Malignant mesothelioma is a rare cancer that arises from mesothelial cells; it occurs most commonly in the pleura and peritoneum but is also known to cause primary tumors in the testes and heart.1,2 Asbestos exposure is linked to the vast majority of mesothelioma cases. The median age at diagnosis of malignant mesothelioma is 40 years, and the disease is typically diagnosed 20 to 60 years after asbestos exposure.3,4 Because of its long latency period, new cases of asbestos-related mesothelioma will continue to appear for decades, despite bans on asbestos use.
The Centers for Disease Control and Prevention (CDC) reports that the incidence of mesothelioma in the United States is 0.667 cases per 100,000 population (96% CI, 0.629-0.706).5 The incidence of mesothelioma among women has remained steady for the past 20 years, but the incidence in men has decreased from 2.178 to 1.078 from 2000 to 2022. Survival rates for all types of mesothelioma are poor.
Diagnosis and Staging
Diagnosis of mesothelioma typically includes a combination of imaging studies, blood tests, and biopsies.1,2 An accurate diagnosis of mesothelioma requires a biopsy (preferably surgical or endoscopic) and pathologic analysis of tumor cells. Mesothelioma is staged according to the American Joint Committee on Cancer (AJCC) TNM (tumor, node, metastasis) stage grouping.6
Histologic Subtypes of Mesothelioma
There are 3 histologic subtypes of mesothelioma: epithelioid, sarcomatoid, or both (biphasic). Epithelioid tumors are the most common, accounting for 60% of mesothelioma cases.7
Factors Affecting Mesothelioma Treatment Options
Treatment for mesothelioma depends on stage, tumor location(s), and patient performance status (PS).8 Both pleural and peritoneal mesothelioma respond best to multimodal therapy, including surgery, chemotherapy, and immunotherapy, as well as radiation in some cases. Tumor debulking surgery is appropriate for both pleural and peritoneal tumors. Surgery for pleural mesothelioma can also involve unilateral resection of the pleura with or without resection of lung and mediastinal tissue.
FDA-Approved Drugs for Mesothelioma
The US Food and Drug Administration (FDA) has approved 3 drugs for first-line treatment of mesothelioma: the chemotherapy drug pemetrexed and combination immunotherapy with ipilimumab plus nivolumab.9 Second-line treatments for mesothelioma approved by the FDA include chemotherapy using gemcitabine plus cisplatin and pembrolizumab.
Pharmacologic Management of Mesothelioma
Adjuvant chemotherapy and immunotherapy are the primary pharmacologic treatments for mesothelioma. Pharmacologic management guidelines listed here come from the American Society of Clinical Oncology (ASCO) clinical practice guideline for the treatment of pleural mesothelioma published in 2018.10
Systemic Chemotherapy
Systemic pemetrexed-based chemotherapy is a first-line treatment for mesothelioma. Pemetrexed is approved by the FDA for mesothelioma treatment and is usually combined with cisplatin, although carboplatin is an acceptable alternative.9,10 The FDA has approved a combination of gemcitabine and cisplatin as a second-line systemic chemotherapy treatment for mesothelioma.9 Gemcitabine is also used to treat recurrent mesothelioma.
Intracavitary Chemotherapy
Regional intracavitary chemotherapy can be effective in treating early mesothelioma. Intracavitary chemotherapy can be used as adjuvant chemotherapy for either pleural or peritoneal mesothelioma following cytoreductive surgery. Compared with systemic chemotherapy, intracavitary infusions have fewer systemic side effects while allowing the use of higher concentrations of medications. However, due to the shallow penetration of intracavitary infusions, near-complete cytoreductive surgery is needed first.
HIPEC
Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the infusion of heated (42 °C) chemotherapy agents into the abdominal cavity to treat peritoneal mesothelioma. Patients undergoing HIPEC for peritoneal mesothelioma experience greatly increased survival odds.11 A combination of cisplatin and doxorubicin has the greatest benefit, with a mean survival time of 53 months compared with 38 months with either cisplatin or mitomycin alone.11,12 Mitomycin may be used in place of doxorubicin.
HITHOC
Hyperthermic intrathoracic chemotherapy (HITHOC) involves the infusion of heated chemotherapy (42 °C) into the chest cavity to treat pleural mesothelioma.13 Treatment with HITHOC should be performed after cytoreductive surgery during the same operation. Cisplatin plus doxorubicin are the recommended agents; cytarabine has also been used in place of doxorubicin.
Immunotherapy
Immunotherapy can play a crucial role in mesothelioma treatment.10 A combination of immune checkpoint inhibitors — a programmed cell death ligand 1 (PD-L1) inhibitor and a CTLA inhibitor — improves T-cell activation.14 The PD-L1 inhibitors nivolumab and pembrolizumab, as well as the CTLA-4 inhibitor ipilimumab, are approved by the FDA for treatment of mesothelioma.9 Immunotherapy agents that target the vascular endothelial growth factor (VEGF) pathway are also used for first- or second-line mesothelioma treatment.14 These immunotherapy agents include the VEGF-A inhibitor bevacizumab and the VEGFR2 antagonist ramucirumab. Ramucirumab is also used to treat recurrent mesothelioma.
