Surgery With or Without Internal Radiation Therapy Compared With Stereotactic Body Radiation Therapy in Treating Patients With High-Risk Stage I Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Surgery with or without internal radiation therapy may be an effective treatment for non-small cell lung cancer. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Stereotactic body radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether stereotactic body radiation therapy is more effective than surgery with or without internal radiation therapy in treating non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying how well surgery with or without internal radiation therapy works compared with stereotactic body radiation therapy in treating patients with high-risk stage IA or stage IB non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary To ascertain whether patients treated by stereotactic body radiation therapy (SBRT) have a 3-year overall survival (OS) rate that is no more than 10% less than patients treated with sublobar resection (SR). Secondary To compare loco-regional recurrence-free survival between study arms. To compare disease-free survival between study arms. To compare grade 3 or higher specific adverse event profiles between study arms at 1, 3, 6, and 12 months post-therapy. To compare pulmonary function between patients treated with SBRT and patients treated with SR. To compare the adverse events and pulmonary function tests (PFTs) in each arm for patients with low or high Charlson comorbidity index scores, including a test interaction between Charlson comorbidity index scores (low vs high) and treatment arm. Tertiary To compare the quality-adjusted survival between the SBRT and SR treatments in terms of time to death (primary) and time until recurrence (secondary). To examine whether pre-operative and post-operative clinically significant deficits in previously identified prognostic PRO domains (overall quality of life [QOL], fatigue, anxiety, and dyspnea) are associated with shorter patient survival in this patient population and to compare the relative effectiveness of each treatment (SBRT and SR). To contribute to an ACOSOG bank of normative data in order to improve short/long-term outcomes of cancer patients by identifying patients experiencing clinically significant deficits in patient-reported outcomes and the relationship to genetic variables. To explore whether blood-based biomarkers, including osteopontins, will be able to predict which patients will be at high risk for recurrence by treatment with either SBRT or SR. (exploratory) To explore whether blood-based biomarkers, including TGF-β1, will be able to predict which patients will be at high risk for pulmonary complications by treatment with either SBRT or SR. (exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to planned brachytherapy (yes vs no) and ECOG performance status (0 vs 1 vs 2). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo sublobar resection comprising either a wedge resection or anatomical segmentectomy with or without intraoperative brachytherapy* comprising an iodine I 125 implant at the resection margin. Arm II: Patients undergo 3 fractions of stereotactic body radiation therapy at 2-8 days apart. NOTE: *Patients may receive brachytherapy at the discretion of treating physician. Patients may undergo blood sample collection at baseline and periodically during study for correlative studies. Tumor tissue samples may also be collected from patients who undergo resection. Patients complete the Lung Cancer Symptom Scale (LCSS), the Linear Analogue Self-Assessment (LASA), and the UCDS Shortness of Breath quality-of-life questionnaires at baseline and periodically during study and follow-up. After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, every 6 months for 1 year, and then yearly for 2 years.

Official Title
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A Randomized Phase III Study of Sublobar Resection (+/- Brachytherapy) Versus Stereotactic Body Radiation Therapy in High Risk Patients With Stage I Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Lung Cancer

