Mesothelioma

Practice Essentials

Malignancies involving mesothelial cells that normally line the body cavities, including the pleura (see the images below), peritoneum, pericardium, and testis, are known as malignant mesothelioma.^[1] Asbestos, particularly the types of amphibole asbestos known as crocidolite and amosite asbestos, is the principal carcinogen implicated in the pathogenesis of malignant pleural mesothelioma.^[2]

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Computed tomography scan of a 58-year-old patient with mesothelioma and shortness of breath. This image shows the extensive pleural thickening that is....

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The classic description of malignant pleural mesothelioma is a thickening in the pleural space with encasement of the lung by a rindlike visceral pleu....

Signs and symptoms

Dyspnea and nonpleuritic chest wall pain are the most common presenting symptoms of malignant pleural mesothelioma, with at least 1 of these occurring in 60-90% of patients. Other common accompanying symptoms are as follows:

• Chest discomfort
• Pleuritic pain
• Easy fatigability
• Fever
• Sweats
• Weight loss

On physical examination, findings of pleural effusion are usually noted upon percussion and auscultation. Patients may also be asymptomatic, with evidence of a pleural effusion noted incidentally on physical examination or by chest radiograph.

See Presentation for more detail.

Diagnosis

Thoracentesis:

• More than 90% of patients with pleural mesothelioma present with pleural effusion that decreases after thoracentesis
• Typically, the pleural fluid findings are nondiagnostic, with < 1000 leukocytes/μL, few erythrocytes, elevated protein levels, and normal lactate dehydrogenase levels
• Pleural fluid cytologic findings are diagnostic in only 32% of patients and are suggestive in 56%
• FISH to distinguish malignant mesothelioma from reactive mesothelial cells in effusions had 79% sensitivity^[3]

Thoracoscopically guided biopsy:

• Indicated if mesothelioma is suggested
• Diagnostic in 98% of cases

Routinely stained biopsy preparations are the most valuable diagnostic tool in malignant mesothelioma. Diagnostic features that distinguish malignant mesothelioma from adenocarcinoma include the following:

• Negative results for periodic acid–Schiff stain, mucicarmine stain, carcinoembryonic antigen, and Leu M1
• Positive test results for calretinin, vimentin, and cytokeratin

Serum biomarkers:

• Soluble mesothelin (the current reference biomarker)
• Megakaryocyte potentiating factor

Chest radiographs

Findings in malignant pleural mesothelioma include one or more of the following:

• Obliteration of the diaphragm
• Nodular thickening of the pleura
• Decreased size of the involved chest
• Radiolucent, sheetlike encasement of the pleura
• A loculated effusion (> 50% of patients), with opacification of a major portion of the pleura

See Workup for more detail.

Management

Currently, no therapy is considered standard. Treatment options for the management of localized malignant mesothelioma include the following:

• Surgery (reasonable when disease is confined to the pleural space)
• Chemotherapy
• Radiation (provides significant palliation of chest pain and chest wall metastasis in 50% of patients)
• Multimodality treatment

For metastatic disease, generally used chemotherapy/immunotherapy regimens include the following:

• Cisplatin – For single-agent therapy
• Cisplatin/pemetrexed 
• Cisplatin/pemetrexed/bevacizumab – A reasonable option if no contradindication to bevacizumab
• Ipilimumab/nivolumab – New standard for metastatic disease
• Pemetrexed/gemcitabine – For patients who cannot take cisplatin
• Pemetrexed – For single-agent therapy
• Cisplatin/gemcitabine

See Treatment and Medication for more detail.

Go to Oncology Decision Point for expert commentary on mesothelioma treatment decisions and related guidelines. For patient education information, see Mesothelioma.

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Background

Malignancies involving mesothelial cells that normally line the body cavities, including the pleura, peritoneum, pericardium, and testis, are known as malignant mesothelioma. The 3 major histologic types are sarcomatous, epithelial, and mixed. The condition may be localized or diffuse. (See Etiology.)

Primary sites for malignant mesothelioma include the pleura (87%), the peritoneum (5.1%), the pericardium (0.4%), and the right side of the thorax (more so than the left side, by a right-to-left ratio of 1.6:1). (See Etiology, Presentation, and Workup.)

Among patients with malignant pleural mesothelioma, 77% have previously been exposed to asbestos.^[4]  Clinical presentation occurs decades after exposure.^[5] Diagnosis is difficult because results from fluid analysis of the tumor’s effusion are not usually diagnostic. Death from malignant mesothelioma is usually due to infection or respiratory failure from the progression of the disease. (See Etiology, Presentation, and Workup.)

Malignant pleural mesothelioma

Malignant pleural mesothelioma usually begins as discrete plaques and nodules that coalesce to produce a sheetlike neoplasm. Tumor growth usually starts at the lower part of the chest. The tumor may invade the diaphragm and encase the surface of the lung and interlobar fissures.

The tumor may also grow along drainage and thoracotomy tracts. As the disease progresses, it often extends into the pulmonary parenchyma, chest wall, and mediastinum. Malignant pleural mesothelioma may also extend into the esophagus, ribs, vertebra, brachial plexus, and superior vena cava.

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Etiology

Asbestos

Asbestos, particularly the types of amphibole asbestos known as crocidolite and amosite asbestos, is the principal carcinogen implicated in the pathogenesis of malignant pleural mesothelioma. Exposure to chrysotile asbestos is also associated malignant mesothelioma, but at a lower incidence than occurs with the other types. (The rod-shaped amphiboles are more carcinogenic than the chrysotile.)^[6]

Approximately 8 million people in the United States have been exposed to asbestos in the workplace. A substantial proportion of patients with malignant pleural mesothelioma were exposed to asbestos in asbestos mills, shipping yards, mines, or their homes. The crocidolite in asbestos is associated with mesothelioma in miners, manufacturers who use asbestos, and heating and construction workers. Family members of workers exposed to asbestos can also be at risk of exposure if asbestos becomes embedded in the workers’ clothing.

