Pemetrexed and Radiation for Poor-Risk Stage III Non-Small Cell Lung Cancer

Inclusion Criteria:

* Histological or cytological proof of Non Small Cell Lung Cancer (NSCLC)
* Measurable or non-measurable disease per RECIST as evaluated by imaging within 28 days prior to registration for protocol therapy
* Unresectable Stage IIIA or IIIB disease as evaluated by imaging within 28 days prior to registration for protocol therapy
* Weight loss of greater than 10% in the preceding six months prior to registration for protocol therapy.
* Serum albumin \< 0.85 x institutional lower limit of normal
* Able and willing to interrupt non-steroidal anti-inflammatory agents for 2 days before (5 days for long acting agents such as piroxicam), the day of, and 2 days following administration of pemetrexed
* Lung V20 \< 35% within 14 days prior to registration for protocol therapy, as planned by the radiation oncologist
* Mean lung dose \< 20 Gy within 14 days prior to registration for protocol therapy, as planned by the radiation oncologist
* Written informed consent and HIPAA authorization for release of personal health information
* Age ≥ 18 years
* Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time of consent until at least 90 days following completion of study treatment.
* Females of childbearing potential must have a negative pregnancy test within 7 days prior to registration for protocol therapy. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.

Exclusion Criteria:

* Patients with malignant pleural effusions are not eligible. The only exception is a patient with a pleural effusion visible only on CT scan (and not visible on CXR) OR deemed too small to tap.• No CNS metastases. All patients must undergo a CT scan/MRI of the brain within 28 days prior to registration for protocol therapy to exclude brain metastasis.
* No prior chemotherapy, adjuvant therapy or radiotherapy for lung cancer.
* No metastatic disease as determined by PET scan within 28 days prior to registration for protocol therapy.
* No active clinically serious infections as judged by the treating investigator (\> CTC v3, Grade 2) including known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
* No other active malignancies.
* No history of collagen vascular disease (CVD).
* No significant history of cardiac disease. Must not have unstable angina (anginal symptoms at rest).
* No history of psychiatric illness/social situations that would limit compliance with study requirements.
* Females must not be breastfeeding.