Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy may kill more tumor cells. It is not yet known if chemotherapy plus radiation therapy is more effective with or without surgery for lung cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of combining cisplatin, etoposide, and radiation therapy with or without surgery in treating patients who have stage IIIA non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Compare the progression-free survival, median (2-year) survival, and long-term (5-year) survival in patients with newly diagnosed, stage IIIA (N2) non-small cell lung cancer treated with radiotherapy concurrently with cisplatin and etoposide with or without surgical resection. Secondary Compare the patterns of local and distant failure in patients treated with these regimens. Determine the relationship of tobacco use, alcohol use, and diet with toxicity of these regimens and outcome in both men and women. OUTLINE: This is a randomized, multicenter study. Patients are stratified by contralateral mediastinal sampling or biopsy (yes vs no), tumor stage (T1 vs T2 vs T3), and performance status (70-80% vs 90-100%). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive induction with cisplatin IV over 1 hour on days 1 and 8 and etoposide IV over 1 hour on days 1-5. Treatment continues every 4 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Beginning within 24 hours of the first dose of chemotherapy, patients undergo induction radiotherapy 5 days a week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients without local progression or distant metastases at 2-4 weeks after completion of course 2 undergo resection approximately 3-5 weeks after completion of course 2. All visible, accessible bronchopulmonary, hilar, and mediastinal lymph nodes are excised. The choice of surgical procedure (thoracotomy, lobectomy, or pneumonectomy with en bloc resection of tumor extending into the parietal pleura, chest wall, pericardium, or diaphragm) is at the discretion of the surgeon. Patients who undergo resection receive 2 additional courses of chemotherapy alone beginning 4-6 weeks postoperatively. Patients with unresectable disease or who are medically unfit for or refuse resection receive 2 additional courses of chemotherapy alone beginning immediately after completion of course 2. Arm II: Patients undergo induction chemoradiotherapy as in arm I but do not undergo resection. Patients without local progression or distant metastases within 1 week before anticipated completion of induction radiotherapy receive 2 additional courses of chemotherapy beginning immediately after completion of course 2. Patients without local or distant progression after completion of course 4 undergo boost radiotherapy for 8 days. Patients are followed every 2 months for 1 year, every 3 months for 2 years, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 510 patients will be accrued for this study within 4.9 years.

Official Title
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A Phase III Comparison Between Concurrent Chemotherapy Plus Radiotherapy and Concurrent Chemotherapy Plus Radiotherapy Followed by Surgical Resection for Stage IIIA (N2) Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: etoposide
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically proven newly diagnosed, stage IIIA (T1-3, N2) non-small cell lung cancer Eligible subtypes: Adenocarcinoma Large cell carcinoma Squamous cell carcinoma Nonlobar and nondiffuse bronchoalveolar cell carcinoma Measurable or evaluable disease on chest x-ray and/or contrast CT scan Contrast thoracic CT required to complete staging Single primary bronchogenic tumor (no more than 1 parenchymal lung lesion) Pleural effusions allowed if 1 of the following conditions is met: Negative cytology on thoracentesis if effusions present before mediastinoscopy or exploratory thoracotomy Effusion seen on CT scan but not on chest x-ray and deemed too small to tap under CT or ultrasound guidance Positive ipsilateral mediastinal node(s) with or without positive ipsilateral hilar nodes Mediastinal nodes separate from primary lesion on CT scan or surgical exploration Histologic or cytologic proof of N2 disease by thoracotomy, mediastinoscopy, mediastinotomy, Chamberlain procedure, Wang needle, or fine needle aspiration under bronchoscopic or CT guidance Nodal biopsy or aspiration waived if all of the following conditions are met: Paralyzed left true vocal cord documented by bronchoscopy or indirect laryngoscopy Nodes visible in Level 5 region on CT scan Distinct primary lesion separate from nodes on CT scan All mediastinal nodal involvement mapped (positive or negative) No positive nodes in contralateral mediastinum (supraclavicular areas and higher) and neck Mediastinoscopy, mediastinotomy, Chamberlain procedure, or thoracotomy required for nodes larger than 1 cm on contrast CT scan Surgery waived if nodes negative or no larger than 1 cm on CT scan Lymphadenopathy allowed if biopsy proof of a benign cause No metastases by contrast CT or MRI scan of the brain, bone scan, CT scan of the lungs to exclude other ipsilateral or contralateral parenchymal lesions, and contrast CT scan of the upper abdomen including entire liver and adrenals No hepatomegaly or splenomegaly by physical examination or CT scan unless documentation of a benign cause No pericardial effusion No superior vena cava syndrome No prior diagnosis of lung cancer PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 90-100% (70-80% allowed if albumin at least 0.85 times lower limit of normal and weight loss no greater than 10% within 3 months before diagnosis) Hematopoietic: White blood cell count (WBC) at least 4,000/mm^3 OR Granulocyte count at least 2,000/mm^3 Platelet count normal Hemoglobin at least 10.0 g/dL (less than 8.5 g/dL allowed if no marrow involvement with tumor) Hepatic: See Performance status Bilirubin no greater than 1.5 times upper limit of normal (ULN)* Serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) no greater than 1.5 times ULN* NOTE: * Unless documentation of a benign cause Renal: Creatinine clearance at least 50 mL/min Cardiovascular: No myocardial infarction within the past 3 months No active angina No unstable arrhythmia No congestive heart failure Pulmonary: Forced expiratory volume at one second (FEV1) at least 2.0 liters OR Predicted postresection FEV1 at least 800 mL based on quantitative V/Q scan Diffusion capacity of lung for carbon monoxide (DLCO) at least 50% predicted (corrected for hemoglobin) if pneumonectomy planned or likely after induction chemotherapy Other: No clinically significant hearing loss unless willing to accept the potential of further loss No symptomatic peripheral neuropathy No peptic ulcer disease under active treatment No other medical illness not controllable by appropriate medical therapy No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent colony-stimulating factors Chemotherapy: No prior chemotherapy for lung cancer No concurrent chemotherapy for another condition (such as arthritis) Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy for lung cancer Surgery: See Disease Characteristics No prior resection of primary tumor

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: RT + chemotherapy followed by surgery + chemotherapy<br>Induction radiation therapy (RT) + concurrent induction chemotherapy followed by surgery and additional chemotherapy | Drug: cisplatin<br> <br> Drug: etoposide<br> <br> Procedure: conventional surgery<br> <br> Radiation: radiation therapy<br> <br> |
| Active Comparator: RT + chemotherapy followed by chemotherapy + RT<br>Induction RT + concurrent induction chemotherapy followed by additional chemotherapy + RT | Drug: cisplatin<br> <br> Drug: etoposide<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median overall survival |  | From randomization to date of death or last follow-up. Analysis occurs after patients have been potentially followed for 2.5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free survival |  | From randomization to date of death or last follow-up. Analysis occurs after patients have been potentially followed for 2.5 years. | 
| Patterns of local and distant failure |  | From randomization to date of failure (local, regional or distant progression). Analysis occurs after patients have been potentially followed for 2.5 years. | 

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