The industries associated with asbestos exposure include the following:

• Mining
• Shipbuilding involving the use of asbestos
• Asbestos cement manufacture
• Ceramics
• Paper milling
• Auto parts (asbestos brake lining)
• Railroad repair
• Insulation

Environmental exposure to naturally occurring asbestos released by farming and urban development may also increase the incidence of mesothelioma.^[7]

Erionite

Erionite is a fibrous mineral similar to amphibole asbestos that has been linked to malignant mesothelioma.^[8] For example, in the Cappadocia region of Turkey, the use of erionite in building construction and road paving led to an epidemic of pulmonary mesothelioma. Deposits of naturally occurring erionite are also found elsewhere in the world, including at least 12 US states. In North Dakota, where erionite-containing gravel was used to surface more than 300 miles of roads, airborne erionite concentrations measured in transiting school buses have been similar to those measured in the affected Turkish villages.^[9]

Other sources of mesothelioma

Interleukin-8 has direct growth-potentiating activity in mesothelial cell lines. Malignant mesothelioma has also been linked to therapeutic radiation using thorium dioxide and zeolite, a silicate in the soil.

An etiologic role for simian virus 40 in malignant mesothelioma has been suggested. However, although asbestos exposure alone has been associated with malignant mesothelioma, simian virus 40 alone has not. Thus, some epidemiologic evidence exists that simian virus 40 is a possible cocarcinogen. Its direct role at this point is still controversial.^[10]

Alcohol, dietary factors, and tobacco smoke have no effect on the incidence of pleural mesothelioma.

Genetics

Most malignant mesotheliomas have complex karyotypes, with extensive aneuploidy and the rearrangement of many chromosomes.^[11] Loss of 1 copy of chromosome 22 is the single most common karyotypic change in malignant mesothelioma. Other chromosomal changes commonly observed include deletions in the chromosome arms 1p, 3p, 9p, and 6q. Several changes in the tumor suppressor genes p16 (CDKN2A) and p14 (ARF) and loss of function of neurofibromin-2 (NF2) have also been noted.^[12]

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Epidemiology

Occurrence in the United States

Approximately 3000 cases of malignant mesothelioma are diagnosed annually. In the absence of occupational exposure to asbestos, the incidence is 0.1-0.2 per 100,000 population in both sexes. The risk of mesothelioma is increased in polluted areas by 2-10 fold compared with nonpolluted areas. Of patients with malignant mesothelioma in the United States, 80% have been exposed to asbestos.

The annual number of deaths from malignant mesothelioma in the US increased by 4.8% from 1999 to 2015, from 2479 to 2579, according to the Centers for Disease Control and Prevention (CDC). However, over that period the age-adjusted mesothelioma death rate decreased nearly 22%, from roughly 14 to 11 per million population. From 199 to 2015, 45,000 deaths were attributed to malignant mesothelioma in people aged 25 and older. Deaths increased in people aged 85 and older, in men and women, and in Whites, Blacks, Asians/Pacific Islanders, and Hispanics.^[13]

International occurrence

Incidence of malignant mesothelioma is 0.9 case per 100,000 persons annually. Marked variability exists in the incidence of malignant mesothelioma in different countries. In some countries, the incidence is low even though asbestos exposure is high. The reasons for these differences are not known.

Sex- and age-related demographics

Malignant mesothelioma is more common in men than in women, with a male-to-female ratio of 3:1.^[14]

Malignant mesothelioma has a peak incidence 35-45 years after asbestos exposure. Two thirds of cases of malignant mesothelioma develop in the fifth to seventh decade of life.

Malignant mesothelioma also occurs in children; however, these cases are not thought to be associated with asbestos exposure.

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Prognosis

Without treatment, malignant mesothelioma is fatal within 4-8 months. Five-year survival in patients treated with surgery and chemotherapy is 15%.^[5] The tumor recurrence rate is 50% for patients treated with surgery.

Median survival for patients with malignant mesothelioma is 11 months. It is almost always fatal. Median survival based on histologic type is 9.4 months for sarcomatous, 12.5 months for epithelial, and 11 months for mixed. Approximately 15% of patients have an indolent course.

In a review of 64 patients undergoing pleurectomy, the overall survival rate was 43%, 28%, and 10% at 1, 2, and 3 years, respectively. The overall median survival with epithelial histology was 21.7 months (n=56 patients); it was 5.8 months for patients with sarcomatous or mixed type mesothelioma (n=28 patients). The causes of morbidity include atrial fibrillation, wound infection, prolonged intubation, pulmonary emboli, myocardial infarction, respiratory failure, deep vein thrombosis, and postoperative bleeding.

In rare cases, malignant mesothelioma manifests as cord compression, brachial plexopathy, Horner syndrome, or superior vena cava syndrome.

Prognostic factors

Based on many clinical factors, 2 separate groups, the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer, identified the following poor prognostic factors^{[15, 16]} :

• Performance status of 2 or greater
• Nonepithelial histology
• Chest pain
• Age older than 75 years
• Male sex
• High platelet count
• Lactate dehydrogenase greater than 500 IU/L
• Low hemoglobin concentration
• High white blood cell count
• Weight loss

Nodal metastasis

The pattern of nodal metastasis is different from that of lung cancer. The mechanism of spread of the disease to the hilar nodes may be through lung invasion and not due to spread directly from the pleura. In a study of 49 patients who underwent surgery, only 7 had no lung invasion and none had positive hilar nodes. In the postpneumonectomy patients, 6 of 14 had positive hilar node and mediastinal nodes.^[17]

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History and Physical Examination

Despite the banning or reduction of asbestos since the 1960s, the incidence of mesothelioma continues to increase because median latency after asbestos exposure is 40 years and can be up to 50 years.^[5] The long latency period adds to the complexities of early diagnosis and treatment of the condition.

