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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lung Cancer

Intervention / Treatment
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* Radiation: Single-fraction stereotactic body radiation therapy (SBRT)
* Radiation: Multiple-fraction stereotactic body radiation therapy (SBRT)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-fraction SBRT (34 Gy)<br>Single-fraction stereotactic body radiation therapy (SBRT) of 34 Gy | Radiation: Single-fraction stereotactic body radiation therapy (SBRT)<br>* 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%.<br>|
| Experimental: Multiple-fraction SBRT (48 Gy)<br>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)<br>* 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%.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | From start of treatment to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-year Primary Tumor Control Rate | 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. | From start of treatment to 1 year | 
| 1-year Overall Survival Rate | 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. | From start of treatment to 1 year | 
| 1-year Disease-free Survival Rate | 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. | From start of treatment to 1 year | 
| Change in Peak Standardized Uptake Value (SUV) at 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. | Baseline and 12 weeks post-radiotherapy | 
| Change in Peak Standardized Uptake Value (SUV) at One Year 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 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. | Baseline and one year | 
| Change in Normalized Standardized Uptake Value (SUV) at 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. | Baseline and 12 weeks | 
| Change in Normalized Standardized Uptake Value (SUV) at 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. | Baseline and one year | 
| 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)] | 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). | From start of treatment to 6 months post-radiotherapy | 
| Change in Percentage of Expected Carbon Monoxide Diffusing Capacity (DLCO) by Best Observed Tumor Response at 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). | From start of treatment to 6 months post-radiotherapy | 
| Association Between Biomarkers and Primary Tumor Control Rate |  | From start of treatment to 1 year | 
| Association Between Biomarkers and Grade 2+ Radiation Pneumonitis |  | From start of treatment to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma of the lung, large cell lung cancer