Stereotactic Body Radiation Therapy in Treating Patients With Stage I Non-Small Cell Lung Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00750269
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 120
• Locations: 58
• Arms: 9
• Duration (Months): 159.5
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Stereotactic body radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue.

PURPOSE: This phase I/II trial is studying the side effects and best dose of stereotactic body radiation therapy and to see how well it works in treating patients with stage I non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Radiation: SBRT 40.0 Gy; Radiation: SBRT 42.5 Gy; Radiation: SBRT 45.0 Gy; Radiation: SBRT 47.5 Gy; Radiation: SBRT 50.0 Gy; Radiation: SBRT 52.5 Gy; Radiation: SBRT 55.0 Gy; Radiation: SBRT 57.5 Gy; Radiation: SBRT 60.0 Gy	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the maximum tolerated dose (MTD) of stereotactic body radiotherapy (SBRT) in medically inoperable patients with centrally located stage I non-small cell lung cancer. (Phase I)

• To estimate the local control rate of SBRT at the MTD in these patients. (Phase II)

Secondary

• To estimate the rates of adverse events (other than dose-limiting toxicity) of ≥ grade 3 that is possibly, probably, or definitely related to treatment and that occurs within 1 year after the start of SBRT in these patients.

• To estimate the rates of late adverse events (i.e., occurs > 1 year after the start of SBRT) in these patients.

• To estimate the local control and progression-free and overall survival rates in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients undergo stereotactic body radiotherapy every 2 days over 1½-2 weeks [total of 5 fractions (FX)] in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 3 months for 2 years, then every 6 months for 2 years, then annually.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non-Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Level 1: 8.0 Gy/FX SBRT 40.0 Gy	Radiation: SBRT 40.0 Gy; SBRT delivered in 5 fractions of 8.0 Gy/fraction over 1.5 to 2 weeks for a total of 40.0 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 2: 8.5 Gy/FX SBRT 42.5 Gy	Radiation: SBRT 42.5 Gy; SBRT delivered in 5 fractions of 8.5 Gy/fraction over 1.5 to 2 weeks for a total of 42.5 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 3: 9.0 Gy/FX SBRT 45.0 Gy	Radiation: SBRT 45.0 Gy; SBRT delivered in 5 fractions of 9.0 Gy/fraction over 1.5 to 2 weeks for a total of 45.0 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 4: 9.5 Gy/FX SBRT 47.5 Gy	Radiation: SBRT 47.5 Gy; SBRT delivered in 5 fractions of 9.5 Gy/fraction over 1.5 to 2 weeks for a total of 47.5 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 5: 10.0 Gy/FX SBRT 50.0 Gy	Radiation: SBRT 50.0 Gy; SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 6: 10.5 Gy/FX SBRT 52.5 Gy	Radiation: SBRT 52.5 Gy; SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 7: 11.0 Gy/FX SBRT 55.0 Gy	Radiation: SBRT 55.0 Gy; SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 8: 11.5 Gy/FX SBRT 57.5 Gy	Radiation: SBRT 57.5 Gy; SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)
Experimental: Level 9: 12.0 Gy/FX SBRT 60.0 Gy	Radiation: SBRT 60.0 Gy; SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy; Other Names: Stereotactic body radiation therapy (SBRT) Stereotactic ablative radiotherapy (SABR)

Outcome Measures

Primary Outcome Measures

1. (Phase I) Maximum Tolerated Dose of Stereotactic Body Radiotherapy (SBRT) as Assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0 [From start of SBRT to 1 year]