History

The patient’s occupational history is important, and family members with exposure to asbestos should also be evaluated.

Dyspnea and nonpleuritic chest wall pain are the most common presenting symptoms of malignant mesothelioma, with at least 1 of these occurring in 60-90% of patients. Chest discomfort, pleuritic pain, easy fatigability, fever, sweats, and weight loss are the other common accompanying symptoms.

Patients may also be asymptomatic, with evidence of a pleural effusion noted incidentally on physical examination or by chest radiograph.

Metastatic disease is uncommon at presentation; contralateral pleural abnormalities are usually secondary to asbestos-related pleural disease rather than to metastatic disease.

Physical examination

In patients with malignant mesothelioma, physical findings of pleural effusion are usually noted upon percussion and auscultation.

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Approach Considerations

Malignant mesothelioma is a difficult diagnosis to establish, so the pathologist should be warned if the index of suspicion is high. The diagnosis could be work related, and a thorough discussion with the patient is warranted.

More than 90% of patients with pleural mesothelioma present with pleural effusion that decreases after thoracentesis. Cytologic examination findings are diagnostic in only 32% of patients and are suggestive in 56% of patients. Repeating pleural cytology may increase the chances of making a diagnosis. However, if pleural cytology is nondiagnostic in a patient with features suggestive of mesothelioma, referral for thoracoscopically guided biopsy is indicated; the results are diagnostic in 98% of cases.

Careful scrutiny of routinely stained biopsy preparations is the most valuable diagnostic tool in malignant mesothelioma. A battery of commercial immunohistochemistry stains (eg, for cytokeratins, vimentin, human milk fat globulin-2, anti-Leu M1, BerEP4, carcinoembryonic antigen) can be used.^[18]

Diagnostic features distinguishing malignant mesothelioma from adenocarcinoma include negative test results for periodic acid–Schiff stain, mucicarmine stain, carcinoembryonic antigen, and Leu M1 and positive test results for calretinin, vimentin, and cytokeratin. Electron microscopy reveals that cells have long microvilli, in contrast to adenocarcinomas, which have short microvilli.

Several pleural fluid and serum biomarkers have been suggested for diagnosing mesothelioma, including soluble mesothelin-related peptide (SMRP), plasmatic osteopontin (pOPN), vimentin, and fibulin-3. SMRP, measured in fluid or serum, is the only mesothelioma buimarker approved by the US Food and Drug Administration (FDA); it has high specificity but sensitivity of only 35–50%, which limits its value for diagnosis; however, levels may correlate with disease status.^{[19, 20, 21]}

Determining the extent of disease by performing a laparoscopy or magnetic resonance imaging (MRI) scan and a cardiopulmonary evaluation is important, if the patient is amenable.

Cardiopulmonary stress test

A cardiopulmonary stress test with pharmacologic agents is a reasonable choice to eliminate the possibility of silent myocardial ischemia.

Laparoscopy, thoracoscopy, and pleuroscopy

Thoracoscopy or pleuroscopy should be performed to confirm the diagnosis of mesothelioma. Laparoscopy is important for staging but is still investigational for evaluation of transdiaphragmatic involvement.

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Laboratory Studies

Pleural fluid findings in patients with mesothelioma are normally not diagnostic. The specific gravity of the pleural fluid is also nondiagnostic. Typically, the pleural fluid has less than 1000 leukocytes per microliter, few erythrocytes, elevated protein levels, and normal lactate dehydrogenase levels.

The results of cytologic examination are occasionally positive for malignant mesothelial cells; most often, however, the pleural fluid cytology results are not diagnostic.^[22]

Savic et al used fluorescence in situ hybridization (FISH) to distinguish malignant mesothelioma from reactive mesothelial cells in effusions. Diagnosis of mesothelioma by detection of chromosomal aberrations with FISH had 79% sensitivity; positive and negative predictive values for detection of mesothelioma were 100% and 72%, respectively.^[3]

Characteristics of new cell lines

Four mesothelioma cell lines have been characterized based on ultrastructural and immunophenotypic analysis.^[23] These cell lines express vimentin, cytokeratins 8 and 18, and mesothelial antigen recognized by HBME-1 monoclonal antibody. All of the lines possess surface human leukocyte antigen (HLA) class I and intercellular adhesion molecule-1 (ICAM-1).

Although HLA class II and cluster of differentiation-86 (CD-86) cannot be detected in the cell lines, HLA class II does become present following interferon gamma stimulation. Abnormal karyotypes with chromosome-6 abnormalities are found in all 4 cell lines.

Owing to the persistence of large T antigen with HLA class I and ICAM-1, large T antigen may serve as a target for cytotoxic-based immunotherapy.

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Imaging Studies

Chest radiographs in malignant pleural mesothelioma show obliteration of the diaphragm; nodular thickening of the pleura; decreased size of the involved chest; radiolucent, sheetlike encasement of the pleura; or a combination of these. A loculated effusion is present in more than 50% of patients, and a major portion of the pleura is opacified by the effusion.

A computed tomography (CT) or MRI scan of the chest or a positron emission tomography (PET) scan can also be used in the diagnosis of mesothelioma.^[24] However, the PET scan is still considered investigational for helping to differentiate between benign and malignant mesothelioma.

