Surgery, Gemcitabine, Cisplatin, and Radiation Therapy in Treating Patients With Stage II or 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 gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well surgery followed by gemcitabine, cisplatin, and radiation therapy works in treating patients with stage II or stage III non-small cell lung cancer.

Detailed Description
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OBJECTIVES: To assess overall survival and progression-free survival of patients with stage II-IIIB non-small cell lung cancer undergoing surgical resection, followed by adjuvant chemotherapy comprising gemcitabine and cisplatin, and radiotherapy. To assess the toxicities of this regimen in these patients. To evaluate the mRNA expression of enzymes (i.e., excision repair cross complementing protein, ribonucleotide reductase, and cytidine/deoxycytidine deaminase and kinase), which may be important in regulating the cytotoxicity of gemcitabine and cisplatin in patient tumors. To correlate mRNA levels with progression-free survival of patients treated with this regimen. To assess BCL2, P53, and HER2-neu expression by IHC and correlation with progression-free survival. OUTLINE: Patients undergo surgical resection of their tumor and mediastinal lymph node dissection. Patients with complete surgical eradication of their disease or pathologic evidence of microscopic residual disease proceed to adjuvant chemotherapy. Within approximately 60 days after surgical resection, patients receive adjuvant chemotherapy comprising gemcitabine IV over 30 minutes on days 1 and 8 and cisplatin IV over 1 hour on day 8. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 130-144 days after surgery, patients undergo radiotherapy once daily, five days a week, for approximately 6 weeks. Tumor tissue specimens are obtained at the time of surgical resection for pharmacodynamic and biomarker correlative studies. Specimens are examined by reverse transcriptase-polymerase chain reaction to measure mRNA expression of target oncogenes (i.e., DNA repair gene ERCC-1 and M2 subunit of the DNA repair gene ribonucleotide reductase) and enzymes (i.e., cytidine/deoxycytidine deaminase and kinase). Resected specimens are also assessed by IHC for the expression of BCL2, P53, and HER2-neu genes. After completion of study therapy, patients are followed every 6 months for 5 years and annually thereafter.

Official Title
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Multimodality Therapy for Stages II and III Non-Small Cell Lung Cancer: Surgical Resection Followed by Sequential Administration of Gemcitabine Plus Cisplatin Chemotherapy and Radiation Therapy

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: gemcitabine hydrochloride
* Genetic: gene expression analysis
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: immunohistochemistry staining method
* Procedure: adjuvant therapy
* Procedure: conventional surgery
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed single, primary bronchogenic non-small cell lung cancer meeting the following subtypes: Adenocarcinoma (no bronchioalveolar cell histology) Squamous cell carcinoma Large cell carcinoma Meeting the following staging criteria: Stage IIB (T2, N1, M0, or T3, N0, M0) Stage IIIA (T1-3, N2, M0 or T3, N1, M0) Stage IIIB (Any T, N3, M0 or T4, Any N, M0) No more than 1 parenchymal lesion in the same lung or in both lungs No tumor involving the superior sulcus (e.g., Pancoast tumor) Patients must undergo evaluation by the involved thoracic surgeon, medical oncologist, and radiation oncologist prior to registration No evidence of metastatic disease Biopsy or aspiration cytology required to confirm the benign diagnosis of CT or MRI abnormalities that potentially represent metastatic disease Biopsy required if all noninvasive tests are indeterminant PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Absolute granulocyte count ≥ 1,500/μL Platelet count ≥ 100,000/μL Bilirubin ≤ 3 times upper limit of normal (ULN) SGOT and SGPT ≤ 3 times ULN Creatinine clearance > 50 mL/min No prior malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, ductal or lobular carcinoma in situ of the breast, or any other cancer from which the patient has been disease-free for 5 years Not pregnant or nursing Negative pregnancy test Fertile patients must use effective protection No significant hearing loss or patient unwilling to accept potential for further hearing loss No uncontrolled medical illness by appropriate medical therapy (e.g., myocardial infarction within the past 3 months or liver cirrhosis) No symptomatic peripheral neuropathy affecting activities of daily living PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy for lung cancer

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine + Cisplatin<br>Surgical resection followed by (within 60 days) by chemotherapy (Gemcitabine at 1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21 day cycle and Cisplatin at 75 mg/m2 IV over 1 hour on day 8 of a 21 day cycle) followed by radiation therapy (treated using linear accelerator with photon beam energy of 6-21 MV) upon completion of 3 cycles of chemotherapy. | Drug: cisplatin<br> <br> Drug: gemcitabine hydrochloride<br> <br> Genetic: gene expression analysis<br> <br> Genetic: reverse transcriptase-polymerase chain reaction<br> <br> Other: immunohistochemistry staining method<br> <br> Procedure: adjuvant therapy<br> <br> Procedure: conventional surgery<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 |
| --- | --- | --- |
| Two-year Progression-free Survival From the Date of Surgery | Estimated using the product-limit method of Kaplan and Meier. Progression defined as a 25% increase or an increase of 10 cm2 (whichever is smaller) in the sum of the products of all measurable lesions over the smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening of any evaluable disease, or reappearance of any lesion that had disappeared, or appearance of any new lesion/site, or failure to return for evaluation or death, or deteriorating condition (unless clearly unrelated to this cancer). | 2 years post-surgery | 

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