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: NCT00960999
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 94
• Locations: 38
• Arms: 2
• Actual Duration (Months): 102.4
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet known which regimen of stereotactic body radiation therapy is more effective in treating patients with non-small cell lung cancer.

PURPOSE: This randomized phase II trial is studying the side effects of two radiation therapy regimens and to see how well they work in treating patients with stage I non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Radiation: Single-fraction stereotactic body radiation therapy (SBRT); Radiation: Multiple-fraction stereotactic body radiation therapy (SBRT)	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the 1-year rate of ≥ grade 3 adverse events that are definitely, probably, or possibly related to treatment with single fraction vs multiple fraction stereotactic body radiotherapy in medically inoperable patients with stage I peripheral non-small cell lung cancer.

Secondary

• To estimate the 1-year primary tumor control rate in these patients.

• To estimate the 1-year overall survival and disease-free survival rate of these patients.

• To assess FDG-PET (fluorodeoxyglucose - positron emission tomography) standardized uptake value changes as a measure of treatment response and outcomes.

• To determine pulmonary function changes by treatment arm and response.

• To determine the association between biomarkers and primary tumor control and/or ≥ grade 2 radiation pneumonitis.

OUTLINE: This is a multicenter study. Patients are stratified according to Zubrod performance status (0 vs 1 vs 2) and T stage (T1 vs T2). Patients are randomized to 1 of 2 treatment arms.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT) Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer
• Actual Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: May 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single-fraction SBRT (34 Gy) Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Radiation: Single-fraction stereotactic body radiation therapy (SBRT); 34 Gy in 1 fraction to the prescription line at the edge of the planning target volume (PTV). The maximum dose must exist within the PTV, and the prescription isodose surface must be ≥ 60% and < 90% of the maximum dose. 99% of the PTV must receive a minimum of 90% of the prescription dose. The maximum dose to any point ≥ 2 cm away from the PTV in any direction must be at least < 50% of the prescription dose. The percent of the lungs (excluding PTV) receiving 20 Gy or more must be < 10%.
Experimental: Multiple-fraction SBRT (48 Gy) Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy	Radiation: Multiple-fraction stereotactic body radiation therapy (SBRT); 48 Gy in four 12 Gy fractions to the prescription line at the edge of the planning target volume (PTV). Treatments are given on 4 consecutive calendar days, but at least 18 hours apart. The maximum dose must exist within the PTV, and the prescription isodose surface must be ≥ 60% and < 90% of the maximum dose. 99% of the PTV must receive a minimum of 90% of the prescription dose. The maximum dose to any point ≥ 2 cm away from the PTV in any direction must be at least < 50% of the prescription dose. The percent of the lungs (excluding PTV) receiving 20 Gy or more must be < 10%.

Outcome Measures

Primary Outcome Measures

1. Counts of ≥ Grade 3 Adverse Events (AE) Graded by CTCAE v4 (Common Terminology Criteria for Adverse Events) That Are Definitely, Probably, or Possibly Related to Treatment (DPPRT) [From start of treatment to 1 year]

   Number of patients with ≥ grade 3 AE occurring within 1 year of treatment (TRT) start and reported as DPPRT among this subset of CTCAE v4: pericardial effusion, pericarditis, restrictive cardiomyopathy, dysphagia, esophagitis, esophageal fistula/obstruction/perforation/stenosis/ulcer/hemorrhage, rib fracture, brachial plexopathy, recurrent laryngeal nerve palsy, myelitis, atelectasis, bronchopulmonary/mediastinal/pleural/tracheal hemorrhage, bronchial/pulmonary/bronchopleural/tracheal fistula, hypoxia, bronchial/tracheal obstruction, pleural effusion, pneumonitis, pulmonary fibrosis, skin ulceration (thorax only), FEV1 (Forced Expiratory Volume) or FVC (forced vital capacity) decline, or grade 5 related to TRT. Each arm is considered independently. For each arm, >=5 of 38 analyzable subjects experiencing a grade ≥ 3 AE during the 1st year following TRT start would determine the respective TRT excessively toxic. For each arm this design provides 88% power with a 0.10 type I error rate.