In a study of fluorodeoxyglucose PET (FDG-PET) scanning in 17 patients with pleural mesothelioma, the survival period in the group with high FDG uptake was shorter than that in the low FDG group.^[25]

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Staging

Six staging categories have been proposed for mesothelioma. In 1996, Sugarbaker and associates proposed the Brigham staging system based on tumor resectability and nodal status, a system validated in a clinical trial.^[26] To date, the accepted system is the tumor/node/metastasis (TNM) classification accepted by the International Mesothelioma Interest Group (IMIG). However, the American Society of Clinical Oncology (ASCO) advies that the TNM classification is difficult to apply to clinical staging with respect to both T and N components, so it may be imprecise for predicting prognosis.^[27]  See the Table below.^[21]

Table 1. TNM Classification for Pleural Mesothelioma

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See Table

The stages of mesothelioma are as follows:

• Stage I - Completely resected within the capsule of the parietal pleura without adenopathy (ie, ipsilateral pleura, lung, pericardium, diaphragm, or chest wall disease limited to previous biopsy sites)
• Stage II - All stage I characteristics, with positive resection margins, intrapleural adenopathy, or a combination
• Stage III - Local extension of disease into the chest wall or mediastinum, into the heart, through the diaphragm or peritoneum, or extrapleurally to involve the lymph nodes
• Stage IV - Distant metastatic disease

Staging procedures

The optimal preoperative staging procedures are debatable. In 1996, Sugarbaker et al recommended MRI as a standard part of staging.^[26] Others argue that laparoscopic thoracoscopy is the best way to determine the extent of the disease. Some argue that PET scans may be helpful, but their role in staging needs to be defined.

MRI performed with different pulse sequences and gadolinium-based contrast material can improve detection of tumor extension, especially to the chest wall and diaphragm. PET scans can provide metabolic and anatomic information, especially for patients with extrathoracic or mediastinal metastasis. The appropriate role of PET scans in the management of malignant mesothelioma is still undefined.

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Histologic Findings

Gross pathology reveals that the pleural surfaces are seeded with malignant mesothelioma cells, which form grouped nodules. As the disease progresses, it covers the entire pleural space and invades the chest wall, mediastinum, and diaphragm. Microscopically, the 3 histologic types are epithelial, sarcomatous, and mixed. The epithelial type correlates with a better prognosis.^[15]

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A solid pattern of mesothelioma on the right of this histologic section transitions to a spindle cell morphology on the left of the image in this pred....

The major growth patterns of malignant mesothelioma are epithelioid and spindled. Tumors of pure epithelioid histology can have patterns described as papillary (cells growing along exophytic fronds with vascular cores), tubulopapillary (a mixture of glandlike formations and papillary structures), and solid (see image below).

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This histologic section stained with hematoxylin and eosin shows papillary structures on the right and a transition to a more solid pattern on the lef....

The cells of mesothelioma often have deceptively uniform nuclei with moderate amounts of cytoplasm; the mitotic rate is often low. These are factors that can make cytologic detection of disease especially difficult and can result in significant diagnostic challenges in tissue samples of reactive pleural conditions.

Histologic variants of malignant mesothelioma, epithelioid type, include cystic growth patterns and cells that resemble decidual cells and variants that resemble small cell carcinoma. Some cases can have abundant extracellular matrix, and rare cases can produce intracellular mucin.

Tumors with spindled cell histology are called sarcomatoid. This group of tumors can be composed of spindled cells without further characterization or differentiation, which is the most common spindled pattern. However, some cases can have very bland spindled cells with minimal atypia amid abundant acellular collagen in a storiform pattern, and this variant is called desmoplastic mesothelioma when the pattern represents 50% of the tumor.^[28]

Well-differentiated papillary mesothelioma represents a proliferation of bland mesothelial cells along fibrovascular cores (papillary architecture), and they are often incidentally discovered growths in the abdominal cavity, although they can also occur in the chest. These are more common in women and are not associated with asbestos exposure. These can have superficially infiltrative growth, but not deeply invasive growth into skeletal muscle or fat, and can be multifocal. While they can recur, these proliferations generally have a very indolent behavior (see image below).

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Well differentiated papillary mesothelioma is characterized with a single layer of bland cuboidal cells lining fibrovascular cores, as demonstrated in....

Benign cystic mesothelioma is composed of multilocular, sometimes multifocal, mesothelial cysts lined by flat to cuboidal mesothelial cells. They occur more commonly in the abdomen but can be seen in the chest. They may be associated with prior surgery. While these lesions can recur, only very rare cases have been associated with subsequent mesothelial malignancy.

Fibrous mesothelioma is an obsolete term used to describe a solitary fibrous tumor not of mesothelial origin. This does not refer to sarcomatoid mesothelioma.

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Approach Considerations

Treatment options for the management of malignant mesothelioma include surgery, chemotherapy, radiation, and multimodality treatment. Surgery in patients with disease confined to the pleural space is reasonable. 

The histopathologic classification of a patient's malignant mesothelioma (ie, as epithlelioid, sarcomatoid, or biphasic) plays a pivotal role in treatment decisions. Patients whose mesotheliomas are sarcomatoid or biphasic (having both epithelioid and sarcomatoid features) have a worse prognosis and are generally not candidates for surgical intervention.^[5]

Diet and Activity

Patients are usually cachetic after surgery, chemotherapy, and radiation. Good supportive care and a regular nutritional status assessment are warranted. Patients should be referred to a nutritionist.

Beginning physical activity as soon as possible is important to prevent postoperative complications. Pulmonary physiotherapy is very helpful because of the extensive lung resection in patients with malignant pleural mesothelioma.