   Maximum tolerated dose (MTD) defined as dose most closely associated with a 20% probability of experiencing a toxicity <= 1 year from start of SBRT from following dose-limiting toxicities: Gr 3-5 Cardiac: Pericardial effusion, Pericarditis, Restrictive cardiomyopathy; Gr 4-5 GI: Dysphagia, Esophagitis, Esophageal fistula/obstruction/perforation/stenosis/ulcer/hemorrhage; Gr 3-5 Nervous System Disorders: Brachial plexopathy, Recurrent laryngeal nerve palsy, Myelitis; Gr 3-5 Respiratory: Atelectasis (gr 4-5 only), Bronchopulmonary/mediastinal/pleural/tracheal hemorrhage, Bronchial/pulmonary/bronchopleural/tracheal fistula, Hypoxia (provided gr 3 is worse than baseline), Bronchial/tracheal obstruction, Pleural effusion, Pneumonitis, Pulmonary fibrosis; Changes in Pulmonary Function Tests per SBRT Pulmonary Toxicity Scale, Gr 3-5: FEV1 decline, FVC decline; Any Gr 5 adverse event attributed to treatment. Dose level was determined by time-to-event continual reassessment method (TITE-CRM).

2. (Phase II) Primary Tumor Control Rate at the Maximum Tolerated Dose (MTD) [From start of SBRT to 2 years.]

   Primary tumor control is defined as the absence of primary tumor failure. Primary tumor failure (PTF) refers to the primary treated tumor after protocol therapy and corresponds to meeting following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. Marginal Failures (MF) and Involved Lobe Failures were also counted as PTF. The cumulative incidence method was used to estimate primary tumor control rate. The 90% confidence interval for local control was calculated using bootstrapping methods. Per the protocol, only the MTD dose level was to be analyzed. However, due to the quantity of patients enrolled on Dose Level 8 as well as safety concerns, Dose Level 8 was analyzed also.

Secondary Outcome Measures

1. Progression-free Survival [From randomization to date of death, failure (local, regional or distant) or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.]

   Progression-free survival is defined as the state of being alive without progression of disease. A failure is the first of the following: local progression, regional progression, distant metastasis, or death. Progression-free survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested.

2. Overall Survival [From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.]

   An event for overall survival is death due to any cause. Overall survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested.

3. Local Progression [From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months.]

   Local progression is the same as primary tumor failure (PTF) which refers to the primary treated tumor after protocol therapy and corresponds to meeting both of the following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. For outcome analysis, Marginal Failures (MF) and Involved Lobe Failures will also be counted as PTF. Local progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.

4. Nodal Progression [From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.]

   Regional nodal progression is defined as appearance after protocol therapy of measurable tumor within lymph nodes along the natural lymphatic drainage typical for the location of the treated primary disease only with dimension of at least 1.0 cm on imaging studies (preferably CT scans) within the lung, bronchial hilum, or the mediastinum. Regional nodal progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.

5. Distant Metastases [From randomization to date of death, distant failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.]

   Distant metastases is defined as the appearance after protocol therapy of cancer deposits characteristic of metastatic dissemination from non-small cell lung cancer. Distant metastases progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.

6. Rate of Toxicity ≥ Grade 3 (Other Than DLT) Within One Year as Assessed by NCI CTCAE v4.0 [From start of SBRT until 1 year.]

   Rate of patients developing any treatment-related toxicity during the first year following the start of SBRT that is not among the types considered as a dose-limiting toxicity.

7. Rate of Late Toxicity (i.e., Occurs > 1 Year After the Start of SBRT) of ≥ Grade 3 as Assessed by NCI CTCAE v4.0 [From start of treatment to end of follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.]

   Percentage of patients who developed any treatment-related toxicity after the first year following the start of SBRT.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

• Stage T1-2, N0, M0 disease

• Tumor size ≤ 5 cm

• Tumor must be within or touching the zone of the proximal bronchial tree, defined as a volume of 2 cm in all directions around the proximal bronchial tree (i.e., carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right, and left lower lobe bronchi) OR immediately adjacent to the mediastinal or pericardial pleura (PTV touching the pleura)

• Hilar or mediastinal lymph nodes ≤ 1 cm AND no abnormal hilar or mediastinal uptake on positron emission tomography (PET) scan are considered N0

• Mediastinal lymph node sampling by any technique is allowed but not required

• Patients with > 1 cm hilar or mediastinal lymph nodes on CT scan or abnormal PET scan (including suspicious but nondiagnostic uptake) are eligible provided directed tissue biopsies of all abnormally identified areas are negative for cancer