Secondary Outcome Measures

1. 1-year Primary Tumor Control Rate [From start of treatment to 1 year]

   Primary tumor control is defined as the lack of primary tumor failure. Primary tumor failure is defined as the development of in-field or marginal failure. Primary tumor control time is defined as time from randomization to the the date of primary tumor failure, last known follow-up (censored), or death without failure (competing risk). Primary tumor control rates are estimated using the cumulative incidence method.

2. 1-year Overall Survival Rate [From start of treatment to 1 year]

   Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.

3. 1-year Disease-free Survival Rate [From start of treatment to 1 year]

   Disease-free survival is defined as being alive without experiencing in-field, marginal, involved lobe, regional or metastatic failure, development of a second primary, or death due to any cause. Disease-free survival time is defined as time from randomization to the the date of first failure or last known follow-up (censored). Disease-free survival rates are estimated using the Kaplan-Meier method.

4. Change in Peak Standardized Uptake Value (SUV) at 12 Weeks Post-radiotherapy [Baseline and 12 weeks post-radiotherapy]

   Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. Peak SUV is an average SUV computed within a fixed-size volume of interest (VOI), most often containing (and not necessarily centered on) the hottest pixel value. Peak SUV was measured from whole-body FDG-PET (fluorodeoxyglucose - positron emission tomography) scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV.

5. Change in Peak Standardized Uptake Value (SUV) at One Year Post-radiotherapy [Baseline and one year]

   Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. Peak SUV is an average SUV computed within a fixed-size volume of interest (VOI), most often containing (and not necessarily centered on) the hottest pixel value. Peak SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.

6. Change in Normalized Standardized Uptake Value (SUV) at 12 Weeks [Baseline and 12 weeks]

   Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Normalized SUV = peak SUV of regions of interest / mean SUV of the aortic arch. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.

7. Change in Normalized Standardized Uptake Value (SUV) at One Year [Baseline and one year]

   Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Normalized SUV = peak SUV of regions of interest / mean SUV of the aortic arch. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.

8. Change in Percentage of Expected Forced Expiratory Volume in 1 Second (FEV1) by Best Observed Tumor Response at 6 Months Post-radiotherapy [Forced Expiratory Volume in 1 Second (FEV1)] [From start of treatment to 6 months post-radiotherapy]

   Forced expiratory volume (FEV1), a measure of pulmonary function, was reported as percentage of the value that would be expected for the normal general population of the same height, age, and sex. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased FEV1. Best observed tumor response was evaluated using the Revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 (http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).

9. Change in Percentage of Expected Carbon Monoxide Diffusing Capacity (DLCO) by Best Observed Tumor Response at 6 Months Post-radiotherapy [From start of treatment to 6 months post-radiotherapy]

   Carbon monoxide diffusing capacity (DLCO), a measure of pulmonary function, was reported as percentage of the value that would be expected for the normal general population of the same height, age, and sex. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased DLCO. Best observed tumor response was evaluated using the Revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 (http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).

10. Association Between Biomarkers and Primary Tumor Control Rate [From start of treatment to 1 year]

11. Association Between Biomarkers and Grade 2+ Radiation Pneumonitis [From start of treatment to 1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histological confirmation (by biopsy or cytology) of non-small cell lung cancer (NSCLC) prior to treatment; the following primary cancer types are eligible: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, large cell neuroendocrine, or non-small cell carcinoma not otherwise specified; Note: although bronchioloalveolar cell carcinoma is a subtype of NSCLC, patients with the pure type of this malignancy are excluded from this study because the spread of this cancer between adjacent airways is difficult to target on computed tomography (CT).

2. Stage T1, N0, M0 or T2 (≤ 5 cm), N0, M0, (AJCC Staging, 6th Ed.), based upon #3.

3. Minimum diagnostic workup:

• History/physical examination, including weight and assessment of Zubrod performance status, within 4 weeks prior to registration;

• Evaluation by an experienced thoracic cancer clinician (a thoracic surgeon, medical oncologist, radiation oncologist, or pulmonologist) within 8 weeks prior to registration;

• CT scan with intravenous contrast (unless medically contraindicated) within 8 weeks prior to registration of the entirety of both lungs and the mediastinum, liver, and adrenal glands; the primary tumor dimension will be measured on the CT. Positron emission tomography (PET) evaluation of the liver and adrenal glands also is permitted. In addition, if the enrolling institution has a combined PET/CT scanner and both aspects are of diagnostic quality and read by a trained radiologist, the PET/CT will meet the staging requirements for both CT and PET.

