Patient must not have had prior immunotherapy or chemotherapy for malignant pleural mesothelioma Has extensive pleural effusion which occupies greater than % of the total lung volume observed on screening imaging Prior chemotherapy for pleural mesothelioma Participants (all indications) with confirmed bilateral pleural effusion and NSCLC participants with confirmed uni- or bilateral pleural effusion by X-ray are not eligible Patients with active extra-abdominal disease including active malignant pleural effusion; patients who have been successfully treated with neoadjuvant chemotherapy and no longer have (malignant) pleural effusions may be included No clinically significant pleural effusion Participants with confirmed bilateral pleural effusion Patients with non-malignant pleural effusion are eligible\r\n* If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:\r\n** When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative\r\n** Exudative pleural effusions are excluded, regardless of cytology\r\n** Effusions that are minimal (i.e, not visible on chest x-ray) that are too small to safely tap are eligible Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days. For NSCLC, patients with clinical stage IIB-IV patients (American Joint Committee on Cancer [AJCC], th edition [ed.]) are eligible, and for SCLC, limited-stage patients are eligible, if documented to be a candidate for definitive radiation and concurrent chemotherapy in the radiation oncologist or medical oncologist clinic note\r\n* Stage IV NSCLC patients are eligible only if they have a solitary brain metastasis\r\n* Patients with non-malignant pleural effusion are eligible,\r\n** If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:\r\n*** When pleural fluid is visible on both the computed tomography (CT) scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative\r\n*** Exudative pleural effusions are excluded, regardless of cytology\r\n*** Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible Evidence of measurable disease (per Response Evaluation Criteria in Solid Tumors version . [RECIST .]) outside of the peritoneal cavity (ex: mediastinal lymphadenopathy, parenchymal liver metastasis, or symptomatic pleural effusion proven or suspected to be due to cancer)\r\n* Note: Asymptomatic pleural effusion with or without minimal pleural involvement as long as there is no measurable disease outside the peritoneum/retroperitoneum is allowed Participants with bilateral pleural effusion and NSCLC participants with uni- or bilateral effusion confirmed at screening by X-ray are not eligible Pleural or pericardial effusion\r\n *Pleural effusions allowed if one of the following conditions are met: ) negative cytology after adequate sampling by thoracentesis ) effusion seen on CT scan but not on chest x-ray and deemed too small to tap under CT or ultrasound guidance Part B only: Participants must have malignant pleural or peritoneal mesothelioma Pleural effusion as the only evidence of metastatic disease Presence of a significant pleural effusion by chest x-ray A pleural effusion of moderate severity or worse. No clinically significant pleural effusion Pleural effusion: when pleural fluid is visible on both CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative; patients with effusions that are minimal (i.e. not visible on chest x-ray) or that are too small to safely tap are eligible A pleural effusion of moderate severity or worse. No clinically significant pleural effusion Patients must have a histologic diagnosis of malignant pleural mesothelioma Histologically proven malignant pleural mesothelioma MPM that is considered resectable according to the following criteria:\r\n* Confined to one pleural space\r\n* No chest wall invasion\r\n* No transdiaphragmatic involvement\r\n* No invasion of mediastinal structures No pleural or peritoneal serous effusion. Surgically resectable malignant pleural mesothelioma (MPM) with no disease extension beyond the ipsilateral hemithorax Presence of pleural effusion 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\r\n* Patients with effusions that are minimal (i.e. not visible on chest x-ray) and that are too small to safely tap are eligible Prior nephrectomy on the contralateral side of malignant pleural mesothelioma (MPM) Measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v. criteria or non-measurable disease with symptomatic malignant pleural effusion or malignant ascites; if only site of disease is a pleural effusion, cytologic confirmation of recurrence should be obtained Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath. Clinically significant pleural effusion Exudative pleural effusion, regardless of cytology Pleural effusion that cannot be controlled with appropriate interventions Pleural effusion requiring active medical management Cytologically positive pleural effusion Pleural effusion that cannot be controlled despite appropriate interventions If a pleural effusion is present, the following criteria must be met at registration to exclude malignant involvement (incurable Ma disease):\r\n* When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative\r\n* Effusions that are minimal (i.e. not visible under ultrasound guidance) and that are too small to safely tap are eligible If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable Ma disease):\r\n* When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative\r\n* Exudative pleural effusions are excluded, regardless of cytology\r\n* Effusions that are minimal (i.e. not visible under ultrasound guidance) that are too small to safely tap are eligible Malignant pleural effusion Patients must have histologically or cytologically-proven new diagnosis of unresectable stage IIIA/IIIB*, non-small cell lung cancer (adenocarcinoma, bronchioloalveolar cell carcinoma, large cell carcinoma, squamous cell carcinoma, or mixed)\r\n* Per the American Joint Committee on Cancer (AJCC) th edition, pleural and pericardial are now considered stage Ma disease; when pleural fluid is visible on the computed tomography (CT) scan or on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative; patients with exudative pleural effusions are excluded, regardless of cytology; patients with effusions that are minimal (i.e. not visible on chest x-ray) that are too small to safely tap are eligible; a small effusion that has positive fludeoxyglucose F (FDG) uptake on positron emission tomography (PET) has to be proven to be malignant per standard of care diagnostic procedures for the patient to be excluded Stage IIIB with malignant pleural effusion/pleural seeding or stage IV histologically confirmed NSCLC Patients with a pleural effusion that is a transudate, cytologically negative and non-bloody are eligible if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy; if a pleural effusion can be seen on the chest computed tomography (CT) but is too small to tap, the patient is eligible Pleural mesothelioma basket:\r\n* None predominantly epithelial (?