Intervention / Treatment
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* Procedure: therapeutic conventional surgery
* Radiation: iodine I 125
* Radiation: stereotactic body radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Lung nodule suspicious for non-small cell lung cancer (NSCLC) Biopsy confirmation is strongly recommended but not required; if biopsy is attempted and non-diagnostic, if the patient refuses biopsy, or if the risk of biopsy is considered too high, patients may be enrolled if the mass is suspicious for NSCLC based on two or more of the following criteria: Positive smoking history Absence of benign calcifications within suspicious nodule Activity on PET greater than normal tissue Evidence of growth compared to previous imaging Presence of spiculation Tumor ≤ 4 cm maximum diameter, clinical stage IA or selected IB (i.e., with visceral pleural involvement) by PET/CT scan of the chest and upper abdomen performed within 60 days prior to registration All clinically suspicious mediastinal N1, N2, or N3 lymph nodes (> 1 cm short-axis dimension on CT scan and/or positive on PET scan) confirmed negative for involvement with NSCLC by one of the following methods: mediastinoscopy, anterior mediastinotomy, endoscopic and/or endobronchial ultrasonography (EUS/EBUS)-guided needle aspiration, CT-guided, or video-assisted thoracoscopic or open lymph node biopsy Tumor verified by a thoracic surgeon to be in a location that will permit sublobar resection Tumor located peripherally within the lung, defined as not touching any surface within 2 cm of the proximal bronchial tree in all directions Patients with non-peripheral (central) tumors are NOT eligible No evidence of distant metastases PATIENT CHARACTERISTICS: ECOG performance status (PS) 0, 1, or 2 Patient at high-risk for surgery by meeting a minimum of one major criteria or two minor criteria as described below: Major criteria FEV1 ≤ 50% predicted DLCO ≤ 50% predicted Minor criteria Age ≥ 75 years FEV1 51-60% predicted DLCO 51-60% predicted Pulmonary hypertension (defined as a pulmonary artery systolic pressure greater than 40 mm Hg) as estimated by echocardiography or right heart catheterization Poor left ventricular function (defined as an ejection fraction of 40% or less) Resting or exercise arterial pO2 ≤ 55 mm Hg or SpO2 ≤ 88% pCO2 > 45 mm Hg Modified Medical Research Council (MMRC) Dyspnea Scale ≥ 3 Not pregnant or nursing Negative urine or serum pregnancy test Fertile patients must use effective contraception No prior invasive malignancy, unless disease-free for ≥ 3 years prior to registration (except non-melanoma skin cancer, in-situ cancers). PRIOR CONCURRENT THERAPY: No prior intra-thoracic radiotherapy Prior radiotherapy as part of treatment for head and neck, breast, or other non-thoracic cancer is permitted Prior chemotherapy or surgical resection for the lung cancer being treated on this protocol is NOT permitted

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 |
| --- | --- |
| Active Comparator: Arm I (SR+Brachytherapy)<br>Patients undergo sublobar resection comprising either a wedge resection or anatomical segmentectomy with or without intraoperative brachytherapy comprising an iodine I 125 implant at the resection margin. | Procedure: therapeutic conventional surgery<br>* Undergo surgery<br>Radiation: iodine I 125<br>* Undergo seed implant radiotherapy<br>|
| Experimental: Arm II (SBRT)<br>Patients undergo 3 fractions of stereotactic body radiation therapy at 2-8 days apart. | Radiation: stereotactic body radiation therapy<br>* Undergo radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Overall Survival (OS) Rate | Overall survival is defined as the time from randomization until death from any cause. | Up to 3 years post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loco-regional Recurrence-free Survival | Loco-regional recurrence is defined as recurrence within the same lobe or hilum (N1 nodes), or within 2 cm of the staple line or within 2 cm of the PTV after treatment effects such as scarring have subsided. | Up to 5 years post-randomization | 
| Adverse Event Profiles at 1 Month Post-therapy | Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. | 1 month post-therapy | 
| Adverse Event Profiles at 3 Months Post-therapy | Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. | 3 months post-therapy | 
| Adverse Event Profiles at 12 Months Post-therapy | Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death. | 12 months post-therapy | 
| Disease-free Survival | Disease free survival is defined as the time from randomization until documented disease recurrence or death, whichever occurs first. Patient who are disease free and alive at the time of analysis will be censored at the time of their last follow up. | Up to 5 years post-randomization | 
| Pulmonary Function Test Values | Pulmonary function test values include forced expiratory volume 1 (FEV1), carbon monoxide diffusion (DLCO) and forced vital capacity (FVC). | Up to 12 months post-therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IA non-small cell lung cancer, stage IB non-small cell lung cancer