• Tumor deemed technically resectable, in the opinion of an experienced thoracic cancer surgeon, with a reasonable possibility of obtaining a gross total resection with negative margins, defined as a potentially curative resection (PCR)

• Patient deemed "medically inoperable" due to severe underlying physiological medical problems that would prohibit a PCR, including any of the following:

• Baseline forced expiratory volume at one second (FEV1) < 40% predicted

• Postoperative FEV1 < 30% predicted

• Severely reduced diffusion capacity

• Baseline hypoxemia and/or hypercapnia

• Exercise oxygen consumption < 50% predicted

• Severe pulmonary hypertension

• Diabetes mellitus with severe end-stage organ damage

• Severe cerebral, cardiac, or peripheral vascular disease

• Severe chronic heart disease

• Measurable disease as documented by CT scan or whole-body PET scan within the past 8 weeks

• Patients with lesions that cannot be visualized by CT scan are not eligible

• Pleural effusion allowed provided it is deemed too small to tap under CT guidance and is not evident on chest x-ray

• Pleural effusion that appears on chest x-ray is allowed only after thoracotomy or other invasive procedure

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-2

• Not pregnant

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 60 days after completion of study therapy

• No other invasive malignancy within the past 2 years except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix

• Prior lung cancer allowed provided the patient has been disease-free for ≥ 2 years

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields

• No prior chemotherapy for the study cancer

• No other concurrent local therapy (including standard-fractionated radiotherapy and/or surgery) or systemic therapy (including standard chemotherapy or biologic targeted agents) specifically intended as treatment for study cancer

• Local or systemic therapy at the time of disease progression allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Center for Cancer Care - Peoria	Peoria	Arizona	United States	85381
2	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
3	Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center	Burbank	California	United States	91505
4	Radiation Oncology Centers - Cameron Park	Cameron Park	California	United States	95682
5	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
6	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
7	University of California Davis Cancer Center	Sacramento	California	United States	95817
8	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
9	George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus	New Britain	Connecticut	United States	06050
10	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
11	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
12	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
13	M.D. Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806
14	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
15	CCOP - Kansas City	Prairie Village	Kansas	United States	66208
16	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
17	Norton Suburban Hospital	Louisville	Kentucky	United States	40207
18	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
19	Maine Center for Cancer Medicine and Blood Disorders - Scarborough	Scarborough	Maine	United States	04074
20	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
21	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
22	McLaren Cancer Institute	Flint	Michigan	United States	48532
23	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
24	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
25	William Beaumont Hospital - Royal Oak Campus	Royal Oak	Michigan	United States	48073
26	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
27	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
28	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
29	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
30	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
31	Saint Louis University Cancer Center	Saint Louis	Missouri	United States	63110
32	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
33	Cooper CyberKnife Center	Mount Laurel	New Jersey	United States	08054
34	Frederick R. and Betty M. Smith Cancer Treatment Center	Sparta	New Jersey	United States	07871
35	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
36	St. Luke's - Roosevelt Hospital Center - St.Luke's Division	New York	New York	United States	10025
37	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
38	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
39	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
40	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
41	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
42	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
43	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
44	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
45	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
46	Dale and Frances Hughes Cancer Center at Pocono Medical Center	East Stroudsburg	Pennsylvania	United States	18301
47	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
48	Frankford Hospital Cancer Center - Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
49	Albert Einstein Cancer Center	Philadelphia	Pennsylvania	United States	19141
50	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19612-6052
51	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
52	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
53	Sentara Cancer Institute at Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
54	St. Joseph Cancer Center	Bellingham	Washington	United States	98225
55	University Cancer Center at University of Washington Medical Center	Seattle	Washington	United States	98195
56	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
57	Veterans Affairs Medical Center - Milwaukee	Milwaukee	Wisconsin	United States	53295
58	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Andrea Bezjak, MD, MSC, FRCPC, Princess Margaret Hospital, Canada
• Study Chair: Jeffrey Bradley, MD, Mallinckrodt Institute of Radiology at Washington University Medical Center
• Study Chair: Laurie E. Gaspar, MD, MBA, University of Colorado, Denver
• Study Chair: Robert D. Timmerman, MD, University of Texas
• Study Chair: Elizabeth Gore, MD, Medical College of Wisconsin
• Study Chair: Feng-Ming Phoenix Konb, MD, PhD, Georgia Regents University Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00750269
• Other Study ID Numbers: RTOG-0813; CDR0000613524; NCI-2009-01095; NCT01317056
• First Posted: Sep 10, 2008
• Last Update Posted: Jun 9, 2022
• Last Verified: May 1, 2022

