Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients Who Are Undergoing Surgery for Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving paclitaxel and carboplatin together with radiation therapy before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any tumor cells remaining after surgery. PURPOSE: This phase II trial is studying how well giving paclitaxel and carboplatin together with radiation therapy works in treating patients who are undergoing surgery for stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Determine the mediastinal node clearance rate in patients with stage IIIA or IIIB non-small cell lung cancer treated with neoadjuvant induction chemoradiotherapy comprising paclitaxel, carboplatin, and high-dose radiotherapy followed by surgical resection for patients found to be resectable and consolidative chemotherapy comprising paclitaxel and carboplatin. Determine the rate of complete pathological response in patients treated with this regimen. Determine the feasibility of surgical resection after neoadjuvant induction chemoradiotherapy in these patients. Determine disease-free and overall survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients.

Official Title
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A Phase II Trial Of Neoadjuvant Therapy With Concurrent Chemotherapy And High Dose Radiotherapy Followed By Surgical Resection And Consolidative Therapy For Locally Advanced Non-Small Cell Lung Carcinoma

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: Induction Carboplatin
* Drug: Induction Paclitaxel
* Procedure: Resection
* Drug: Consolidation Carboplatin
* Radiation: Radiation Therapy
* Drug: Consolidation Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Stage IIIA (T1-3 N2) or Stage IIIB (N3, excluding supraclavicular involvement) non-small cell lung cancer documented by biopsy or cytology (Pancoast tumors are eligible if pathologic evidence of mediastinal nodal disease is present); Disease must be measurable; Mediastinal lymph nodes must be proven positive by pathologic review. All patients must undergo mediastinoscopy, thoracoscopy, Chamberlain procedure, or transbronchial needle aspirate to evaluate extent of nodal involvement. Any lymph node assessed by mediastinoscopy and found to be positive will be defined as N2 disease; Patients ≥ 18 years of age; Life expectancy ≥ 6 months; Zubrod performance status 0- 1 (See Appendix II); Pretreatment laboratory values must be as follows: White blood cell count (WBC) count: ≥ 3,000/mm^3; Absolute granulocyte count: ≥ 1,500/mm^3; Platelets: ≥ 100,000/mm3; Total bilirubin: ≤ 1.5 x institutional upper limit of normal (ULN); Serum creatinine: ≤ 1.5 x institutional ULN; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN; serum albumin: ≥ 3.0 g/dL Baseline forced expiratory volume (FEV1) must be at least 2.0 liters; if less than 2.0 then V/Q scan is required and projected post-operative FEV1 must be > 800 cc based on the following formula using the quantitative Ventilation/perfusion (V/Q) scan: FEV1 = FEV1 x % perfusion to uninvolved lung from quantitative lung V/Q scan report. Patient evaluation and acceptance by thoracic surgery, medical oncology, and radiation oncology; patient must be a potential surgical candidate prior to the initiation of therapy; Women of childbearing potential and male participants must practice an effective method of contraception during the study; Pretreatment evaluations required for eligibility include: A complete medical history & physical examination to include Zubrod performance status, neurologic assessment, recent weight loss, usual weight, concurrent non-malignant disease and therapy; Location, type, and size of measurable lesion must be recorded prior to treatment; Complete blood count (CBC) with differential, platelet count, electrolytes, and Mg++ within 14 days prior to study entry; Twelve-channel serum multiple analysis (SMA-12): Total protein, Albumin, Calcium, Glucose, Blood urea nitrogen (BUN), Creatinine, Alkaline Phosphatase, Lactate dehydrogenase (LDH), Total Bilirubin, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) within 14 days prior to study entry; Women of childbearing potential must have a negative pre-study serum or urine pregnancy test within 14 days prior to study entry. Mediastinoscopy, thoracoscopy, Chamberlain procedure, or bronchoscopy with transbronchial needle aspirate to evaluate the extent of lymph node involvement; Computed tomography (CT) scan of the chest to include liver, and adrenal glands within 6 weeks prior to study entry; Positron emission tomography (PET) scan within 8 weeks prior to study entry. Any suspicious areas outside of the local regional disease requires documented evaluation of these findings to exclude metastatic disease; CT scan or magnetic resonance imaging (MRI) of the brain within 6 weeks prior to study entry; Electrocardiogram (EKG) and pulmonary function tests including forced vital capacity (FVC), FEV-1, and diffusing capacity of carbon monoxide (DLCO), within 8 weeks prior to study entry; V/Q scan, if applicable, within 8 weeks prior to study entry. Patients must sign a study-specific informed consent prior to study entry. Exclusion Criteria: