Hypofractionated Boost Before Chemoradiation for Patients With Stage II-III Non-small Cell Lung Cancer Unsuitable for Surgery

This phase II trial studies how well giving a hypofractionated boost to the primary tumor before standard chemotherapy and radiation therapy works in treating patients with stage II or III non-small cell lung cancer that cannot be removed by surgery. Advances in radiation oncology have allowed better radiation targeting which may be able to send x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin and etoposide, 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 x-rays to kill tumor cells. Giving more precise and targeted radiation before standard chemotherapy and radiation therapy may kill more tumor cells and prevent the cancer from coming back in the location in which it started.

PRIMARY OBJECTIVES:

I. To estimate the primary tumor control rate at 12 months.

SECONDARY OBJECTIVES:

I. To further establish safety and tolerability of this regimen. II. To estimate the rates of regional, distant control as well as progression-free survival and overall survival.

III. To evaluate the objective response rate (ORR) to this regimen. IV. To evaluate the response of tumors to stereotactic (high-dose) radiation using magnetic resonance tumor perfusion imaging modalities (magnetic resonance \[MR\]-dynamic contrast-enhanced \[DCE\]/perfusion weighted imaging \[PWI\], MR-diffusion, blood oxygenation level dependent \[BOLD\] sequences).

OUTLINE:

Patients will receive a hypofractionated boost to the primary tumor over 2 fractions (at least 40 hours apart) during week 1. Beginning week 2, patients receive cisplatin intravenously (IV) on days 8, 15, 36, and 43; and etoposide IV over 60 minutes on days 8-12 and 36-40. If carboplatin and paclitaxel is administered concurrently with radiotherapy, 2 cycles of carboplatin (AUC=6 mg/min/mL IV on day 1, 22) and paclitaxel (200 mg/m2 IV on day 1, 22) consolidation chemotherapy are required, to be administered starting 4-6 weeks after concurrent chemoradiation has ended. Each cycle is 21 days long. If cisplatin and etoposide is administered concurrently with radiotherapy, consolidation chemotherapy is not allowed. Patients also undergo standard conformal radiation therapy once daily (QD) 5 days a week for a total of 30 fractions. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

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

Eligibility Criteria:
Inclusion Criteria:

* All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) =\< grade 1 (except alopecia) at the time of enrollment
* Adequate baseline organ function obtained within 30 days of study registration
* Absolute neutrophil count \>= 1.5 x 10\^9/L
* Hemoglobin \>= 9 g/dL
* Platelets \>= 100 x 10\^9/L
* Total bilirubin =\< 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN
* Creatinine =\< 1.5 ULN AND
* Calculated creatinine \>= 50 mL/min (calculated by the Cockcroft-Gault formula) or
* 24-hour urine creatinine clearance \>= 50 mL/min
* Non-small cell lung cancer (NSCLC), histologically and/or cytologically proven
* Clinical American Joint Committee on Cancer (AJCC) stage (7th edition) IIA-IIIB NSCLC (T1-4N1-3M0)
* Patients must be considered unresectable or medically-inoperable
* Patients must have primary tumor =\< 6 cm as defined by CT largest axial dimension
* Within 60 days of registration: patients must have fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)-CT scan (or CT chest/abdomen/pelvis with IV contrast), and magnetic resonance imaging (MRI) brain with IV contrast (or CT scan of the brain with contrast); a non-contrast MRI scans of the chest/abdomen/pelvis or brain are permitted for workup if patient has allergy to CT contrast or renal insufficiency
* Within 30 days of registration: patients must have vital signs, history/physical examination, laboratory studies (complete blood count panel \[CBCP\] with differential, chemistries including liver function tests, creatinine clearance \[CrCl\] assessment, pregnancy test if needed within 14 days of registration)
* If a pleural effusion is present and visible on both CT scan AND chest x-ray, the investigator should exclude malignant disease by pleurocentesis to confirm cytologically-negative pleural fluid; if fluid is exudative or cytologically positive for tumor cells, patient is excluded
* Patients with effusions that are minimal (i.e. not visible on chest x-ray) and that are too small to safely tap are eligible.
* Life expectancy of at least 12 weeks in the opinion of investigator
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 30 days of registration
* Patients must have measurable primary tumor (undetectable NSCLC primary tumor is ineligible)
* Patients must be a minimum of 3 weeks from thoracotomy (if performed) and well-healed before starting treatment
* Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
* Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 14 days of registration; urine human gonadotropin (HCG) is an acceptable pregnancy assessment
* Nursing women may participate only if nursing is discontinued
* Women/men of reproductive potential must be counseled on contraception/abstinence while receiving the study treatment

Exclusion Criteria:

* Patients with contralateral hilar involvement (greater than 1.5 cm on short axis or positive on PET scan, or biopsy-proven)
* Documented or pathologically-proven metastatic disease
* Presence of nodules considered neoplastic in the same lobe or other ipsilateral lobe as the primary tumor (stage T3-4), unless the nodule can be encompassed in the stereotactic boost (gross tumor volume \[GTV\]boost) without exceeding a total GTVboost size of 6 cm as defined by CT largest axial dimension
* Presence of nodules considered neoplastic in contralateral lobes (M1a)
* Patients with history of pneumonectomy
* Prior cytotoxic chemotherapy or molecularly-targeted agents (e.g. erlotinib, crizotinib), unless \> 2 years prior
* Any concurrent malignancy other than non-melanoma skin cancer, non-invasive bladder cancer, or carcinoma in situ of the cervix; patients with a previous malignancy without evidence of disease for \>= 3 years will be allowed to enter the trial
* History of active connective tissue disease (scleroderma) or idiopathic pulmonary fibrosis
* History of previous radiation therapy which would result in overlapping radiation fields
* Uncontrolled neuropathy grade 2 or greater, regardless of cause
* Subjects who are breast-feeding and plan to continue breast-feeding during therapy, or have a positive pregnancy test will be excluded from the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Medical contraindication to MR imaging (e.g. pacemakers, metallic implants, aneurysm clips, known contrast allergy to Gadolinium contrast, pregnancy, nursing mothers, weight greater than 350 pounds) \[first 10 patients\]
* Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator; this could include severe, active co-morbidities such as:

  * Unstable angina and/or congestive heart failure requiring hospitalization within the last months
  * Transmural myocardial infarction within the last 6 months
  * Acquired immune deficiency syndrome (AIDS) based upon the current CDC definition; note, however, that HIV testing is not required for entry to protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved may be significantly immunosuppressive
  * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration
  * Hepatic insufficiency resulting in jaundice and/or coagulation defects