• Keywords provided by Radiation Therapy Oncology Group: stage I non-small cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Recruitment Details	This study was designed to start at dose level 5. Dose levels 1-4 were in place only to be used if the regimen in general proved too toxic and lower dose levels were needed. No patients were accrued to levels 1-4.

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT 50.0 Gy SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT 52.5 Gy SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT 55.0 Gy SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Period Title: Overall Study
STARTED	8	8	18	43	43
COMPLETED	8	7	14	38	33
NOT COMPLETED	0	1	4	5	10

Baseline Characteristics

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX	Total
Arm/Group Description	SBRT 50.0 Gy SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT 52.5 Gy SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT 55.0 Gy SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy	Total of all reporting groups
Overall Participants	8	7	14	38	33	100
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	74	75	72	71	72	72
Sex: Female, Male (Count of Participants)
Female	6 75%	3 42.9%	6 42.9%	15 39.5%	13 39.4%	43 43%
Male	2 25%	4 57.1%	8 57.1%	23 60.5%	20 60.6%	57 57%

Outcome Measures

1. Primary Outcome

Title	(Phase I) Maximum Tolerated Dose of Stereotactic Body Radiotherapy (SBRT) as Assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0
Description	Maximum tolerated dose (MTD) defined as dose most closely associated with a 20% probability of experiencing a toxicity <= 1 year from start of SBRT from following dose-limiting toxicities: Gr 3-5 Cardiac: Pericardial effusion, Pericarditis, Restrictive cardiomyopathy; Gr 4-5 GI: Dysphagia, Esophagitis, Esophageal fistula/obstruction/perforation/stenosis/ulcer/hemorrhage; Gr 3-5 Nervous System Disorders: Brachial plexopathy, Recurrent laryngeal nerve palsy, Myelitis; Gr 3-5 Respiratory: Atelectasis (gr 4-5 only), Bronchopulmonary/mediastinal/pleural/tracheal hemorrhage, Bronchial/pulmonary/bronchopleural/tracheal fistula, Hypoxia (provided gr 3 is worse than baseline), Bronchial/tracheal obstruction, Pleural effusion, Pneumonitis, Pulmonary fibrosis; Changes in Pulmonary Function Tests per SBRT Pulmonary Toxicity Scale, Gr 3-5: FEV1 decline, FVC decline; Any Gr 5 adverse event attributed to treatment. Dose level was determined by time-to-event continual reassessment method (TITE-CRM).
Time Frame	From start of SBRT to 1 year

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	All Participants
Arm/Group Description
Measure Participants	100
Number [Gy/FX]	12.0

2. Primary Outcome

Title	(Phase II) Primary Tumor Control Rate at the Maximum Tolerated Dose (MTD)
Description	Primary tumor control is defined as the absence of primary tumor failure. Primary tumor failure (PTF) refers to the primary treated tumor after protocol therapy and corresponds to meeting following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. Marginal Failures (MF) and Involved Lobe Failures were also counted as PTF. The cumulative incidence method was used to estimate primary tumor control rate. The 90% confidence interval for local control was calculated using bootstrapping methods. Per the protocol, only the MTD dose level was to be analyzed. However, due to the quantity of patients enrolled on Dose Level 8 as well as safety concerns, Dose Level 8 was analyzed also.
Time Frame	From start of SBRT to 2 years.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	38	33
Number (90% Confidence Interval) [percentage of participants]	89.4 1117.5%	87.7 1252.9%

