This partially randomized phase I/II trial studies the side effects and best dose of image-guided, intensity-modulated photon or proton beam radiation therapy and to see how well they work in treating patients with stage II-IIIB non-small cell lung cancer. This trial is testing a new way of delivering radiation dose when only the tumor receives dose escalation while the surrounding normal structure is kept at standard level. Photon beam radiation therapy is a type of radiation therapy that uses x-rays or gamma rays that come from a special machine called a linear accelerator (linac). The radiation dose is delivered at the surface of the body and goes into the tumor and through the body. Proton beam radiation therapy is a type of radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. Both methods are designed to give a higher than standard dose of treatment to the tumor and may reduce the amount of radiation damage to healthy tissue near a tumor.

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of image-guided intensity-modulated photon (IMRT) and proton therapy (IMPT) both with simultaneous integrated boost (SIB) dose escalation to the SIBVi (internal SIB volume; defined as the gross tumor volume with consideration of respiratory motion plus setup uncertainty margin) for patients with stage II/IIIB non-small cell lung cancer (NSCLC) receiving concurrent standard chemotherapy and proton irradiation. (Phase I) II. Assess and compare survival free of grade III treatment related toxicity and local progression-free survival from day 1 of concurrent chemoradiation for stage II-IIIB NSCLC patients treated with image-guided robustly-optimized IMPT versus (vs.) IMRT, both delivered with simultaneous integrated boost (SIB). (Phase II)

SECONDARY OBJECTIVES:

I. Determine treatment-related acute and late toxicity. II. Correlate changes in standardized uptake values (SUV) on positron emission tomography (PET) and study endpoints (toxicity, tumor response, local control).

III. Correlate changes in peripheral blood biomarkers (genes, micro-ribonucleic acid [RNA], proteins) and the study endpoints.

IV. Estimate progression-free and overall survival. V. Document and compare symptom burden before starting chemoradiation, weekly during treatment, bi-weekly from end of treatment until first follow up, and at each follow-up visit thereafter by using the MD Anderson Symptom Inventory - Plus (MDASI-Plus) and European Quality of Life Instrument-5 dimensions (EQ-5D).

VI. Perform cost effectiveness between IMPT and IMRT both with SIB treatment. VII. Correlate imaged response, clinical response, blood biomarkers and symptom burdens to dose distribution patterns.

OUTLINE: This is a phase I, dose-escalation study followed by a randomized phase II study.

PHASE I: Patients undergo image-guided IMRT with SIB or IMPT with SIB once daily (QD) 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo image-guided IMRT SIB QD 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo image-guided IMPT SIB QD 5 days a week for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-8 weeks, every 3-4 months for 3 years, every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

• Pathologically proven diagnosis of unresected stage II-IIIB, or recurrent after surgical resection or stereotactic body radiation therapy (SBRT) non-small cell lung cancer
• Suitability for concurrent chemoradiation therapy per treating physician's assessment
• Karnofsky performance status (KPS) score >= 70
• Weight loss < 15% in the 3 months before diagnosis
• Prior receipt of induction chemotherapy followed by referral for concurrent chemoradiation is allowed
• Adequate lung function indicated by forced expiratory volume at 1 second (FEV1) >= 1 L is required
• The primary tumor and/or regional lymph nodes must be evaluable radiographically
• The gross target volume (GTV) is suitable for motion management using 4 dimensional computed tomography (4D CT), internal target volume (ITV), or respiratory gating; in addition, the target coverage and normal tissue constraints must be met as specified in protocol accounting for the respiratory motion of anatomy as a whole (not just the tumor)
• No prior radiation to the mediastinal structures
• Hemoglobin >= 9.0 g/dL
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Total bilirubin =< 1.5 times the upper limit of normal (ULN)
• Alanine and aspartate transaminases (ALT and AST) =< 2.5 times the ULN (=< 5 x ULN for patients with liver involvement)
• Creatinine =< 1.5 times ULN
• Patients must sign an informed consent indicating that they are aware of the investigational nature of the study in keeping with the policy of MD Anderson Cancer Center (MDACC)

Exclusion Criteria:

• Prior radiotherapy to any anatomic regions that would result in overlap of radiation dose distribution to critical structures (esophagus, heart, spinal cord, brachial plexus)
• T4 tumor with direct invasion of esophagus, spinal cord, major blood vessel, or heart
• Pregnancy
• Patients of childbearing potential must practice appropriate contraception
• Patient refusal