Follow-up

Regular follow-up visits with the following are recommended:

• Internist
• Pulmonary specialist
• Medical oncologist
• Radiation oncologist

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Chemotherapy and Immunotherapy

Pharmacologic therapy is used in concert with surgery and in unresectable mesothelioma. Pembrolizumab or nivolumab plus ipilimumab is the most effective treatment for metastatic malignant pleural mesothelioma that is unresectable.^{[21, 29]}  

Ipilimumab/nivolumab

In 2020, the FDA approved nivolumab in combination with ipilimumab for first-line treatment of unresectable metastatic pleural mesothelioma.^[30] Approval was based on the phase III CheckMate-743 clinical trial (n=605), in which nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival (OS) versus standard-of-care platinum doublet chemotherapy (cisplatin or carboplatin plus pemetrexed). Two-year OS rates were 41% in the nivolumab plus ipilimumab group and 27% in the chemotherapy group. OS benefit was seen predominantly in the patients with non-epithelioid histology, who comprised 25% of participants. Progression-free survival (PFS) and response rates were comparable with nivolumab/ipilimumab and chemotherapy.^[31]

On 3-year follow-up osf CheckMate-743, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61–0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year PFS rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response.^[32]

Cisplatin/pemetrexed

In a phase III study, Vogelzang et al showed the superior benefits of a regimen using pemetrexed in combination with cisplatin over administration of cisplatin alone. Pemetrexed (500 mg/m²/day) and cisplatin (75 mg/m²/day) or cisplatin alone (75 mg/m²/day) was given on day 1. Both arms were given every 21 days. The median survival time in the cisplatin/pemetrexed arm was 12.1 months versus 9.3 months for cisplatin alone. The response rate was 41.3% for the cisplatin/pemetrexed arm and 16.7% for the cisplatin arm. Folic acid and vitamin B12 were given routinely to prevent the adverse effects of pemetrexed. This trial established the regimen as the standard of care for this disease.^[33]

Santoro et al reported that carboplatin/pemetrexed is as effective as cisplatin/pemetrexed in this setting. In their study, chemonaive patients with malignant pleural mesothelioma who received either pemetrexed/cisplatin (n = 843) or pemetrexed/carboplatin (n = 861) had similar time to progressive disease and 1-year survival rates. The response rate in the pemetrexed/cisplatin group was 26.3%, compared with 21.7% for the pemetrexed/carboplatin group. The 1-year survival rates were 63.1% and 64%, respectively, and the median times to progressive disease were 7 and 6.9 months, respectively.^[34]

Cisplatin/pemetrexed/bevacizumab

In the open-label phase III Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), Zalcman et al reported significantly longer overall survival with the addition of bevacizumab to the cisplatin/pemetrexed regimen as first-line treatment of advanced malignant pleural mesothelioma. Median survival in the 223 patients treated with cisplatin/pemetrexed/bevacizumab was 18.8 months (95% confidence index [CI] 15.9–22.6]), versus 16.1 months (95% CI, 14.0–17.9; hazard ratio 0.77 [0.62–0.95]; P=0.0167) in the 225 patients treated with cisplatin/pemetrexed. However, patients receiving bevacizumab experienced more grade 3 or higher hypertension (23% vs 0%) and thrombotic events (6% vs 1%).^[35]

Cisplatin/pemetrexed/pembrolizumab

Pembrolizumab, a monoclonal antibody to programmed cell death–1 protein (PD-1), was approved by the FDA in September 2024 for first-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma, in combination wth pemetrexed and platinum chemotherapy.^[36] In KEYNOTE-483, an open-label, international, randomized phase III trial in 440 patients with previously untreated advanced pleural mesothelioma, adding pembrolizumab to platinum-pemetrexed chemotherapy was tolerable and significantly improved overall survival. The 3-year overall survival rate was 25% with pembrolizumab plus chemotherapy versus 17% with chemotherapy alone.^[37]  

Pemetrexed/gemcitabine

As first-line chemotherapy for patients with peritoneal mesothelioma, the combination of pemetrexed plus gemcitabine is active and can be an option for patients who cannot take platinum agents. A phase II study of gemcitabine 1000 mg/m² on day 1 and day 8 and pemetrexed 500 mg/m² day 8 every 21 days for six cycles or until progression showed a response rate of 15% (95% CI, 3.2-37.9%), with 3 patients exhibiting partial response. The disease control rate was 50%. The most common nonhematologic toxicities included fatigue (20%), constipation (10%), vomiting (10%), and dehydration 10%. Hematologic toxicities included neutropenia (60%) and febrile neutropenia (10%).^[38]

Single-agent pemetrexed

Single-agent pemetrexed therapy is also an option for patients who are not candidates for platinum-containing regimens. A study of single-agent pemetrexed in 247 chemonaïve and 396 pretreated patients with mesothelioma showed a response rate of 10.5%, a median time to progressive disease of 6 months, and a median survival time of 14 months in chemonaive patients. In the pretreated patients, the response rate was 12.1% and median time to progressive disease was 4.9 months.^[39]

Cisplatin/gemcitabine

Phase II studies of cisplatin (or carboplatin^[40] ) plus gemcitabine have demonstrated the benefit of this combination for treatment of mesothelioma. Arrieta et al reported that continuous infusion of low-dose gemcitabine plus cisplatin is not only an effective and safe treatment for unresectable malignant pleural mesothelioma, it is significantly less expensive than other frequently used regimens, and so should be strongly considered for patients with limited economic resources.^[41]

Durvalumab plus chemotherapy

In unresectable malignant pleural mesothelioma, the combination of the programmed death ligand–1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria in two single-arm phase II trials: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505.^{[42, 43]}  In the DREAM trial, 31 of 54 patients (57%) were alive and progression-free at 6 months, and the safety profile of durvalumab plus chemotherapy proved acceptable.^[42]  In the PrE0505 trial, median survival in 55 patients treated with durvalumab plus chemotherapy was 20.4 months, versus 12.1 months with historical control (cisplatin and pemetrexed chemotherapy).^[43]

A phase III study of durvalumab plus chemotherapy, DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM3R) is currently recruiting.^[44]

Additional drug combinations

The following combinations have also been found to be active:

• Cisplatin/doxorubicin
• Cisplatin/doxorubicin/mitomycin C
• Cisplatin/vinblastine/mitomycin C
• Bleomycin/intrapleural hyaluronidase

Additional research

With the isolation of mesothelial cell lines, several chemotherapeutic agents are being tested to assess their efficacy. One explanation for the poor response to chemotherapy is the low apoptotic rate, as evidenced by low BCL2 and BAX expression.^[45] These data suggest that apoptosis is not a key phenomenon in mesothelioma development and histologic differentiation.

