This is a single institution Phase II study for patients with unresectable Stage IIIA and IIIB non-small cell lung cancer. The treatment started with 2 cycles of gemcitabine and carboplatin followed by concurrent chemotherapy with radiation. The chemoradiation included using paclitaxel and carboplatin with daily thoracic radiation to a total dose of 74 Gy. Response rate was determined following the chemotherapy with gemcitabine and carboplatin and evaluated again after the chemoradiation. Treatment toxicities were also assessed.

In this trial we adopted the approach of using both induction and concurrent chemotherapy together with Thoracic Radiation Therapy (TRT) planned conformally to a tumor dose of 74 Gy. Substitution of gemcitabine for paclitaxel in the induction chemotherapy allowed us to evaluate the impact of RRM1 expression on the activity of this agent. The expression of Ribonucleotide Reductase, M1 Subunit (RRM1) was evaluated prior to initiation of therapy, following induction chemotherapy but prior to concurrent chemoradiation, and following completion of all therapy by CT-guided core needle biopsies. This is a single institution phase II clinical trial, of induction treatment with gemcitabine and carboplatin followed by concurrent chemoradiation using paclitaxel and carboplatin and daily thoracic radiation to a total dose of 74 Gy for patients with unresectable Stage IIIA and IIIB NSCLC. The specific clinical objectives of this study are as follows: To determine the response rate (both CT scan and PET scan assessment) to two cycles of induction chemotherapy with gemcitabine and carboplatin; To determine the response rate (both CT scan and PET scan assessment) to concurrent thoracic radiation and weekly paclitaxel and carboplatin; To evaluate the patterns of local and distant failure for patients treated with induction chemotherapy followed by concurrent chemoradiation according to this regimen; To estimate the median, 1 year, and overall survival; To assess acute and long term toxicities of treatment.

Eligibility Criteria:

• Histologically confirmed unresectable non-small cell carcinoma of the lung (adenocarcinoma, squamous cell carcinoma or anaplastic large cell carcinoma). See below for TNM eligibility. Mediastinoscopy or thoracoscopy in patients with mediastinal lymph node enlargement of < 2 cm on CT scans of suspicious on PET scan to confirm suspected involvement. These staging procedures are not mandatory for patients with obvious nodal involvement (2.0 cm or greater). Staging system: The New International Staging System for lung cancer (Clifton F. Mountain, 1997) will be followed. The following stages will be eligible:
• Patients with stage IIIa disease will be eligible if it is felt that they are not candidates for possible resection following neo-adjuvant therapy (unresectable T3N1 or T1-3 primary tumors with metastasis limited to single station ipsilateral mediastinal lymph nodes). Patients with stage IIIb disease without significant* pleural effusion will be eligible. This includes patients with metastases to contralateral mediastinal or supraclavicular nodes.
• Patients without significant pleural effusion will constitute those in whom 1) it is seen on CT scan only or 2) does not reaccumulate after one thoracentesis and is cytologically negative.
• No evidence of distant metastasis.
• Patients must have measurable disease by the Recist Evaluation Criteria in Solid Tumors (RECIST) criteria. Baseline measurements/evaluations must be obtained within 4 weeks prior to registration.
• Patients must not have small cell carcinoma as part of the histological specimen (World Health Organization [WHO] classification 22.40)
• Performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 at time of registration.
• Patients with preexisting clinically significant peripheral neuropathy are ineligible.
• Weight loss of ≤ 5% in the preceding three months
• No prior systemic chemotherapy or thoracic radiotherapy.
• Patients must have adequate bone marrow reserve as determined by the following laboratory values: Obtained within 14 days prior to registration.
• White blood cell count 4000/ul or greater and granulocyte count of 1500/ul or greater
• Platelet count of 100,000/ul or greater
• Hemoglobin of 10 gms/dl or greater.
• Adequate renal and liver function as determined by the following laboratory values: Obtained within 14 days prior to registration.
• Serum creatinine < 1.5 mg/dl or creatinine clearance greater than 50 cc/min
• Bilirubin less than 1.5 mg/dl
• SGOT less than 1.5 times normal
• No history of a prior or concomitant malignancy in the past five years except for surgically cured basal cell carcinoma of the skin or carcinoma in situ of the cervix.
• No concomitant life threatening or uncontrolled serious medical illness such as cardiac arrhythmia, end stage congestive heart failure, liver disease with significant hepatic insufficiency, organic brain syndrome.
• Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception.
• Age greater than or equal to 18 years
• Written, informed consent must be obtained prior to registration.

Ranging from 2 weeks up to 4 years, 9 months