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

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

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.

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.

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.

4. 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.

5. 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.

6. The patient must have measurable disease.

7. Zubrod Performance Status 0-2;

8. Age ≥ 18;

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

10. 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

11. 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.