Treatment Recommendations
ASCO treatment guidelines for mesothelioma recommend cytoreductive surgery with regional (intracavitary) chemotherapy in eligible patients.10 For patients who are not good candidates for surgery, guidelines recommend either combination immunotherapy or systemic chemotherapy plus immunotherapy.
Early Mesothelioma
For stage I mesothelioma, recommended first-line treatment is surgical resection of the tumor followed by either HIPEC or HITHOC intracavitary chemotherapy.12 Treatment with HIPEC significantly improves survival odds in patients with peritoneal mesothelioma.
Advanced Mesothelioma
For stages II-IV mesothelioma, recommended first-line therapies are either systemic chemotherapy with pemetrexed and a platinum agent or immunotherapy with ipilimumab plus nivolumab.10,12 Ipilimumab plus nivolumab provides comparable disease-free survival and adverse events as pemetrexed plus platinum therapy. Patients should also be offered the option to enroll in a clinical trial.10
For systemic chemotherapy, pemetrexed plus cisplatin is recommended, but carboplatin may be used in patients who cannot tolerate cisplatin. Immunotherapy with bevacizumab should be added to pemetrexed-based chemotherapy in patients without contraindications: PS 2 or higher, substantial cardiovascular comorbidity, uncontrolled hypertension, age older than 75, and bleeding or clotting risk. Studies show that bevacizumab is more effective when combined with a chemotherapy regimen that includes cisplatin but not carboplatin. Intracavitary chemotherapy may also be used in patients undergoing cytoreductive surgery.
Recommended second-line therapy for advanced mesothelioma is participation in a clinical trial. Patients who previously achieved more than 6 months of disease control with pemetrexed-based chemotherapy may be retreated with pemetrexed-based therapy. Other treatment options include intravenous (IV) gemcitabine plus ramucirumab, vinorelbine, or pembrolizumab. Although pemetrexed does not increase survival among patients with recurrent mesothelioma, it may be useful as palliative chemotherapy and may improve quality of life.
Special Populations
Patients with PS 2 or higher should be offered alternative treatment options. Although dual-agent chemotherapy is recommended, patients with PS 2 should be offered single-agent chemotherapy or palliative care. Patients who are not candidates for surgery may also be offered single-agent chemotherapy with pemetrexed, vinorelbine, or gemcitabine.15 Patients with PS 3 or higher should receive palliative care.
Table 1. Chemotherapy Management Guidelines for Mesothelioma
| Drug | Dose | Administration | Treatment Duration |
| Pemetrexed and cisplatin (or carboplatin) | Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 | IV infusion | Once every 21 d for up to 6 cycles |
| Gemcitabine | 1250 mg/m2 | IV infusion | Days 1, 8, and 15 every 28 d, up to 10 cycles |
| Vinorelbine | 30 mg/m2 | IV infusion | Once weekly for 12 wk |
| Cisplatin | 100 mg/m2 | Intracavitary infusion | Single dose (pleural) or once every 28 d (peritoneal) |
| Doxorubicina | 30-60 mg/m2 | Intracavitary infusion | Single dose (pleural) or once every 28 d (peritoneal) |
| Cytarabineb | 1200 mg | Intracavitary infusion | Single dose |
| Mitomycinc | 5-10 mg | Intracavitary infusion | Once every 28 d, 7 d after cisplatin |
IV = intravenous.
aAdded to cisplatin for intracavitary infusion.
bPleural mesothelioma.
cPeritoneal mesothelioma.
From FDA prescribing information.16-23
Table 2. Management Guidelines for Immunotherapy for Mesothelioma
| Drug | Dose | Administration | Treatment Duration |
| Ipilimumab and nivolumab | Ipilimumab 1 mg/kg and nivolumab 3 mg/kg | IV infusion | Ipilimumab once every 6 weeks and nivolumab once every 2 weeks |
| Bevacizumaba | 15 mg/kg | IV infusion | Once every 21 days |
| Pembrolizumab | 200 mg or 400 mg | IV infusion | Once every 3 weeks or once every 6 weeks |
| Ramucirumab | 10 mg/kg | IV infusion | Once every 21 days |
IV = intravenous.
aAdded to pemetrexed-based chemotherapy.
From FDA prescribing information.24-28
Adverse Events and Drug-Drug Interactions Associated With Mesothelioma Treatments
Steps should be taken to reduce the toxic side effects of chemotherapy agents used for systemic or regional therapy.
Patients receiving pemetrexed and cisplatin systemic chemotherapy should receive supplementation with oral folic acid and intramuscular (IM) vitamin B12 beginning 1 to 3 weeks before treatment.10 Folic acid 350 to 1000 mg orally should be given daily and continued for 1 to 3 weeks after treatment ends. Vitamin B12 1000 mg IM should be given every 9 weeks until the end of treatment.