• Whole body or wide field FDG-PET within 8 weeks prior to registration with adequate visualization of the primary tumor and draining lymph node basins in the hilar and mediastinal regions and adrenal glands; in the event of lung consolidation, atelectasis, inflammation or other confounding features, PET-based imaging correlated with CT imaging will establish the maximal tumor dimensions. Standardized uptake value (SUV) must be measured on PET. To be included in this analysis, the patient's PET studies must be performed with a dedicated bismuth germanium oxide (BGO), lutetium oxyorthosilicate (LSO), or gadolinium oxyorthosilicate (GSO) PET or PET/CT scanner. PET scanners with sodium iodide (Nal) detectors are not acceptable. If the baseline PET study is performed at the treating institution (or its affiliated PET facility), it is recommended that the reassessment PET scans be performed at the same site.

• Pulmonary function tests (PFTs): Routine spirometry, lung volumes, and diffusion capacity, within 8 weeks prior to registration; arterial blood gases are optional. Note: All patients enrolled in this study must have these pulmonary assessments whether or not the reason for their medical inoperability is pulmonary based, since the objective assessment of pulmonary factors is a component of the outcomes assessment for this study.

1. Patients with hilar or mediastinal lymph nodes ≤ 1cm and no abnormal hilar or mediastinal uptake on PET will be considered N0. Patients with > 1 cm hilar or mediastinal lymph nodes on CT or abnormal PET (including suspicious but non-diagnostic uptake) may still be eligible if directed tissue biopsy of all abnormally identified areas are negative for cancer.

2. The patient's resectable NSCLC must be considered medically inoperable by an experienced thoracic cancer clinician (a thoracic surgeon, medical oncologist, radiation oncologist, or pulmonologist) or a standard lobectomy and mediastinal lymph node dissection/sampling procedure. The patient may have underlying physiological medical problems that would prohibit a surgery due to a low probability of tolerating general anesthesia, the operation, the postoperative recovery period, or the removal of adjacent functioning lung. These types of patients with severe underlying health problems are deemed "medically inoperable." Standard justification for deeming a patient medically inoperable based on pulmonary function for surgical resection of

NSCLC may include any of the following:

• Baseline forced expiratory volume in 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 organ damage;

• Severe cerebral, cardiac, or peripheral vascular disease;

• Severe chronic heart disease. If the patient has resectable disease but declines surgery after consulting with a thoracic surgeon, he/she will be considered eligible.

1. The patient must have measurable disease.

2. Zubrod Performance Status 0-2;

3. Age ≥ 18;

4. Negative serum or urine pregnancy test within 72 hours prior to registration for women of childbearing potential;

5. Women of childbearing potential and male participants must agree to use a medically effective means of birth control, such as condom/diaphragm and spermicidal foam, intrauterine device (IUD), or prescription birth control pills, throughout their participation in the treatment phase of the study

6. The patient must provide study specific informed consent prior to study entry.

Exclusion Criteria:

1. Patients with T2 primary tumors > 5 cm or involving the central plural and/or structures of the mediastinum;

2. The primary tumor of any T-stage within or touching the zone of the proximal bronchial tree, defined as a volume 2 cm in all directions around the proximal bronchial tree (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);

3. Direct evidence of regional or distant metastases after appropriate staging studies, or synchronous primary malignancy or prior malignancy in the past 2 years except for invasive malignancy that has been treated definitively and the patient remains disease free for > 3 years with life expectancy of > 3 years or carcinoma in situ or early stage skin cancers that have been treated definitively;

4. Previous radiotherapy to the lung or mediastinum;

5. Previous chemotherapy for this lung or mediastinum tumor; chemotherapy for another invasive malignancy is permitted if it has been treated definitively and the patient has remained disease free for > 3 years.

