapy

In terms of dosimetry, the use of protons as a source of therapeutic radiation provides a

Furthermore, in a previous study (Tucker and Liao 2012), investigators at MD Anderson

Mean heart dose between patients randomized to proton versus IMRT

Association of OS and GTV, heart, and lung dose

1.1 Patient-Reported Outcome Study: Health-Related Quality of Life (HRQOL), Symptom

Time points and rationale are as follows:

Pre CXRT Mean 2.87 2.22 1.88 .37 1.30 .36

SD 2.43 2.26 1.86 1.07 2.098 .95

SD 2.60 2.47 2.38 2.58 2.450 2.20

ANOVA, P-value .013 .044 .007 .000 .015 .000

RTOG 1308; version

Weeks from radiation start

1.1.2 UCSD Shortness of Breath Questionnaire (SOBQ)

1.3 Changes in Pulmonary Function After Concurrent Chemoradiation for NSCLC