Inclusion Criteria:

1. Histologically proven diagnosis of MPM stages I to III. Patients will be clinically staged using the AJCC/UICC TNM staging criteria (see Protocol Appendix 2). Eligible stages:

   • Patients must be M0.
   • Patients with T1, T2, and T3 disease (without cardiac involvement) are eligible. T status can be established clinically and radiologically or at exploratory thoracotomy without surgical resection.
   • Patients with N0, N1, or N2 disease are eligible.
2. Performance status of 0 to 2 on the ECOG performance status schedule. See protocol Appendix 3
3. No prior systemic chemotherapy. No prior intracavitary cytotoxic drugs or immunomodulators, unless given for the purpose of chemical pleurodesis.
4. No previous surgical procedure for mesothelioma, with the exception of previous chemical pleurodesis and biopsy.
5. No previous radiation therapy for mesothelioma, or to the thorax.
6. Patients must be judged to be suitable candidates for this therapy at the UHN by the attending medical oncologist, thoracic surgeon, and radiation oncologist before enrolment.
7. Estimated life expectancy of at least 12 weeks.

8. Adequate organ function including the following:

   • Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ³1,500/uL , platelets

     • 100,000/uL, hemoglobin ³ 9g/dL
   • Hepatic: bilirubin £1.5 times institutional upper limit of normal, alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) £3 times institutional upper limit of normal
   • Renal: Creatinine £1.5 times institutional upper limit of normal; or Creatinine clearance ³50 mL/min/1.73 m² for patients with creatinine levels above institutional normal upper limit level. Cockcrot and Gault formula Appendix 4.
   • Pulmonary function tests:

   Predicted post-operative DLCO (ppoDLCO) of > 35%.

   If the ppoDLCO is </= 35%, then additional studies will be done to determine the patient’s ability to tolerate the resection. The surgeon will correlate these results with the patient’s clinical status and make a decision as to the feasibility of resection.

9. Female patients of childbearing potential must test negative for pregnancy at the time of enrolment based on a serum pregnancy test. Male and female patients must agree to use a reliable method of birth control during and for 3 months following the last dose of radiation therapy.
10. Patients must sign an informed consent

Exclusion Criteria:

1. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
2. Have previously completed or withdrawn from this study or any other study investigating pemetrexed
3. Pregnancy or breast-feeding.
4. Serious concomitant systemic disorders (e.g., active infection) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient’s ability to complete the study.
5. Second active primary malignancy except in situ carcinoma of the cervix, adequately treated non-melanomatous carcinoma of the skin, low grade (Gleason score < 6) localized adenocarcinoma of the prostate or other malignancy treated at least 2 years previously with no evidence of recurrence.

6. Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents for a 5-day period (8 day

   period for long-acting agents such as piroxicam).

7. Inability or unwillingness to take folic acid, vitamin B12 supplementation, or dexamethasone.
8. Refusal to have any of the treatment in the protocol (chemotherapy, extrapleural pneumonectomy, and radiation therapy).