Results from a phase I study that included 25 patients with malignant pleural mesothelioma showed evidence of benefit from intrapleural administration of chimeric antigen receptor (CAR) T cells that target mesothelin, followed by immune checkpoint blockade. In a subgroup of 18 patients who received cyclophosphamide preconditioning, CAR T cells, and at least three doses of anti-PD1 therapy with pembrolizumab, median overall survival (OS) after CAR T-cell treatment was 23.9 months, and one-year OS was 83%.^[46]  

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Trimodality Therapy

Trimodality therapy involves a combination of all 3 standard strategies: surgery, chemotherapy, and radiation. In one study, patients undergoing a trimodality approach involving extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy had an overall median survival rate of 24% at 2 years. Seven patients were still alive at the end of the study, including 2 patients who by that time had survived for 40-45 months.^[47]

Lymph node involvement was a significant negative prognostic factor in the study. The median length of survival for patients with lymph node metastasis was 13 months, while the median length of survival for patients without lymph node involvement was 24 months. Patients with the epithelial type of mesothelioma had a better survival rate than did patients with the sarcomatous or mixed type (65% vs 20% at 2y and 27% vs 0% at 5y, respectively).

Survival based on the Brigham staging system for mesothelioma was as follows:

• Stage I: 22 months
• Stage II: 17 months
• Stage III : 11 months

Overall median survival was 17 months, yielding a 2-year survival rate of 36% and a 5-year survival rate of 14%. Survival in patients with epithelial cell mesothelioma was better, with a 2-year survival rate of 68% and 5-year survival rate of 46%.

Chemotherapeutic regimens found to be useful in the trimodality treatment include cyclophosphamide/doxorubicin (Adriamycin)/cisplatin, carboplatin/paclitaxel, and cisplatin/methotrexate/vinblastine. External beam radiotherapy is delivered in a standard fractionation over 5.5-6 weeks.

• References

Pleurectomy and Pneumonectomy

Measuring the diffusion capacity of the lung preoperatively is important because most patients have poor pulmonary reserve secondary to interstitial lung disease.

Surgical resection has been relied upon because radiation and chemotherapy have been ineffective primary treatments.^[48] The 2 surgical procedures used are pleurectomy with decortication and extrapleural pneumonectomy (EPP). A meta-analysis showed no statistically significant difference in 2-year mortality after pleurectomy with decortication compared with EPP, but pleurectomy with decortication was associated with a significantly lower proportion of short-term deaths (perioperatively and within 30 days) than EPP (1.7% vs 4.5%).^[49]  

Pleurectomy with decortication is a more limited procedure and requires less cardiorespiratory reserve. It involves dissection of the parietal pleura, incision of the parietal pleura, and decortication of the visceral pleura, followed by reconstruction. It has a morbidity rate of 25% and a mortality rate of 2%.^[50] It is a difficult procedure because the tumor encases the whole pleura, and the local recurrence rate is high, but it is preferred due to lower morbidity and mortality.

Extrapleural pneumonectomy is a more extensive procedure and has a higher mortality rate, although the mortality rate has improved, falling to 3.8%. The procedure involves dissection of the parietal pleura, division of the pulmonary vessels, and en bloc resection of the lung, pleura, pericardium, and diaphragm, followed by reconstruction. It provides the best local control because it removes the entire pleural sac along with the lung parenchyma.

With surgery alone, the recurrence rate is very high and most patients die after a few months. At least half of the patients who have local control with surgery have distant metastasis upon autopsy.

A study by Cao et al found that patients with nonepithelial malignant pleural mesothelioma and nodal involvement have a worse prognosis after extrapleural pneumonectomy, questioning their eligibility as candidates.^[51]

In patients with epithelioid-type malignant pleural mesothelioma who are fit enough to tolerate a thoracotomy, the best option is still a thoracotomy and macroscopic clearance of the tumor as part of multimodality therapy.

• References

Radiation Therapy

Malignant pleural mesothelioma has traditionally been considered to be resistant to radiotherapy. In patients who have undergone limited or no surgical resection and have an intact lung, high-dose radiation therapy has shown significant toxicity and no significant survival benefit. However, the development of highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT) has resulted in positive outcomes in combination with surgical resection.^[52]

IMRT given after extrapleural pneumonectomy (EPP) has been shown to provide excellent local control, although distant metastases have remained a significant problem and limit survival.^[53]  With the increasing use of pleurectomy-decortication (P-D) rather than EPP, adjuvant pleural IMRT after P-D has also entered practice, as has definitive IMRT with chemotherapy in patients with inoperable pleural mesothelioma.^{[53, 54]}  

Neoadjuvant IMRT may have a role, particularly in patients with epithelial subtypes of mesothelioma. In a study by Cho et al of the Surgery for Mesothelioma After Radiation Therapy (SMART) approach in 25 patients with resectable malignant pleural mesothelioma, a 1-week course of high-dose hemithoracic IMRT before EPP proved feasible and prolonged survival. Cumulative 3-year survival was 84% among patients with epithelial subtypes (more than double the rate seen without IMRT), but was 13% among those with biphasic subtypes. No grade 3 or higher toxicities were associated with IMRT.^{[55, 56]}   

