The investigators aim to evaluate the safety of delivering a one-time single fraction of Lattice Extreme Ablative Dose (LEAD) radiotherapy followed one day later by standard-dose, conventionally fractionated concurrent chemotherapy and radiation delivered over 6 weeks in patients with bulky stage III non-small cell lung cancer in the setting of a single-arm phase I clinical trial. The investigators hypothesize that the addition of a one-time single fraction of LEAD radiation is safe and feasible, and will not result in additional toxicity above that expected with standard-dose concurrent chemotherapy and radiation alone.

Paarticipants will receive a single fraction of LEAD radiation on day 1, followed one day later by conventionally fractionated concurrent chemoradiation consisting of 60 Gy of radiation delivered to involved sites of disease and a platinum doublet.

The investigational radiation treatment, a single fraction of LEAD radiation, is to be followed by conventionally fractionated radiation delivered concurrently with a standard chemotherapy regimen for stage III non-small cell lung cancer. The following day, patients will begin concurrent chemotherapy and radiation. Chemotherapy will be delivered under the management of the treating medical oncologist. Chemotherapy must be a platinum doublet. Carboplatin and cisplatin are both considered acceptable platinum agents. The use of cisplatin over carboplatin is strongly encouraged, unless the patient has a contraindication to cisplatin. The second agent will be at the discretion of the treating medical oncologist; in the current era, chemotherapy agents are tailored to each patient based on tumor histology, as well as comorbidities that dictate the tolerance of certain chemotherapeutic agents. Chemotherapy will be delivered concurrently throughout radiation therapy, beginning on day 2 of the treatment protocol and on the same day as the start of standard-dose radiation. Weekly regimens or regimens delivered every 3 weeks are acceptable. Additional cycles of consolidation chemotherapy are encouraged and will be given at the discretion of the treating medical oncologist.

Inclusion Criteria:

1. Patients must have histologically or cytologically documented stage III non-small cell lung cancer including squamous cell, adenocarcinoma, large cell carcinoma and poorly differentiated non-small cell lung cancer.

2. Patients must have a minimum of 4 cm of measurable disease in any one continuous dimension as seen on diagnostic CT scan.

3. Pulmonary function tests with forced expiratory volume in 1 second (FEV1) ≥1.45 liters/second.

4. Patients must be 21 years of age or older. There is no maximum age restriction.

5. Patients must have a Zubrod performance status of 0 or 1.

6. Patients must have normal organ and marrow function as defined below:

   • leukocyte > 3,000/:I
   • absolute neutrophil count >1,500/:I
   • platelets >100,000/:I
   • bilirubin within normal institutional limits
   • Aspartate transaminase (AST/SGOT)/Alanine transaminase (ALT/SGPT) 2.5 X institutional upper limit of normal
   • Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.

7. Patients must have weight loss ≤ 10% over the past three months.

8. Women of child-bearing potential and men will be asked to use adequate contraception.

9. Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients may not have had prior thoracic radiation at any time, or prior chemotherapy for the study cancer at any time.
2. Patients may not be receiving any other investigational agents for the study cancer.
3. Patients may not have evidence of brain metastases on baseline CT scan or MRI.
4. Patients may not have measurable gross disease in the thorax <4 cm in any one continuous dimension.
5. Patients may not have a cytologically positive pleural effusion.
6. Patients may not have a prior invasive malignancy (unless disease-free for at least 3 years).
7. Patients may not have had surgical resection of the present cancer.
8. Women who are pregnant or breastfeeding will be excluded.
9. Patients must not have any co-morbidity with life expectancy ≤ 6 months, or any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Patients must not have severe lung disease defined by a history of severe chronic obstructive pulmonary disease (COPD) requiring 3 or more hospitalizations over the past year, or history of interstitial pneumonitis.
11. Patients must not have any concurrent active malignancy.
12. Patients must not have evidence of metastatic disease.

A minimum sample size of 10 study participants was required for the analysis of most outcome measures. Minimum enrollment was not met, therefore, the data for these applicable outcome measures were not analyzed.