6. Previous surgery for this lung or mediastinum tumor;

7. Plans for the patient to receive other concomitant antineoplastic therapy (including standard fractionated radiotherapy, chemotherapy, biological therapy, vaccine therapy, and surgery) while on this protocol except at disease progression;

8. Patients with active systemic, pulmonary, or pericardial infection;

9. Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo or fetus.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Auburn Radiation Oncology	Auburn	California	United States	95603
2	Alta Bates Summit Comprehensive Cancer Center	Berkeley	California	United States	94704
3	Radiation Oncology Centers - Cameron Park	Cameron Park	California	United States	95682
4	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
5	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
6	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
7	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
8	M.D. Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806
9	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
10	Community Cancer Center	Normal	Illinois	United States	61761
11	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois	United States	60068-1174
12	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
13	Parkview Regional Cancer Center at Parkview Health	Fort Wayne	Indiana	United States	46805
14	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
15	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
16	James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky	United States	40202
17	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
18	Great Lakes Cancer Institute at McLaren Regional Medical Center	Flint	Michigan	United States	48532
19	CCOP - Kansas City	Kansas City	Missouri	United States	64131
20	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
21	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
22	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
23	Stony Brook University Cancer Center	Stony Brook	New York	United States	11794-9446
24	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
25	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
26	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
27	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon	United States	97213-2967
28	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
29	Dale and Frances Hughes Cancer Center at Pocono Medical Center	East Stroudsburg	Pennsylvania	United States	18301
30	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
31	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
32	INOVA Alexandria Hospital	Alexandria	Virginia	United States	22304
33	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
34	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
35	Veterans Affairs Medical Center - Milwaukee	Milwaukee	Wisconsin	United States	53295
36	Grand River Regional Cancer Centre at Grand River Hospital	Kitchener	Ontario	Canada	N2G 1G3
37	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
38	McGill Cancer Centre at McGill University	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

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

Investigators

• Study Chair: Gregory Videtic, MD, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00960999
• Other Study ID Numbers: RTOG-0915; CDR0000652101
• First Posted: Aug 18, 2009
• Last Update Posted: Mar 4, 2020
• Last Verified: Feb 1, 2020

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

Study Results

Participant Flow

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Period Title: Overall Study
STARTED	47	47
Eligible	39	45
Started Protocol Treatment	39	45
Primary Endpoint Population	38	38
Peak SUV at 8 Weeks	3	11
Peak SUV at 1 Year	4	7
Normalized SUV at 8 Weeks	3	9
Normalized SUV at 1 Year	4	7
FEV1 by Best Response	26	33
DLCO by Best Response	23	28
COMPLETED	39	45
NOT COMPLETED	8	2

Baseline Characteristics

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)	Total
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy	Total of all reporting groups
Overall Participants	39	45	84
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	75	75	75
Sex: Female, Male (Count of Participants)
Female	23 59%	23 51.1%	46 54.8%
Male	16 41%	22 48.9%	38 45.2%

Outcome Measures

1. Primary Outcome

Title	Counts of ≥ Grade 3 Adverse Events (AE) Graded by CTCAE v4 (Common Terminology Criteria for Adverse Events) That Are Definitely, Probably, or Possibly Related to Treatment (DPPRT)
Description	Number of patients with ≥ grade 3 AE occurring within 1 year of treatment (TRT) start and reported as DPPRT among this subset of CTCAE v4: pericardial effusion, pericarditis, restrictive cardiomyopathy, dysphagia, esophagitis, esophageal fistula/obstruction/perforation/stenosis/ulcer/hemorrhage, rib fracture, brachial plexopathy, recurrent laryngeal nerve palsy, myelitis, atelectasis, bronchopulmonary/mediastinal/pleural/tracheal hemorrhage, bronchial/pulmonary/bronchopleural/tracheal fistula, hypoxia, bronchial/tracheal obstruction, pleural effusion, pneumonitis, pulmonary fibrosis, skin ulceration (thorax only), FEV1 (Forced Expiratory Volume) or FVC (forced vital capacity) decline, or grade 5 related to TRT. Each arm is considered independently. For each arm, >=5 of 38 analyzable subjects experiencing a grade ≥ 3 AE during the 1st year following TRT start would determine the respective TRT excessively toxic. For each arm this design provides 88% power with a 0.10 type I error rate.
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

First 38 eligible patients per arm who started treatment

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	38	38
Number [participants]	3 7.7%	6 13.3%

2. Secondary Outcome

Title	1-year Primary Tumor Control Rate
Description	Primary tumor control is defined as the lack of primary tumor failure. Primary tumor failure is defined as the development of in-field or marginal failure. Primary tumor control time is defined as time from randomization to the the date of primary tumor failure, last known follow-up (censored), or death without failure (competing risk). Primary tumor control rates are estimated using the cumulative incidence method.
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	39	45
Number (95% Confidence Interval) [percentage of participants]	97.1 249%	97.6 216.9%

