The purpose of this study is to find out whether intraperitoneal or intravenous chemotherapy given after cytoreductive surgery and HIPEC are effective treatments for people with malignant peritoneal mesothelioma. Outcomes will be compared by observing intraperitoneal versus intravenous treatments to analyze if one is better than the other.

Inclusion Criteria:

• Patient age 18 years or older, both sexes.
• Clinical diagnosis of MPM at enrolling institution.
• Prior to randomization, intraoperative pathologic confirmation of epithelioid MPM at enrolling institution.
• Complete or near-complete CRS achieved.
• Patient must be planning to undergo complete cytoreduction of all peritoneal disease.
• ECOG performance status ≤ 1.
• Hematology: ANC ≥ 1,500/µl.
• Platelets > 75,000/µl.
• Adequate renal function: creatinine < 1.5× the upper limit of normal (ULN) or calculated creatinine clearance of ≥50 ml/min.
• Adequate hepatic function: bilirubin < 1.5 mg/dl (except in patients with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL).
• Women of childbearing potential with a negative pregnancy test result (urine or blood) who agree to use an effective contraceptive method. Reliable contraception should be used from trial screening and must be continued throughout the study. A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant.
• A man participating in this study must agree to utilize a reliable barrier form of contraception for the duration of the study
• Signed and dated written informed consent to participate in this clinical trial must be obtained prior to any study procedure.

Exclusion Criteria:

• Subjects who have previously undergone intraperitoneal chemotherapy or systemic chemotherapy for peritoneal mesothelioma.
• Subjects who have previously received platinum-containing chemotherapy regimens.
• Subjects with preoperative or intraoperative biopsy consistent with sarcomatoid mesothelioma, well-differentiated papillary mesothelioma, or benign multicystic mesothelioma.
• Other prior malignancies, except for cured non-melanoma skin cancer, curatively treated in situ carcinoma of the cervix, adequately treated malignancies for which there has been no evidence of activity for more than three years, or indolent tumors for which observation over two years is a reasonable option.
• High suspicion for extra-abdominal metastases.
• Women who are pregnant or lactating.
• Active coronary artery disease (defined as unstable angina or a positive cardiac stress test). Subjects with a history of coronary artery disease may be included if they have had a normal stress test within 60 days of enrollment or are determined by a cardiologist to be of acceptable perioperative risk.
• Uncontrolled hypertension defined as >140/90 and not cleared for surgery at the time of consent.
• New York Heart Association (NYHA) Class II or higher congestive heart failure; restrictive or obstructive pulmonary disease that would limit study compliance or place the patient at unacceptable risk for participation in the study.
• History of cerebrovascular disease that would limit study compliance or place the patient at unacceptable risk for participation in the study.
• Subjects with other concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or place them at an unacceptable risk for participation in the study.
• Patients with known cisplatin, carboplatin, pemetrexed or mitomycin allergy.
• Evidence of extensive intraperitoneal adhesions at the time of surgery which prohibits intraperitoneal therapy, as determined by the operating surgeon.
• Any condition that would preclude the ability to deliver appropriate IP therapy.
• Use of an oral medication, lacking a suitable non-oral substitute, that if held for up to ten days, would be felt an unacceptable risk by the investigator.
• Life expectancy < 12 weeks.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.