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival is defined as the state of being alive without progression of disease. A failure is the first of the following: local progression, regional progression, distant metastasis, or death. Progression-free survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested.
Time Frame	From randomization to date of death, failure (local, regional or distant) or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of participants]	50.0 625%	57.1 815.7%	57.1 407.9%	52.2 137.4%	54.5 165.2%

4. Secondary Outcome

Title	Overall Survival
Description	An event for overall survival is death due to any cause. Overall survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested.
Time Frame	From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of participants]	75.0 937.5%	57.1 815.7%	71.4 510%	70.2 184.7%	72.7 220.3%

5. Secondary Outcome

Title	Local Progression
Description	Local progression is the same as primary tumor failure (PTF) which refers to the primary treated tumor after protocol therapy and corresponds to meeting both of the following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. For outcome analysis, Marginal Failures (MF) and Involved Lobe Failures will also be counted as PTF. Local progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.
Time Frame	From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of participants]	12.5 156.3%	0 0%	14.3 102.1%	10.6 27.9%	12.3 37.3%

6. Secondary Outcome

Title	Nodal Progression
Description	Regional nodal progression is defined as appearance after protocol therapy of measurable tumor within lymph nodes along the natural lymphatic drainage typical for the location of the treated primary disease only with dimension of at least 1.0 cm on imaging studies (preferably CT scans) within the lung, bronchial hilum, or the mediastinum. Regional nodal progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.
Time Frame	From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of patients]	0	0	7.1	5.3	6.1

7. Secondary Outcome

Title	Distant Metastases
Description	Distant metastases is defined as the appearance after protocol therapy of cancer deposits characteristic of metastatic dissemination from non-small cell lung cancer. Distant metastases progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested.
Time Frame	From randomization to date of death, distant failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of participants]	0 0%	14.3 204.3%	14.3 102.1%	7.9 20.8%	15.2 46.1%

8. Secondary Outcome

Title	Rate of Toxicity ≥ Grade 3 (Other Than DLT) Within One Year as Assessed by NCI CTCAE v4.0
Description	Rate of patients developing any treatment-related toxicity during the first year following the start of SBRT that is not among the types considered as a dose-limiting toxicity.
Time Frame	From start of SBRT until 1 year.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT 50.0 Gy SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT 52.5 Gy SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT 55.0 Gy SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	7	14	38	33
Number (95% Confidence Interval) [percentage of participants]	0 0%	0 0%	0 0%	12.1 31.8%	16.7 50.6%

9. Secondary Outcome

Title	Rate of Late Toxicity (i.e., Occurs > 1 Year After the Start of SBRT) of ≥ Grade 3 as Assessed by NCI CTCAE v4.0
Description	Percentage of patients who developed any treatment-related toxicity after the first year following the start of SBRT.
Time Frame	From start of treatment to end of follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment who were observed more than 1 year after start of SBRT

Arm/Group Title	Level 5: 10.0 Gy/FX	Level 6: 10.5 Gy/FX	Level 7: 11.0 Gy/FX	Level 8: 11.5 Gy/FX	Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT 50.0 Gy SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy	SBRT 52.5 Gy SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy	SBRT 55.0 Gy SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy	SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy	SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
Measure Participants	8	5	12	32	31
Number (95% Confidence Interval) [percentage of participants]	0 0%	0 0%	16.7 119.3%	6.3 16.6%	16.1 48.8%