3. Secondary Outcome

Title	1-year Overall Survival Rate
Description	Overall survival time is defined as time from registration/randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method.
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	39	45
Number (95% Confidence Interval) [percentage of participants]	85.4 219%	91.1 202.4%

4. Secondary Outcome

Title	1-year Disease-free Survival Rate
Description	Disease-free survival is defined as being alive without experiencing in-field, marginal, involved lobe, regional or metastatic failure, development of a second primary, or death due to any cause. Disease-free survival time is defined as time from randomization to the the date of first failure or last known follow-up (censored). Disease-free survival rates are estimated using the Kaplan-Meier method.
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	39	45
Number (95% Confidence Interval) [percentage of participants]	78.0 200%	84.4 187.6%

5. Secondary Outcome

Title	Change in Peak Standardized Uptake Value (SUV) at 12 Weeks Post-radiotherapy
Description	Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. Peak SUV is an average SUV computed within a fixed-size volume of interest (VOI), most often containing (and not necessarily centered on) the hottest pixel value. Peak SUV was measured from whole-body FDG-PET (fluorodeoxyglucose - positron emission tomography) scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV.
Time Frame	Baseline and 12 weeks post-radiotherapy

Outcome Measure Data

Analysis Population Description

eligible patients with PET SUV data at at baseline and 12 weeks

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	3	11
Median (Full Range) [SUV]	2.8	1.4

6. Secondary Outcome

Title	Change in Peak Standardized Uptake Value (SUV) at One Year Post-radiotherapy
Description	Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. Peak SUV is an average SUV computed within a fixed-size volume of interest (VOI), most often containing (and not necessarily centered on) the hottest pixel value. Peak SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.
Time Frame	Baseline and one year

Outcome Measure Data

Analysis Population Description

eligible patients with PET SUV data at at baseline and one year

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	4	7
Median (Full Range) [SUV]	-0.8	3.6

7. Secondary Outcome

Title	Change in Normalized Standardized Uptake Value (SUV) at 12 Weeks
Description	Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Normalized SUV = peak SUV of regions of interest / mean SUV of the aortic arch. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

eligible patients with normalized SUV at baseline and 12 weeks

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	3	9
Median (Full Range) [SUV]	3.9	1.4

8. Secondary Outcome

Title	Change in Normalized Standardized Uptake Value (SUV) at One Year
Description	Standardized uptake value (SUV) describes the level of biologic activity in a particular spot compared to activity elsewhere in the body. An SUV reading of 1 is considered normal cellular activity, with higher values indicating increased activity. SUV was measured from whole-body FDG-PET scans that were required at baseline and requested (not required) at 12 weeks and 12 months post-radiotherapy. Normalized SUV = peak SUV of regions of interest / mean SUV of the aortic arch. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased SUV. SUV does not have a unit.
Time Frame	Baseline and one year

Outcome Measure Data

Analysis Population Description

eligible patients with normalized SUV at baseline and one year

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	4	7
Median (Full Range) [SUV]	1.0	3.9

9. Secondary Outcome

Title	Change in Percentage of Expected Forced Expiratory Volume in 1 Second (FEV1) by Best Observed Tumor Response at 6 Months Post-radiotherapy [Forced Expiratory Volume in 1 Second (FEV1)]
Description	Forced expiratory volume (FEV1), a measure of pulmonary function, was reported as percentage of the value that would be expected for the normal general population of the same height, age, and sex. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased FEV1. Best observed tumor response was evaluated using the Revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 (http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).
Time Frame	From start of treatment to 6 months post-radiotherapy

Outcome Measure Data

Analysis Population Description

Eligible patients with FEV1 at baseline and 6 months, and with best tumor response of complete response, partial response, or stable disease

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	26	33
Complete Response	-2.0 (10.8)	-12.4 (28.0)
Partial Response	-0.7 (7.9)	5.9 (9.0)
Stable Disease	-0.5 (7.6)	-6.1 (11.0)

