Platinum Doublet Chemotherapy and Proton Beam Radiation Therapy in Treating Patients with Stage II-III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

This randomized phase II trial studies how well platinum doublet chemotherapy and proton beam radiation therapy work in treating patients with stage II-III non-small cell lung cancer that cannot be removed by surgery (unresectable). Drugs used in chemotherapy, such as carboplatin, paclitaxel, etoposide, cisplatin, and pemetrexed work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Giving platinum doublet chemotherapy and proton beam radiation therapy may work better in treating patients with non-small cell lung cancer.

PRIMARY OBJECTIVE:

I. To compare the 1-year progression-free survival rates of 72 gray (Gy) and 60 Gy conventionally fractionated proton beam therapy (PBT) (as part of concurrent combined modality therapy).

SECONDARY OBJECTIVE:

I. To assess the adverse events, survival, quality of life, and patterns of failure (local regional, distant metastatic) associated with two dose levels of conventionally fractionated PBT (as part of concurrent combined modality therapy).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo lower dose proton beam radiation therapy daily for a total of 60 Gy for up to 30 weekdays in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive platinum based doublet chemotherapy consisting of low dose carboplatin and paclitaxel, standard etoposide cisplatin or carboplatin or standard pemetrexed with cisplatin or carboplatin weekly for up to 6 weeks at the discretion of the treating medical oncologist. Patients also undergo higher dose proton beam radiation therapy daily for a total of 72 Gy for up to 36 weekdays in the absence of disease progression or unacceptable toxicity.

All patients undergo computed tomography (CT) throughout the study, magnetic resonance imaging (MRI) or CT, and positron emission tomography (PET)/CT during screening.

After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

Eligibility Criteria:
Inclusion Criteria:

* Age \>= 18 years
* Histological confirmation of non-small cell lung cancer
* Forced expiratory volume in 1 second (FEV1) \> 1.0 L
* Unresectable or medically inoperable stage 2-3 non-small cell lung cancer (based on computed tomography/positron emission tomography \[CT/PET\], magnetic resonance imaging \[MRI\] or CT of brain, and physical exam);

  * Eligible if recurrence after surgery and now has the equivalent stage 2-3 non-small cell lung cancer (NSCLC) OR had sub totally resected stage 2-3 NSCLC
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Negative pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only
* White blood cell (WBC) \>= 3.0 x 10\^9/L
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
* Hemoglobin (Hgb) \>= 9 g/dl
* Platelets (plts) \> 100 x 10\^9/L
* Serum creatinine \< 1.5 x upper limits of normal (ULN)
* Serum bilirubin \< 1.5 x ULN
* Provide informed written consent
* Willing to return to enrolling institution for follow-up for a minimum of 1 year
* Ability to undergo potentially curative chemotherapy plus radiotherapy

Exclusion Criteria:

* Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  * Pregnant women
  * Nursing women
  * Men or women of childbearing potential who are unwilling to employ adequate contraception
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Weight loss of \> 10% in the past 3 months
* Distant metastases (M1 disease)
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, lupus, usual interstitial pneumonitis (UIP), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving any investigational agent, that would be considered as a treatment for the primary neoplasm
* Active second malignancy
* History of myocardial infarction =\< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* Received chemotherapy for lung cancer within 6 months of registration
* Previous chest radiotherapy that would overlap with the proton field