Preoperative Chemoradiotherapy vs. Chemotherapy Alone in NSCLC Patients

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as docetaxel and cisplatin, use 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 chemotherapy with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known if chemotherapy plus radiation therapy is more effective than chemotherapy alone before surgery in treating non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying docetaxel and cisplatin with or without radiation therapy to see how well they work when given before surgery in treating patients with stage IIIA non-small cell lung cancer that has spread to lymph nodes in the chest.

Detailed Description
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The main objective of this trial is to compare feasibility and efficacy of sequential neoadjuvant chemoradiotherapy with 44 Gy concomitant boost to neoadjuvant chemotherapy alone. Secondary objectives are to assess the value of PET in predicting pathological response and eventfree survival in stage IIIA NSCLC, and a health economic analysis of the two regimens. Further to compare the amount of serum DNA in patients with stage IIIA, pN2 NSCLC before chemotherapy, before surgery and at the second follow-up visit (i.e. four months after surgery or treatment failure for patients who can not be operated) in patients randomized into the trial SAKK 16/00 and to correlate the DNA variation with tumor response, remission duration and overall survival. OUTLINE: This is a prospective randomized phase III trial. Patients are stratified according to mediastinal bulk (5 cm or more vs less than 5 cm), weight loss in the past 6 months (5% or more vs less than 5%), and participating center. Patients are randomized to 1 of 2 treatment arms.

Official Title
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Preoperative Chemoradiotherapy vs. Chemotherapy Alone in Non-small Cell Lung Cancer (NSCLC) Patients With Mediastinal Lymph Node Metastases (Stage IIIA, N2): A Randomized Prospective Phase III Trial

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: Chemotherapy
* Radiation: Radiotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed non-small cell lung cancer Squamous, adenosquamous, large cell, or poorly differentiated Stage IIIA (T1-3, N2, M0) N2 disease confirmed by 1 of the following: Mediastinoscopy Bronchoscopy with fine-needle aspiration or esophagoscopy All N3 lymph nodes must be negative by positron-emission tomography (PET) AND CT scan (< 1 cm in the largest diameter) PET scan Both the primary tumor and at least 1 N2 lymph node must be positive in PET scan At least 1 of the PET scan positive N2 lymph nodes is positive in the CT scan (> 1 cm in the largest diameter) All N3 lymph nodes negative in PET scan PATIENT CHARACTERISTICS: Age: 18 to 75 Performance status: WHO 0-1 Life expectancy: Not specified Hematopoietic: WBC at least 4,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin normal AST/ALT no greater than 1.5 times upper limit of normal (ULN) Alkaline phosphatase no greater than 2.5 times ULN Renal: Creatinine clearance greater than 60 mL/min Cardiovascular: Cardiac function normal No unstable cardiac disease requiring treatment No congestive heart failure No angina pectoris even if medically controlled No significant arrhythmia No myocardial infarction in the past 3 months Pulmonary: Lung function appropriate Neurologic: No history of significant neurologic or psychiatric disorders No psychotic disorders No dementia No seizures Other: No other prior or concurrent malignancies except nonmelanoma skin cancer, adequately treated carcinoma in situ of the cervix, or any other neoplastic disease with a disease-free interval ≥ 5 years No active uncontrolled infection No uncontrolled diabetes mellitus No gastric ulcers No pre-existing peripheral neuropathy greater than grade 1 No contraindications to corticosteroids No other serious underlying medical condition that would preclude study participation No socioeconomic or geographic condition that would preclude study participation Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior cytostatic chemotherapy Endocrine therapy: No concurrent prednisone except for treatment of acute hypersensitivity reactions or chronic low-dose treatment initiated more than 6 months prior to study entry (i.e., no greater than 20 mg methylprednisolone or equivalent) Radiotherapy: No prior radiotherapy to chest Surgery: Not specified Other: At least 30 days since participation in another clinical study No other concurrent experimental drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Neoadjuvant Chemoradiotherapy + Chemotherapy + Surgery | Drug: Chemotherapy<br>* Docetaxel (Taxotere®) 85 mg/m2 1 hour iv infusion d1 Cisplatin 100 mg/m2 1 hour iv infusion d1 Schedule: 3 cycles repeated every 21 days<br>Radiation: Radiotherapy<br>* Radiotherapy (3 weeks after last chemotherapy administration) 44 Gy in 22 fractions concomitant boost technique in 3 weeks<br>Procedure: Surgery<br>* 3-4 weeks after termination of radiotherapy<br>|
| Active Comparator: Arm B<br>Neoadjuvant Chemotherapy + Surgery | Drug: Chemotherapy<br>* Docetaxel (Taxotere®) 85 mg/m2 1 hour iv infusion d1 Cisplatin 100 mg/m2 1 hour iv infusion d1 Schedule: 3 cycles repeated every 21 days<br>Procedure: Surgery<br>* 3-4 weeks after termination of radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Time from randomization to relapse/progression/second tumor/death, whichever occurs first (for all randomized patients). If no event is observed, the patients will be censored at the last time they were known to be alive. | 1 month after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative mortality assessed | All deaths occurring within 30 days of the thoracic surgery to remove the primary tumor | 1 month after surgery | 
| Toxicity (hematological, renal and neurological toxicities, nausea and vomiting, weight changes as well as esophageal toxicities) | Assessed according to the NCIC-CTG Expanded Common Toxicity Criteria grading. Special attention shall be given to hematological, renal and neurological toxicities, nausea and vomiting, weight changes as well as esophageal toxicities. | During treatment | 
| Complete resection rate after surgery | Assessed according to the NCIC-CTG Expanded Common Toxicity Criteria grading. | 1 month after surgery | 
| Objective response rate measured after completion of chemoradiotherapy | Response rate will be evaluated according to the WHO response criteria TNM classification after surgery. | 43 days | 
| Operability | Patients who are able to undergo radical resection of their lung cancer after neoadjuvant therapy, as assessed by the thoracic surgeon. | 1 month after chemo | 
| Overall survival | Calculated from randomization to the date of death from any cause. Patients not experiencing an event will be censored at the last time they were known to be alive. | Life-long follow-up until death of patient (up to 30 years) | 
| Failure pattern | Defined as location of first tumor progression or relapse. Failure can be local relapse (area of primary tumor or mediastinum), distant relapse (all others) or the combination thereof. | Life-long follow-up until death of patient (up to 30 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, adenosquamous cell lung cancer