10. Secondary Outcome

Title	Change in Percentage of Expected Carbon Monoxide Diffusing Capacity (DLCO) by Best Observed Tumor Response at 6 Months Post-radiotherapy
Description	Carbon monoxide diffusing capacity (DLCO), a measure of pulmonary function, was reported as percentage of the value that would be expected for the normal general population of the same height, age, and sex. Change from baseline is calculated by subtracting the follow-up value from the baseline value. A positive change from baseline indicates decreased DLCO. Best observed tumor response was evaluated using the Revised Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 (http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).
Time Frame	From start of treatment to 6 months post-radiotherapy

Outcome Measure Data

Analysis Population Description

Eligible patients with DLCO at baseline and 6 months, and with best tumor response of complete response, partial response, or stable disease

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	23	28
Complete Response	0.1 (23.1)	-2.7 (20.5)
Partial Response	4.1 (9.8)	2.6 (9.1)
Stable Disease	12.7 (10.7)	-28.0 (30.6)

11. Secondary Outcome

Title	Association Between Biomarkers and Primary Tumor Control Rate
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	0	0

12. Secondary Outcome

Title	Association Between Biomarkers and Grade 2+ Radiation Pneumonitis
Time Frame	From start of treatment to 1 year

Outcome Measure Data

Analysis Population Description

The protocol did not provide sufficient detail to meet National Cancer Institute requirements for release of specimens from the NRG tissue bank for the protocol-specified analysis, therefore no assays were performed and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Arm/Group Title	Single-fraction SBRT (34 Gy)	Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	Eligible participants who started protocol treatment. Participants experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Single-fraction SBRT (34 Gy)		Multiple-fraction SBRT (48 Gy)
Arm/Group Description	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy		Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy
All Cause Mortality
	Single-fraction SBRT (34 Gy)		Multiple-fraction SBRT (48 Gy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Single-fraction SBRT (34 Gy)		Multiple-fraction SBRT (48 Gy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/39 (7.7%)		3/45 (6.7%)
Cardiac disorders
Heart failure	1/39 (2.6%)		0/45 (0%)
General disorders
Death NOS	1/39 (2.6%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/39 (2.6%)		0/45 (0%)
Dyspnea	0/39 (0%)		1/45 (2.2%)
Hypoxia	0/39 (0%)		1/45 (2.2%)
Respiratory failure	0/39 (0%)		1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Single-fraction SBRT (34 Gy)		Multiple-fraction SBRT (48 Gy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/39 (69.2%)		30/45 (66.7%)
Cardiac disorders
Pericardial effusion	2/39 (5.1%)		1/45 (2.2%)
Gastrointestinal disorders
Dysphagia	1/39 (2.6%)		3/45 (6.7%)
Nausea	0/39 (0%)		3/45 (6.7%)
Vomiting	0/39 (0%)		4/45 (8.9%)
General disorders
Fatigue	7/39 (17.9%)		10/45 (22.2%)
Infections and infestations
Lung infection	2/39 (5.1%)		1/45 (2.2%)
Injury, poisoning and procedural complications
Fracture	7/39 (17.9%)		2/45 (4.4%)
Investigations
Carbon monoxide diffusing capacity decreased	5/39 (12.8%)		1/45 (2.2%)
Forced expiratory volume decreased	3/39 (7.7%)		2/45 (4.4%)
Vital capacity abnormal	2/39 (5.1%)		1/45 (2.2%)
Weight loss	0/39 (0%)		3/45 (6.7%)
Metabolism and nutrition disorders
Anorexia	1/39 (2.6%)		3/45 (6.7%)
Musculoskeletal and connective tissue disorders
Chest wall pain	8/39 (20.5%)		2/45 (4.4%)
Musculoskeletal and connective tissue disorder - Other	2/39 (5.1%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	7/39 (17.9%)		6/45 (13.3%)
Cough	4/39 (10.3%)		7/45 (15.6%)
Dyspnea	7/39 (17.9%)		5/45 (11.1%)
Hypoxia	1/39 (2.6%)		6/45 (13.3%)
Pleural effusion	10/39 (25.6%)		12/45 (26.7%)
Pneumonitis	6/39 (15.4%)		8/45 (17.8%)
Productive cough	2/39 (5.1%)		2/45 (4.4%)
Pulmonary fibrosis	9/39 (23.1%)		7/45 (15.6%)
Wheezing	2/39 (5.1%)		0/45 (0%)

Limitations/Caveats

[Not Specified]

More Information

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.