A study of accelerated hemithoracic IMRT followed by EPP in 62 patients with resectable malignant pleural mesothelioma reported median overall survival of 51 months and disease-free survival of 47 months in epithelial subtypes, compared with 10 and 8 months, respectively, in biphasic subtypes.^[57]

These findings and other single-arm study results have led to the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomythe introduction of adjuvant pleural IMRT after pleurectomy-decortication as well as.^{[52, 54]}

Prophylactic irradiation of scars from thoracoscopy or drainage procedures has been used to reduce the likelihood of seeding metastases. Guidelines generally recommend against the use of this procedure.^{[58, 27, 21, 59]}

Radiation therapy has proved effective at providing relief of chest pain, bronchial or esophageal obstruction, and other symptoms. Current guidelines recommend its use in palliatiative care.^{[58, 27, 21, 59]}

NovoTTF-100L System 

Approved by the FDA in 2019 under the Humanitarian Device Exemption, the NovoTTF-100L System (Novocure, Portsmouth, NH) is the first device used in conjunction with standard two-drug chemotherapy to treat patients with unresectable malignant pleural mesothelioma. The device uses electric fields to stop mesothelioma tumors from dividing.  Patients use the device at home for at least 18 hours a day, with minimal breaks.

In a clinical trial of 80 patients with unresectable malignant pleural mesothelioma who used the NovoTTF-100L System along with a standard 2-drug chemotherapy regimen, the median overall survival for patients was 18 months, demonstrating the device's potential to extend life expectancy in this patient population.^[60]

In the trial, the most common complication of using the device included skin irritation, red rash, and small sores or blisters on a patient’s skin where the transducer arrays attached to the chest, which occurred in 57 of the 80 patients. Mild-to-moderate skin irritation was treated with steroid cream and by relocating the transducer arrays to other parts of the chest or back.  Four patients reported severe skin problems, which resolved after stopping treatment.^[60]

• References

Consultations and Referrals

A good working relationship among the occupational medicine specialist, the environmental hazard team, and the community at large is important.

If an infection is suggested initially, consultation with a pulmonary specialist is essential if the infection does not resolve within 2 weeks with adequate antibiotic treatment. Chest radiographs are mandatory for follow-up if the infection has resolved. If the patient has diffuse calcification of the pleura and a history of weight loss with chronic cough, a full evaluation by a pulmonary specialist and oncologist is necessary.

A referral for thoracoscopy is warranted if the diagnosis is considered and the initial workup is not diagnostic.

• References

Guidelines Summary

The following organizations have released guidelines on the diagnosis and treatment of malignant pleural mesothelioma (MPM):

• American Society of Clinical Oncology (ASCO)
• National Comprehensive Cancer Network (NCCN)
• The European Respiratory Society/European Society of Thoracic Surgeons/European Association for Cardio-Thoracic Surgery/European Society for Radiotherapy and Oncology (ERS/ESTS/EACTS/ESTRO)
• European Society for Medical Oncology (ESMO)
• British Thoracic Society (BTS)

NCCN guidelines recommend that patients be managed by a multidisciplinary team with experience in MPM.^[21]  Treatment options include surgery, radiation therapy (RT), and/or chemotherapy. Select patients may be candidates for multimodality treatment.

Diagnosis

All the guidelines recommend performing the following tests in the initial evaluation and diagnosis of MPM^{[21, 58, 27, 29]} :

• Chest CT with contrast
• Thoracentesis for cytologic assessment
• Pleural biopsy (thoracoscopic biopsy is preferred)

In addition, NCCN guidelines suggest that soluble mesothelin-related peptide (SMRP) measurement may be considered and may correlate with disease status,.^[21] In contrast, ESMO guidelines state that circulating tumor markers cannot adequately distinguish MPM.^[29]

ASCO and BTS guidelines concur on the following recommendations for the pathological diagnosis of MPM^{[58, 27]} :

• Do not rely on cytology alone to make a diagnosis of MPM. If effusion cytology is frankly malignant, the diagnosis may be strongly suggested but confirmation by biopsy, if possible, is recommended. 
• Immunohistochemistry (IHC) is recommended for the differential diagnosis of MPM in both biopsy and cytology-type specimens.
• A combination of at least two positive mesothelial (calretinin, cytokeratin 5/6, Wilms tumor 1, D-240) and at least two negative adenocarcinoma immunohistochemical markers (TTF1, CEA, Ber-EP4) should be used in the differential diagnosis of MPM. 
• MPM should be reported as epithelial, sarcomatoid, or biphasic, because these subtypes have a clear prognostic significance 

Chemotherapy

NCCN and ASCO concur on the following recommendations for first-line chemotherapy^{[27, 21]} :

• Chemotherapy should be offered either alone for medically inoperable patients or as part of a multimodality regimen for patients with medically operable disease
• In asymptomatic patients with epithelial histology and minimal pleural disease who are not surgical candidates, a trial of close observation may be offered prior to the initiation of chemotherapy.
• First-line chemotherapy of pemetrexed plus cisplatin or carboplatin
• Addition of bevacizumab to pemetrexed–platinum agent in selected patients 
• Bevacizumab not recommended for patients with significant cardiovascular comorbidity, uncontrolled hypertension, or bleeding/clotting risk.

