Stereotactic Body 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: Stereotactic body radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue. PURPOSE: This phase I/II trial is studying the side effects and best dose of stereotactic body radiation therapy and to see how well it works in treating patients with stage I non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose (MTD) of stereotactic body radiotherapy (SBRT) in medically inoperable patients with centrally located stage I non-small cell lung cancer. (Phase I) To estimate the local control rate of SBRT at the MTD in these patients. (Phase II) Secondary To estimate the rates of adverse events (other than dose-limiting toxicity) of ≥ grade 3 that is possibly, probably, or definitely related to treatment and that occurs within 1 year after the start of SBRT in these patients. To estimate the rates of late adverse events (i.e., occurs > 1 year after the start of SBRT) in these patients. To estimate the local control and progression-free and overall survival rates in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients undergo stereotactic body radiotherapy every 2 days over 1½-2 weeks [total of 5 fractions (FX)] in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months for 2 years, then every 6 months for 2 years, then annually.

Official Title
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Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non-Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients

Conditions
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Lung Cancer

Intervention / Treatment
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* Radiation: SBRT 40.0 Gy
* Radiation: SBRT 42.5 Gy
* Radiation: SBRT 45.0 Gy
* Radiation: SBRT 47.5 Gy
* Radiation: SBRT 50.0 Gy
* Radiation: SBRT 52.5 Gy
* Radiation: SBRT 55.0 Gy
* Radiation: SBRT 57.5 Gy
* Radiation: SBRT 60.0 Gy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) Stage T1-2, N0, M0 disease Tumor size ≤ 5 cm Tumor must be within or touching the zone of the proximal bronchial tree, defined as a volume of 2 cm in all directions around the proximal bronchial tree (i.e., 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) OR immediately adjacent to the mediastinal or pericardial pleura (PTV touching the pleura) Hilar or mediastinal lymph nodes ≤ 1 cm AND no abnormal hilar or mediastinal uptake on positron emission tomography (PET) scan are considered N0 Mediastinal lymph node sampling by any technique is allowed but not required Patients with > 1 cm hilar or mediastinal lymph nodes on CT scan or abnormal PET scan (including suspicious but nondiagnostic uptake) are eligible provided directed tissue biopsies of all abnormally identified areas are negative for cancer Tumor deemed technically resectable, in the opinion of an experienced thoracic cancer surgeon, with a reasonable possibility of obtaining a gross total resection with negative margins, defined as a potentially curative resection (PCR) Patient deemed medically inoperable due to severe underlying physiological medical problems that would prohibit a PCR, including any of the following: Baseline forced expiratory volume at 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-stage organ damage Severe cerebral, cardiac, or peripheral vascular disease Severe chronic heart disease Measurable disease as documented by CT scan or whole-body PET scan within the past 8 weeks Patients with lesions that cannot be visualized by CT scan are not eligible Pleural effusion allowed provided it is deemed too small to tap under CT guidance and is not evident on chest x-ray Pleural effusion that appears on chest x-ray is allowed only after thoracotomy or other invasive procedure PATIENT CHARACTERISTICS: Zubrod performance status 0-2 Not pregnant Negative pregnancy test Fertile patients must use effective contraception during and for ≥ 60 days after completion of study therapy No other invasive malignancy within the past 2 years except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix Prior lung cancer allowed provided the patient has been disease-free for ≥ 2 years PRIOR CONCURRENT THERAPY: No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields No prior chemotherapy for the study cancer No other concurrent local therapy (including standard-fractionated radiotherapy and/or surgery) or systemic therapy (including standard chemotherapy or biologic targeted agents) specifically intended as treatment for study cancer Local or systemic therapy at the time of disease progression allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Level 1: 8.0 Gy/FX<br>SBRT 40.0 Gy | Radiation: SBRT 40.0 Gy<br>* SBRT delivered in 5 fractions of 8.0 Gy/fraction over 1.5 to 2 weeks for a total of 40.0 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 2: 8.5 Gy/FX<br>SBRT 42.5 Gy | Radiation: SBRT 42.5 Gy<br>* SBRT delivered in 5 fractions of 8.5 Gy/fraction over 1.5 to 2 weeks for a total of 42.5 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 3: 9.0 Gy/FX<br>SBRT 45.0 Gy | Radiation: SBRT 45.0 Gy<br>* SBRT delivered in 5 fractions of 9.0 Gy/fraction over 1.5 to 2 weeks for a total of 45.0 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 4: 9.5 Gy/FX<br>SBRT 47.5 Gy | Radiation: SBRT 47.5 Gy<br>* SBRT delivered in 5 fractions of 9.5 Gy/fraction over 1.5 to 2 weeks for a total of 47.5 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 5: 10.0 Gy/FX<br>SBRT 50.0 Gy | Radiation: SBRT 50.0 Gy<br>* SBRT delivered in 5 fractions of 10.0 Gy/fraction over 1.5 to 2 weeks for a total of 50.0 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 6: 10.5 Gy/FX<br>SBRT 52.5 Gy | Radiation: SBRT 52.5 Gy<br>* SBRT delivered in 5 fractions of 10.5 Gy/fraction over 1.5 to 2 weeks for a total of 52.5 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 7: 11.0 Gy/FX<br>SBRT 55.0 Gy | Radiation: SBRT 55.0 Gy<br>* SBRT delivered in 5 fractions of 11.0 Gy/fraction over 1.5 to 2 weeks for a total of 55.0 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 8: 11.5 Gy/FX<br>SBRT 57.5 Gy | Radiation: SBRT 57.5 Gy<br>* SBRT delivered in 5 fractions of 11.5 Gy/fraction over 1.5 to 2 weeks for a total of 57.5 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|