Adverse Events

Adverse Event Reporting Description	Patients experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Level 5: 10.0 Gy/FX		Level 6: 10.5 Gy/FX		Level 7: 11.0 Gy/FX		Level 8: 11.5 Gy/FX		Level 9: 12.0 Gy/FX
Arm/Group Description	SBRT 50.0 Gy SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy		SBRT 52.5 Gy SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy		SBRT 55.0 Gy SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy		SBRT 57.5 Gy SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy		SBRT 60.0 Gy SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy
All Cause Mortality
	Level 5: 10.0 Gy/FX		Level 6: 10.5 Gy/FX		Level 7: 11.0 Gy/FX		Level 8: 11.5 Gy/FX		Level 9: 12.0 Gy/FX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Level 5: 10.0 Gy/FX		Level 6: 10.5 Gy/FX		Level 7: 11.0 Gy/FX		Level 8: 11.5 Gy/FX		Level 9: 12.0 Gy/FX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		0/7 (0%)		2/14 (14.3%)		9/38 (23.7%)		7/33 (21.2%)
Cardiac disorders
Heart failure	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Sinus bradycardia	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Sinus tachycardia	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Gastrointestinal disorders
Dysphagia	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Esophageal perforation	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Esophagitis	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		1/33 (3%)
Gastritis	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
General disorders
Death NOS	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Infections and infestations
Lung infection	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Nervous system disorders
Intracranial hemorrhage	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		1/33 (3%)
Bronchial obstruction	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Bronchopulmonary hemorrhage	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		1/33 (3%)
Cough	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Dyspnea	0/8 (0%)		0/7 (0%)		0/14 (0%)		3/38 (7.9%)		1/33 (3%)
Hypoxia	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		1/33 (3%)
Pleural effusion	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Pneumonitis	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Pulmonary fibrosis	0/8 (0%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Respiratory failure	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders - Other	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		2/33 (6.1%)
Vascular disorders
Hypertension	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Level 5: 10.0 Gy/FX		Level 6: 10.5 Gy/FX		Level 7: 11.0 Gy/FX		Level 8: 11.5 Gy/FX		Level 9: 12.0 Gy/FX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)		7/7 (100%)		13/14 (92.9%)		34/38 (89.5%)		27/33 (81.8%)
Cardiac disorders
Chest pain - cardiac	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		0/33 (0%)
Conduction disorder	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		0/33 (0%)
Heart failure	0/8 (0%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		2/33 (6.1%)
Mitral valve disease	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		0/33 (0%)
Pericardial effusion	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		1/38 (2.6%)		1/33 (3%)
Pericarditis	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		1/33 (3%)
Tricuspid valve disease	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		0/33 (0%)
Gastrointestinal disorders
Constipation	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		1/33 (3%)
Diarrhea	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Dyspepsia	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Dysphagia	0/8 (0%)		0/7 (0%)		4/14 (28.6%)		5/38 (13.2%)		9/33 (27.3%)
Esophageal fistula	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		1/33 (3%)
Esophageal hemorrhage	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		0/38 (0%)		0/33 (0%)
Esophageal obstruction	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		0/38 (0%)		1/33 (3%)
Esophageal pain	0/8 (0%)		1/7 (14.3%)		0/14 (0%)		2/38 (5.3%)		1/33 (3%)
Esophageal stenosis	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		1/33 (3%)
Esophageal ulcer	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		1/33 (3%)
Esophagitis	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		3/38 (7.9%)		2/33 (6.1%)
Gastroesophageal reflux disease	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
General disorders
Death NOS	0/8 (0%)		1/7 (14.3%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Edema limbs	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Fatigue	4/8 (50%)		3/7 (42.9%)		6/14 (42.9%)		12/38 (31.6%)		8/33 (24.2%)
Fever	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Pain	2/8 (25%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		2/33 (6.1%)
Infections and infestations
Bronchial infection	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		1/33 (3%)