Small cell lung cancer; distant metastatic disease; Evidence of clinical or radiographic supraclavicular lymph node involvement; Bronchioalveolar carcinoma with lobar or multilobar involvement; Unintentional weight loss > 5% within 6 months prior to study entry, or Zubrod performance status 2 or greater; Primary tumor location prevents delivery of 60 Gy and simultaneously limiting spinal cord dose to 48 Gy; Patients with malignant pleural effusion; Clinically evident superior vena cava syndrome; Prior systemic chemotherapy or radiation therapy to the thorax; Patients with known hypersensitivity to Cremophor EL; Patients receiving other investigational therapy; Pregnant or lactating women are ineligible, as treatment involves unforeseeable risks to the participant and to the embryo or fetus; Patients with an active serious infection or other serious underlying medical condition that would impair their ability to complete protocol treatment; Dementia or significantly altered mental status that would prohibit the understanding and/or giving of informed consent.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoradiation, Surgery, Chemotherapy<br>Induction paclitaxel(50 mg/m2 I.V. in a one-hour infusion) and induction carboplatin (AUC 2.0 I.V. in a thirty-minute infusion): 1x/week for 6 weeks. Concurrent radiation therapy (RT): 1.8 Gy/day, 5 fx/week, for a total of 50.4 Gy in 28 fractions plus a boost of 1.8 Gy/day, 5 fx/week, for a total of 10.8 Gy in 6 fractions. Followed by an assessment to determine whether patient will undergo a resection or not. Followed by consolidation paclitaxel (200 mg/m2 I.V. over three hours) and consolidation carboplatin (AUC 6.0 over one hour) q 21 days x 2. | Drug: Induction Carboplatin<br> <br> Drug: Induction Paclitaxel<br> <br> Procedure: Resection<br> <br> Drug: Consolidation Carboplatin<br> <br> Radiation: Radiation Therapy<br> <br> Drug: Consolidation Paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mediastinal Nodal Clearance Rate | If at least 12 of the first 21 evaluable patients and at least 27 of the the first 45 evaluable patients have mediastinal nodal clearance (MNC), then a conclusion of a 70% MNC rate (compared to 50%) is made using Simon's two-stage design with 90% power and 10% type I error. | At completion of concurrent chemotherapy and radiation therapy, up to 14 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Complete Pathological Response After Concurrent Chemotherapy and Radiation Therapy | Complete pathologic response is defined as complete resection achieved and no evidence of viable tumor in the entire resection specimen. | At time of surgery (16-18 weeks) | 
| Percentage of Patients With Major Surgical Morbidities Within 30 Days of Surgery | The surgical morbidities occurring within 30 days following resection were assessed and graded using the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. A major morbidity is considered a grade 3 or higher of any of the following: pneumonitis, infection, atelectasis, chest tube drainage/bronchial stump leak, pneumothorax, chylothorax, cardiac ischemia/infarction, pulmonary thrombosis/embolism, supraventricular atrial arrhythmia, ventricular arrhythmia, post-operative hemorrhage, pulmonary/upper respiratory fistula, pleural effusion, or death. | From 0 to 30 days following surgery (surgery occurs within 16-18 weeks after registration) | 
| Percentage of Patients Able to Undergo Surgical Resection |  | At time of surgery (16-18 weeks) | 
| Distribution of R0, R1, and R2 Resections After Chemotherapy | An R0 resection is defined as a complete resection of all disease with negative margins and the highest lymph node resected negative for residual tumor. An R1 resection is defined as a complete resection of all disease with pathology of positive margins, pathologic evidence of tumor cells in the highest lymph node resected in the mediastinum, or extracapsular nodal spread. An R2 resection is defined as gross residual disease left behind after surgical resection. | At time of surgery (16-18 weeks) | 
| Overall Survival at Two Years | Overall survival time is defined as time from registration to the date of death from any cause. Overall survival rate is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From registration to two years | 
| Progression-free Survival at Two Years | Progression is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. An event for progression-free survival is the first occurrence of progression or death due to any cause. Progression-free survival time is defined as the time from study entry to the the date progression or death, or last known follow-up (censored) if neither progression nor death occurred. Progression-free survival rate is estimated using the Kaplan-Meier method. | From registration to two years | 
| Distribution of Highest Grade Adverse Event | The number of patients whose highest grade adverse event (AE) reported was 3, 4, or 5 was calculated. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Number of patients with highest grade of 3, 4, and 5 are presented. | From start of treatment to end of follow-up, a maximum of 64.3 months | 

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