Inclusion Criteria:

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA

• Pathologically (histologically or cytologically) confirmed diagnosis of epithelioid or biphasic malignant pleural mesothelioma (MPM) within 90 days prior to Step 1 Registration -Imaging proof of clinical stage (American Joint Committee on Cancer [AJCC] 8th edition) I-IIIA MPM by PET/CT within 42 days prior to Step 1 Registration.
• MPM is amenable to resection by P/D as determined by a thoracic surgeon within 42 days prior to Step 1 Registration.
• History/physical examination within 42 days prior to Step 1 Registration.
• Karnofsky performance status ≥ 80 within 42 days prior to Step 1 Registration.
• Pulmonary function tests within 42 days prior to Step 1 Registration:
  • ≥ 40% predicted post-forced expiratory volume in 1 second (FEV1);
  • ≥ 40% predicted post-operative diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin [Hgb]).
• Leukocytes ≥ 3000 cells/mm^3 (within 30 days prior to Step 1 Registration).
• Absolute neutrophil count ≥ 1500 cells/mm^3 (within 30 days prior to Step 1 Registration).
• Platelets ≥ 100,000 cells/mm^3 (within 30 days prior to Step 1 Registration)..
• Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) (within 30 days prior to Step 1 Registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine a minotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 X ULN (within 30 days prior to Step 1 Registration).
• Glomerular filtration rate (GFR): ≥ 50 mL/min/1.73 m^2 (must be calculated using estimated creatinine clearance [CrCl] by the Cockcroft-Gault [C-G] equation [Nephron 1976;16:31-41]) (within 30 days prior to Step 1 Registration).
• Negative serum pregnancy test within 14 days of Step 1 Registration for pre-menopausal women of childbearing potential.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.
• EORTC QLQ-C30 and QLQ-LC13 within 42 days prior to Step 1 Registration.

PRIOR TO STEP 2 RANDOMIZATION INCLUSION CRITERIA

• Patients must have received at least 2 cycles of pemetrexed/platinum chemotherapy and undergone a pleurectomy/decortication with the goal of macroscopic complete resection following step 1 Registration.
• Karnofsky performance status ≥ 70 within 30 days prior to Step 2 Randomization.
• History/physical examination within 30 days prior to Step 2 Randomization.
• EORTC QLQ-C30 and QLQ-LC13 within 30 days prior to Step 2 Randomization.

Exclusion Criteria:

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA

• Pregnant or lactating women, or sexually active men or women not using effective contraception (risk for fetal defects from teratogenic chemotherapy and radiation therapy) within 14 days prior to Step 1 Registration
• Diagnosis of sarcomatoid mesothelioma.
• Severe, active co-morbidity defined as follows:
  • New York Heart Association (NYHA) class III or IV heart failure;
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are allowed;
  • Unstable angina requiring hospitalization and/or transmural myocardial infarction within the last 3 months;
  • Interstitial lung disease;
  • Hemodialysis or peritoneal dialysis;
  • Concurrent active malignancy (with the exception of current or prior non-melanomatous skin cancer or low-grade malignancies followed observantly for which treatment has not or does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen).
• If evidence of disease < 3 years, institution must consult with the principal investigator, Andreas Rimner, Doctor of Medicine (MD)
• Hepatic impairment defined by ChildPugh class (ChildPugh class B & C);
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy within 30 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured.
• For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 30 days prior to registration.
• Active tuberculosis.
• Patients on immunosuppressive therapy, for example history of organ or bone marrow transplant or chronic lymphocytic leukemia (CLL).
• CD4 count < 200 cells/microliter.
  • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count  200 cells/microliter within 30 days prior to registration.
  • Note also that HIV testing is not required for eligibility for this protocol.
• Prior nephrectomy on the contralateral side of MPM.
• Ipsilateral thoracic electronic implant; e.g., pacemaker, defibrillator, unless switched to the contralateral side prior to initiation of radiation therapy (RT).
• Prior thoracic radiation therapy (patients with prior thoracic RT cannot be planned to 50-60 Gy without exceeding normal tissue constraints).

PRIOR TO STEP 2 RANDOMIZATION EXCLUSION CRITERIA

• Progressive disease.
• Supplemental oxygen use.
• Third space fluid that cannot be controlled by drainage or insufficient lung expansion after P/D (this prevents targeting the pleura without exceeding normal tissue constraints).
• Prior intrapleural therapy (i.e., intrapleural chemotherapy, photodynamic therapy); pleurodesis is permitted.
• Bulky residual disease in the major fissure preventing pleural IMRT.
• Patients who have undergone extrapleural pneumonectomy.
• Patients with active infection that requires systemic I.V. antibiotics, antiviral, or antifungal treatments.