| Experimental: Level 9: 12.0 Gy/FX<br>SBRT 60.0 Gy | Radiation: SBRT 60.0 Gy<br>* SBRT delivered in 5 fractions of 12.0 Gy/fraction over 1.5 to 2 weeks for a total of 60.0 Gy<br>* Other names: Stereotactic ablative radiotherapy (SABR);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Phase I) Maximum Tolerated Dose of Stereotactic Body Radiotherapy (SBRT) as Assessed by NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0 | Maximum tolerated dose (MTD) defined as dose most closely associated with a 20% probability of experiencing a toxicity <= 1 year from start of SBRT from following dose-limiting toxicities: Gr 3-5 Cardiac: Pericardial effusion, Pericarditis, Restrictive cardiomyopathy; Gr 4-5 GI: Dysphagia, Esophagitis, Esophageal fistula/obstruction/perforation/stenosis/ulcer/hemorrhage; Gr 3-5 Nervous System Disorders: Brachial plexopathy, Recurrent laryngeal nerve palsy, Myelitis; Gr 3-5 Respiratory: Atelectasis (gr 4-5 only), Bronchopulmonary/mediastinal/pleural/tracheal hemorrhage, Bronchial/pulmonary/bronchopleural/tracheal fistula, Hypoxia (provided gr 3 is worse than baseline), Bronchial/tracheal obstruction, Pleural effusion, Pneumonitis, Pulmonary fibrosis; Changes in Pulmonary Function Tests per SBRT Pulmonary Toxicity Scale, Gr 3-5: FEV1 decline, FVC decline; Any Gr 5 adverse event attributed to treatment. Dose level was determined by time-to-event continual reassessment method (TITE-CRM). | From start of SBRT to 1 year | 
| (Phase II) Primary Tumor Control Rate at the Maximum Tolerated Dose (MTD) | Primary tumor control is defined as the absence of primary tumor failure. Primary tumor failure (PTF) refers to the primary treated tumor after protocol therapy and corresponds to meeting following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. Marginal Failures (MF) and Involved Lobe Failures were also counted as PTF. The cumulative incidence method was used to estimate primary tumor control rate. The 90% confidence interval for local control was calculated using bootstrapping methods. Per the protocol, only the MTD dose level was to be analyzed. However, due to the quantity of patients enrolled on Dose Level 8 as well as safety concerns, Dose Level 8 was analyzed also. | From start of SBRT to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival is defined as the state of being alive without progression of disease. A failure is the first of the following: local progression, regional progression, distant metastasis, or death. Progression-free survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested. | From randomization to date of death, failure (local, regional or distant) or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study. | 
| Overall Survival | An event for overall survival is death due to any cause. Overall survival was assessed at the maximum tolerated dose using the Kaplan-Meier method to estimate the 2-year survival rate. Arms were not compared/tested. | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study. | 
| Local Progression | Local progression is the same as primary tumor failure (PTF) which refers to the primary treated tumor after protocol therapy and corresponds to meeting both of the following two criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) The measurable tumor with criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should be biopsied confirming viable carcinoma. For outcome analysis, Marginal Failures (MF) and Involved Lobe Failures will also be counted as PTF. Local progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested. | From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months. | 
| Nodal Progression | Regional nodal progression is defined as appearance after protocol therapy of measurable tumor within lymph nodes along the natural lymphatic drainage typical for the location of the treated primary disease only with dimension of at least 1.0 cm on imaging studies (preferably CT scans) within the lung, bronchial hilum, or the mediastinum. Regional nodal progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested. | From randomization to date of death, regional failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study. | 
| Distant Metastases | Distant metastases is defined as the appearance after protocol therapy of cancer deposits characteristic of metastatic dissemination from non-small cell lung cancer. Distant metastases progression was assessed using the cumulative incidence method to estimate the 2-year failure rate. Arms were not compared/tested. | From randomization to date of death, distant failure or last follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study. | 
| Rate of Toxicity ≥ Grade 3 (Other Than DLT) Within One Year as Assessed by NCI CTCAE v4.0 | Rate of patients developing any treatment-related toxicity during the first year following the start of SBRT that is not among the types considered as a dose-limiting toxicity. | From start of SBRT until 1 year. | 
| Rate of Late Toxicity (i.e., Occurs > 1 Year After the Start of SBRT) of ≥ Grade 3 as Assessed by NCI CTCAE v4.0 | Percentage of patients who developed any treatment-related toxicity after the first year following the start of SBRT. | From start of treatment to end of follow-up. Analysis occurs after all patients have been potentially followed for 24 months, approximately 7.5 years from the start of the study. | 

 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