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

Phase 2

Completed

Conditions: Lung Cancer

Interventions: Radiation: Single-fraction stereotactic body radiation therapy (SBRT)
Radiation: Multiple-fraction stereotactic body radiation therapy (SBRT)

Registration Number: NCT00960999

Lead Sponsor: Radiation Therapy Oncology Group

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 94

Inclusion Criteria

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).
Stage T1, N0, M0 or T2 (≤ 5 cm), N0, M0, (AJCC Staging, 6th Ed.), based upon #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.
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.
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.
The patient must have measurable disease.
Zubrod Performance Status 0-2;
Age ≥ 18;
Negative serum or urine pregnancy test within 72 hours prior to registration for women of childbearing potential;
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
The patient must provide study specific informed consent prior to study entry.

Exclusion Criteria

Patients with T2 primary tumors > 5 cm or involving the central plural and/or structures of the mediastinum;
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);
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;
Previous radiotherapy to the lung or mediastinum;
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.
Previous surgery for this lung or mediastinum tumor;
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;
Patients with active systemic, pulmonary, or pericardial infection;
Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo or fetus.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Single-fraction SBRT (34 Gy)	Single-fraction stereotactic body radiation therapy (SBRT)	Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy
Multiple-fraction SBRT (48 Gy)	Multiple-fraction stereotactic body radiation therapy (SBRT)	Multiple-fraction stereotactic body radiation therapy (SBRT) given in four daily 12 Gy fractions for a total dose of 48 Gy

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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).
Association Between Biomarkers and Grade 2+ Radiation Pneumonitis	From start of treatment to 1 year
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.
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.
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.
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).
Association Between Biomarkers and Primary Tumor Control Rate	From start of treatment to 1 year

Trial Locations

Locations (38): Geisinger Cancer Institute at Geisinger Health
🇺🇸
Danville, Pennsylvania, United States
Parkview Regional Cancer Center at Parkview Health
🇺🇸
Fort Wayne, Indiana, United States
Dale and Frances Hughes Cancer Center at Pocono Medical Center
🇺🇸
East Stroudsburg, Pennsylvania, United States
Baptist Cancer Institute - Jacksonville
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Jacksonville, Florida, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center
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Rochester, New York, United States
Great Lakes Cancer Institute at McLaren Regional Medical Center
🇺🇸
Flint, Michigan, United States
Grand River Regional Cancer Centre at Grand River Hospital
🇨🇦
Kitchener, Ontario, Canada
Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
OSF St. Francis Medical Center
🇺🇸
Peoria, Illinois, United States
Memorial Hospital of South Bend
🇺🇸
South Bend, Indiana, United States
Stony Brook University Cancer Center
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Stony Brook, New York, United States
Community Cancer Center
🇺🇸
Normal, Illinois, United States
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Robert H. Lurie Comprehensive Cancer Center at Northwestern University
🇺🇸
Chicago, Illinois, United States
M. D. Anderson Cancer Center at University of Texas
🇺🇸
Houston, Texas, United States
Case Comprehensive Cancer Center
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Taussig Cancer Center
🇺🇸
Cleveland, Ohio, United States
Auburn Radiation Oncology
🇺🇸
Auburn, California, United States
Alta Bates Summit Comprehensive Cancer Center
🇺🇸
Berkeley, California, United States
Radiation Oncology Centers - Cameron Park
🇺🇸
Cameron Park, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center
🇺🇸
San Francisco, California, United States
Mercy Cancer Center at Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
Advocate Lutheran General Cancer Care Center
🇺🇸
Park Ridge, Illinois, United States
Flower Hospital Cancer Center
🇺🇸
Sylvania, Ohio, United States
INOVA Alexandria Hospital
🇺🇸
Alexandria, Virginia, United States
McGill Cancer Centre at McGill University
🇨🇦
Montreal, Quebec, Canada
Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Lucille P. Markey Cancer Center at University of Kentucky
🇺🇸
Lexington, Kentucky, United States
University of Colorado Cancer Center at UC Health Sciences Center
🇺🇸
Aurora, Colorado, United States
M.D. Anderson Cancer Center at Orlando
🇺🇸
Orlando, Florida, United States
CCOP - Kansas City
🇺🇸
Kansas City, Missouri, United States
Josephine Ford Cancer Center at Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
James Graham Brown Cancer Center at University of Louisville
🇺🇸
Louisville, Kentucky, United States
Virginia Commonwealth University Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Medical College of Wisconsin Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
Providence Cancer Center at Providence Portland Medical Center
🇺🇸
Portland, Oregon, United States
Veterans Affairs Medical Center - Milwaukee
🇺🇸
Milwaukee, Wisconsin, United States