Lung infection	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Sinusitis	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Skin infection	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Upper respiratory infection	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		2/33 (6.1%)
Wound infection	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Injury, poisoning and procedural complications
Dermatitis radiation	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		0/38 (0%)		0/33 (0%)
Fracture	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Tracheal hemorrhage	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Tracheal obstruction	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Investigations
CD4 lymphocytes decreased	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Carbon monoxide diffusing capacity decreased	2/8 (25%)		1/7 (14.3%)		1/14 (7.1%)		2/38 (5.3%)		1/33 (3%)
Forced expiratory volume decreased	1/8 (12.5%)		2/7 (28.6%)		3/14 (21.4%)		5/38 (13.2%)		1/33 (3%)
Investigations - Other	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Vital capacity abnormal	1/8 (12.5%)		1/7 (14.3%)		0/14 (0%)		1/38 (2.6%)		0/33 (0%)
Weight loss	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		3/38 (7.9%)		2/33 (6.1%)
Metabolism and nutrition disorders
Anorexia	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		5/38 (13.2%)		3/33 (9.1%)
Dehydration	1/8 (12.5%)		0/7 (0%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Back pain	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		2/33 (6.1%)
Chest wall pain	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		3/38 (7.9%)		2/33 (6.1%)
Flank pain	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Joint range of motion decreased	0/8 (0%)		1/7 (14.3%)		0/14 (0%)		0/38 (0%)		0/33 (0%)
Musculoskeletal and connective tissue disorder - Other	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Myositis	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		1/33 (3%)
Neck pain	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Pain in extremity	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Nervous system disorders
Brachial plexopathy	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Headache	1/8 (12.5%)		1/7 (14.3%)		0/14 (0%)		0/38 (0%)		1/33 (3%)
Myelitis	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		0/38 (0%)		0/33 (0%)
Neuralgia	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Recurrent laryngeal nerve palsy	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		1/33 (3%)
Psychiatric disorders
Anxiety	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Insomnia	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Renal and urinary disorders
Renal and urinary disorders - Other	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Aspiration	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Atelectasis	5/8 (62.5%)		1/7 (14.3%)		3/14 (21.4%)		13/38 (34.2%)		13/33 (39.4%)
Bronchial fistula	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Bronchial obstruction	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		3/38 (7.9%)		3/33 (9.1%)
Bronchial stricture	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Bronchopleural fistula	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Bronchopulmonary hemorrhage	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Bronchospasm	1/8 (12.5%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Cough	3/8 (37.5%)		2/7 (28.6%)		3/14 (21.4%)		11/38 (28.9%)		4/33 (12.1%)
Dyspnea	5/8 (62.5%)		1/7 (14.3%)		5/14 (35.7%)		11/38 (28.9%)		11/33 (33.3%)
Hypoxia	1/8 (12.5%)		2/7 (28.6%)		2/14 (14.3%)		8/38 (21.1%)		7/33 (21.2%)
Laryngeal hemorrhage	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Mediastinal hemorrhage	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Nasal congestion	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Pleural effusion	2/8 (25%)		3/7 (42.9%)		5/14 (35.7%)		7/38 (18.4%)		11/33 (33.3%)
Pleural hemorrhage	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Pleuritic pain	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		1/38 (2.6%)		0/33 (0%)
Pneumonitis	4/8 (50%)		2/7 (28.6%)		3/14 (21.4%)		13/38 (34.2%)		5/33 (15.2%)
Productive cough	1/8 (12.5%)		0/7 (0%)		4/14 (28.6%)		2/38 (5.3%)		0/33 (0%)
Pulmonary fibrosis	3/8 (37.5%)		2/7 (28.6%)		3/14 (21.4%)		5/38 (13.2%)		7/33 (21.2%)
Pulmonary fistula	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders - Other	1/8 (12.5%)		0/7 (0%)		2/14 (14.3%)		1/38 (2.6%)		3/33 (9.1%)
Sore throat	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		0/38 (0%)		0/33 (0%)
Tracheal fistula	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Wheezing	0/8 (0%)		0/7 (0%)		2/14 (14.3%)		3/38 (7.9%)		2/33 (6.1%)
Skin and subcutaneous tissue disorders
Dry skin	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Rash acneiform	0/8 (0%)		0/7 (0%)		1/14 (7.1%)		0/38 (0%)		1/33 (3%)
Skin hyperpigmentation	0/8 (0%)		1/7 (14.3%)		1/14 (7.1%)		0/38 (0%)		0/33 (0%)
Vascular disorders
Hot flashes	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		0/33 (0%)
Hypertension	0/8 (0%)		0/7 (0%)		0/14 (0%)		2/38 (5.3%)		3/33 (9.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.