This study aims to find the maximum tolerated dose level for malignant pleural mesothelioma patients receiving background radiation + boost radiation, and surgery. Boost radiation is an experimental form of radiation that involves targeting non-uniform high doses of radiation to bulky pleural masses. We hypothesize the immunologic abscopal effect is an important component in controlling disease, and may be stimulated with highly hypofractionated doses. Doses will increase with every three patients who will be enrolled in the study until the background radiation reaches 1800 cGy or the maximum tolerated dose, whichever is lower.

This study aims to find the maximum tolerated dose level for mesothelioma patients receiving background radiation + boost radiation, and surgery. 3 patients will start with a background radiation therapy (RT) dose of 0 cGy, and boost RT of at least 2100 cGy. If the radiation is manageable (radiation related AEs grade < 4), the next set of 3 patients will be enrolled, and the background radiation dose will be increased by 600 cGy. This will continue until the background radiation dose reaches 1800 cGy. If 1 patient exhibits dose limiting toxicities (AEs grade 4 & 5), the dose level will repeat with the next 3 patients. If 2 or more patients exhibit DLTs, the previous dose level will be determined as the maximum tolerated dose level. Surgery will be scheduled to occur approximately 1-2 weeks after completing radiation therapy, and will subsequently be followed up as per study schedule.

Inclusion Criteria:

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Good pulmonary function precluding radiation therapy (FEV1>1 L or >40% predicted or DLCO >45% predicted)
• Any patient with a new histological diagnosis of malignant pleural mesothelioma (MPM). Sarcomatoid or biphasic histologies can be included but will be analyzed separately due to their poor prognosis.
• Stage T1-3 N0-1 M0 according to the 8th edition of the tumor, node, and metastases (TNM) staging system based on conventional investigations and tests (Appendix 1). Note that the updated TNM staging system now categorizes ipsilateral mediastinal nodes as N1 disease.
• Suitable for combined modality therapy
• Informed consent.

Exclusion Criteria:

• Age < 18 years.
• Contralateral mediastinal nodal disease (N2)
• Distant metastatic disease (M1).
• Poor performance status ECOG 3-4.
• Poor pulmonary function precluding radiation therapy (FEV1<1 L or <40% predicted or diffusion lung capacity for carbon monoxide (DLCO) <45% predicted)
• Failure to provide informed consent.
• Previous thoracic irradiation.
• Serious non-malignant disease (e.g. cardiovascular, pulmonary, systemic lupus erythematosus (SLE), scleroderma) which would preclude definitive radiation treatment.
• Previous chemotherapy for this or concurrent malignancy.
• Previous or concomitant malignancies except for patients with non-melanoma skin cancer, contralateral non-invasive breast cancer, prostate cancer treated with curative intent or carcinoma in situ of any other site. In addition, patients with invasive cancers treated more than 3 years previously and without evidence of recurrence will be eligible.
• Women who are currently pregnant or lactating.