Patients receiving pemetrexed should be given dexamethasone 4 mg or another corticosteroid twice daily the day before, the day of, and the day after infusion to prevent skin rash.
Patients receiving cisplatin should receive 1 L of IV fluid before treatment and 3 L after treatment to prevent cisplatin-induced nephrotoxicity. Patients receiving intracavitary cisplatin should be given IV sodium thiosulfate to prevent cisplatin-induced nephrotoxicity.
Table 3. Side Effects and Drug-Drug Interactions Associated With Mesothelioma Treatments
| Drug | Warnings/Adverse Events | Drug-Drug Interactions |
| Pemetrexed | Myelosuppression, increased risk of myelosuppression without vitamin supplementation, renal failure, bullous and exfoliative skin toxicity, interstitial pneumonitis, radiation recall, increased risk of toxicity with ibuprofen in patients with renal impairment, embryo-fetal toxicity | Ibuprofen |
| Cisplatin | Nephrotoxicity, peripheral neuropathy, severe nausea and vomiting, myelosuppression, hypersensitivity reactions, ototoxicity, ocular toxicity, secondary malignancies, embryo-fetal toxicity, injection site reactions | Nephrotoxic and ototoxic drugs |
| Carboplatin | Myelosuppression, gastrointestinal toxicity, neurologic toxicity, nephrotoxicity, hepatic toxicity, electrolyte changes, allergic reactions, injection site reactions, pain, asthenia | |
| Doxorubicin | Cardiomyopathy, arrhythmias, secondary malignancies, extravasation, tissue necrosis, severe myelosuppression, tumor lysis syndrome, toxicity with hepatic impairment, potentiation of radiation toxicity, radiation recall, embryo-fetal toxicity | CYP3A4, CYP2D6, and P-gp inhibitors AND inducers, paclitaxel, trastuzumab, dexrazoxane, 6-mercaptopurine |
| Gemcitabine | Schedule-dependent toxicity, myelosuppression, pulmonary toxicity, respiratory failure, hemolytic uremic syndrome, hepatic toxicity, embryo-fetal toxicity, capillary leak syndrome, posterior reversible encephalopathy syndrome | |
| Vinorelbine | Myelosuppression, hepatic toxicity, severe constipation, bowel obstruction, extravasation, tissue injury, neurologic toxicity, pulmonary toxicity, respiratory failure, embryo-fetal toxicity | CYP3A inhibitors |
| Cytarabine | Myelosuppression, embryo-fetal toxicity, cytarabine syndrome, schedule-dependent cardiotoxicity | |
| Mitomycin | Myelosuppression, integument and mucous membrane toxicity, nephrotoxicity, pulmonary toxicity, hemolytic uremic syndrome, cardiac toxicity | |
| Ipilimumab | Severe and fatal immune-mediated adverse reactions: colitis, hepatitis, rash, bullous and exfoliative dermatitis, pneumonitis, nephritis, renal dysfunction; immune-mediated endocrinopathies: hypophysitis, adrenal insufficiency, hyperthyroidism, hypothyroidism, thyroiditis, type 1 diabetes mellitus; infusion-related reactions; embryo-fetal toxicity | |
| Nivolumab | Severe and fatal immune-mediated adverse reactions: pneumonitis, colitis, hepatitis, hepatotoxicity, nephritis, renal dysfunction, rash; immune-mediated endocrinopathies: adrenal insufficiency, hypophysitis, thyroiditis, hyperthyroidism, hypothyroidism; embryo-fetal toxicity | |
| Bevacizumab | Gastrointestinal perforations and fistulae, surgery and wound healing complications, hemorrhage, arterial thrombotic events, venous thrombotic events, hypertension, posterior reversible encephalopathy syndrome, renal injury, proteinuria, infusion-related reactions, embryo-fetal toxicity, ovarian failure, congestive heart failure | |
| Pembrolizumab | Severe and fatal immune-mediated adverse reactions: pneumonitis, colitis, hepatotoxicity, hepatitis, nephritis, renal dysfunction, rash, exfoliative dermatitis; immune-mediated endocrinopathies: adrenal insufficiency, hypophysitis, thyroiditis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus; infusion-related reactions, embryo-fetal toxicity | |
| Ramucirumab | Hemorrhage, gastrointestinal perforations, impaired wound healing, arterial thrombotic events, hypertension, infusion-related reactions, worsening of pre-existing hepatic impairment, posterior reversible encephalopathy syndrome, proteinuria, nephrotic syndrome, hypothyroidism, embryo-fetal toxicity |
P-gp = P-glycoprotein.
From FDA prescribing information.16-28
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Author Bio
Kristopher Bunting, MD, studied chemistry and life sciences at the US Military Academy in West Point, New York. He received his doctor of medicine degree from Tulane University, and he recently completed a postdoctoral research fellowship at Augusta University. He has more than 15 years of experience in behavioral and molecular neuroscience research focusing on memory and learning, including developing new approaches to study post-traumatic stress disorder (PTSD). He has also collaborated on projects in vascular biology and cancer research.