% tumor component) pleural or peritoneal mesothelioma Any clinically significant pleural or peritoneal effusion that cannot be drained with standard approaches; an indwelling drainage device placed prior to enrollment is acceptable Diagnosis of histologically or cytologically documented, malignant pleural effusions (primary non-small cell lung carcinoma, mesothelioma, and other histologies), who have free pleural space (partial or total) that permits the intrapleural drug instillation; this includes cytologically negative pleural effusion in conjunction with histologically proven malignancy involving the pleura Histological documentation of malignant pleural mesothelioma (MPM) overexpressing mesothelin Have clinically significant and/or malignant pleural effusion (pleural effusions that are not clinically significant are allowed, defined as no more than % fluid level of the corresponding hemithorax and stable fluid level [non-progressive] over at least weeks documented radiographically) Documented extensive disease, defined as any tumor beyond the above limited disease definition, including ipsilateral lung metastases and malignant pleural effusion. Have clinically significant and/or malignant pleural effusion Pleural effusion large enough to be detectable on chest x-ray Patients with a pleural effusion which is a transudate, cytologically negative and non-bloody are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy; patients with exudative, bloody, or cytologically malignant effusions are not eligible; if a pleural effusion can be seen on the chest CT but not on CXR and is too small to tap, the patient will be eligible For metastatic solid tumors with documented malignant pleural and/or peritoneal effusions, patients must not be receiving specific therapy for the effusion or have an indwelling drain. Patients with any pulmonary infiltrate including those suspected to be of infectious origin. Exception: Patients with a pleural effusion related to the disease under study as confirmed by the investigator are permitted to enter the study Histopathologically-confirmed diagnosis of malignant mesothelioma (pleural or peritoneal). Must have disease that has relapsed following at least one prior line of chemotherapy. Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible Pleural effusion large enough to be detectable on chest x-ray (CXR) Free flowing pleural effusion requiring management by placement of a pleural catheter; patients with a functional pleural catheter already in place are eligible for the study, as long as there are no clinical concerns of infection No free-flowing pleural effusion Clinically significant pleural effusion. Clinically significant pleural effusion Presence of tumor metastases causing significant pleural disease/effusion unilaterally or bilaterally (significant pleural effusion is defined by need for thoracentesis more frequently than once every days) Malignant pleural effusion or pleural disease Malignant pleural effusion that is recurrent Clinically significant and/or malignant pleural effusion Any cause of dyspnea that is determined by the investigators as readily reversible by other means (e.g. pleural effusion, pulmonary embolism, acute infection, anemia hemoglobin [Hb] < ., etc.) Have clinically significant and/or malignant pleural effusion Pathologic diagnosis of malignant pleural mesothelioma (MPM) confirmed at participating institution Pleural effusion requiring thoracentesis within week of study enrollment or scheduled during the study period Subject has a symptomatic malignant pleural effusion requiring intervention; for an effusion to be defined as malignant, at least one of the following must be true\r\n* There is cytological confirmation of pleural malignancy\r\n* The effusion is an exudate (per Lights criteria) in the context of histocytologically proven malignancy elsewhere, with no other clear cause for fluid identified Subject has sufficient pleural fluid to allow safe insertion of an indwelling tunneled pleural catheter as determined by the principal investigator (PI) Radiographic evidence of brain metastases and/or ipsilateral lung metastases/malignant pleural effusion Patients with minimal pleural effusion evident on chest X-ray (CXR); minimal pleural effusion visible on chest CT is allowed Known re-expandable lung:\r\n* History of recurrent transudative (by Lights criteria) pleural effusions of known etiology, AND\r\n* Has undergone multiple prior thoracenteses, without history of significant chest discomfort, AND\r\n* Strong clinical suspicion that the current effusion is uncomplicated and due to the known underlying etiology Pleural effusion is smaller than expected on bedside pre-procedure ultrasound More than biopsy on the same side requiring more than pleural puncture There is histocytological confirmation of pleural malignancy A CXR shows ?% of the affected hemithorax to be occupied with pleural fluid AFTER a pleural aspiration which resulted in symptoms suggestive of trapped lung (e.g., chest pain or cough). Patients with symptomatic pleural effusion requiring placement of an indwelling pleural catheter (IPC) or new placement of an IPC. Patients with a pleural effusion that is a transudate, cytologically negative and non-bloody are eligible if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy; patients with exudative, bloody, or cytologically malignant effusions are ineligible; if a pleural effusion can be seen on the chest computed tomography (CT) but not on chest x-ray (CXR) and is too small to tap, the patient will be eligible Tumor with pleural contact. Patients with non-measurable non-evaluable lesions such as pleural effusion are not eligible to participate No clinically significant pleural effusion