NCCN guidelines recommend the following as preferred first-line therapy (category 1) for epithelioid mesothelioma^[27] :

• (Cisplatin or carboplatin) + pemetrexed
• (Cisplatin or carboplatin) + pemetrexed + bevacizumab
• (Cisplatin or carboplatin) + pemetrexed + pembrolizumab
• Nivolumab/ipilimumab

NCCN guidelines recommend the following as preferred first-line therapy (category 1) for biphasic or sarcomatoid mesothelioma^[21] :

• Nivolumab/ipilimumab
• (Cisplatin or carboplatin) + pemetrexed + pembrolizumab

The BTS guidelines recommend first-line therapy with cisplatin and pemetrexed in patients with good performance status. Raltitrexed is an alternative to pemetrexed.^[58]

ESMO recommendations for first-line therapy are as follows^[29]

• Pemetrexed combined with cisplatin (or alternatively carboplatin), and vitamin supplementation, for up to six cycles
• Combination of bevacizumab with platinum–pemetrexed
• Nivolumab plus ipilimumab, given up to 2 years equivalent dosing, regardless of histologies or PD-L1 status for unresectable MPM
• Maintenance gemcitabine is not routinely recommended in patients with non-progressive MPM but may prolong progression-free survival and can be considered when the benefits of deferring progression outweigh the inconveniences and toxicities of ongoing treatment
• Maintenance pemetrexed is not recommended in patients with non-progressive MPM after first-line platinum–pemetrexed

Second-line therapy

NCCN recommendations for second-line therapy are as follows^[21] :

• Pemetrexed, if not administered as first-line therapy (category 1); consider rechallenge if the patient had a good sustained response at the time initial chemotherapy was interrupted
• Nivolumab ± ipilimumab, if not administered in first-line therapy
• Pembrolizumab

ASCO guidelines offer the following recommendations for second-line chemotherapy^[27] :

• Retreatment with pemetrexed-based chemotherapy may be offered in pleural mesothelioma patients who achieved durable (> 6 months) disease control with first-line pemetrexed-based chemotherapy 
• Given the very limited activity of second-line chemotherapy, participation in clinical trials is recommended
• In patients for whom clinical trials are not an option, vinorelbine may be offered 

The BTS guidelines advise that pemetrexed or vorinostat should not be offered as second-line treatment for patients with MPM.^[58]

ESMO recommendations for second-line MSM therapy are as follows^[29] :

• Single-agent pembrolizumab in immunotherapy-naïve patients as second-line therapy has similar outcomes to single-agent chemotherapy.
• Single-agent nivolumab is superior to best supportive care in pretreated immunotherapy-naïve patients.
• Combination nivolumab–ipilimumab can be considered in immunotherapy-naïve patients as a second- or third-line treatment option.
• Reintroduction of platinum–pemetrexed or pemetrexed chemotherapy has second-line activity in selected circumstances, as suggested by objective response rates (ORRs).
• Single-agent gemcitabine or vinorelbine has limited second-line activity, as suggested by ORRs or overall survival rates
• Initial evidence shows encouraging activity of gemcitabine combined with ramucirumab.

Surgery

NCCN and ASCO concur on the following recommendations for surgical treatment of MPM^{[27, 21]} :

• In selected patients with early-stage disease, pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) are reasonable surgical options to achieve complete gross cytoreduction.
• Mediastinal node dissection of at least three nodal stations is recommended in patients undergoing either P/D or EPP. 
• Maximal surgical cytoreduction as a single modality treatment is generally insufficient; additional antineoplastic treatment (chemotherapy and/or radiation therapy) should be administered.
• Surgery is not recommended for patients with stage IV disease or saracomatoid or mixed histology. 
• Surgery is not recommended for patients with N2 disease unless performed at a center of expertise or in a clinical trial

However, the ERS/ESTS/EACTS/ESTRO joint guidelines published in 2020 declined to issue a recommendation on the use of P/D or EPP because of the large variability and conflicting results of reported outcomes for morbidity, mortality, quality of life and overall and disease-free survival. ERS/ESTS/EACTS/ESTRO guidelines acknowledge that surgery may be appropriate in select patients. In those cases, P/D is preferred over EPP due to its lower comparative respiratory postoperative morbidity and quality of life. Patients considered for radical surgery should be included in prospective randomized controlled clinical trials or in national/international surgical registries.^[59]

ERS/ESTS/EACTS/ESTRO guidelines for the surgical treatment of MPM include the following recommendations^[59] :

• The first choice to control a recurrent MPM effusion and achieve pleurodesis in patients with expanded lungs is talc poudrage via thoracoscopy.
• Palliative video-assisted thoracic surgery–partial pleurectomy (VATS-PP) to obtain pleural effusion control in symptomatic patients may be considered for patients fit enough to undergo surgery who cannot or did not benefit from chemical pleurodesis or indwelling catheter.

ESMO surgical recommendations are as follows^[29]

• Surgery is recommended for obtaining diagnostic samples of tumor tissue, for staging, and for palliation of pleural effusions when chest tube drainage is not successful.
• Talc poudrage via thoracoscopy remains the first surgical procedure of choice for pleurodesis over VATS partial pleurectomy.
• Macroscopic complete resection, in combination with other modalities, is recommended in selected MPM patients, to be carried out at experienced centers and to be discussed with a multidisciplinary team involving thoracic surgeons, pulmonologists, medical and radiation oncologists.
• Extended pleural decortication is a lung-preserving procedure and is preferred over EPP.

Radiation Therapy

NCCN guidelines recommend the use of radiation therapy (RT) as part of a multimodality regimen, but do not recommend RT alone for treatment, and do not routinely recommend prophylactic RT to prevent instrument-tract recurrence after pleural intervention.^[21] ASCO guidelines recommend against prophylactic RT but recommend adjuvant RT for resection of intervention tracts found to be histologically positive.^[27]

The BTS recommends against preoperative or postoperative RT, prophylactic radiotherapy to chest wall procedure tracts, and hemithorax RT.^[58]  Similarly, the ERS/ESTS/EACTS/ESTRO guidelines strongly recommend against using RT to prevent procedure-tract metastases, and recommend considering postoperative RT only in the context of clinical trials and/or including it in national/international surgical registries.^[59]

All four guidelines recommend RT for palliative therapy to relieve chest pain, bronchial or esophageal obstruction, or symptoms of metastases in the bone or brain.^{[58, 27, 21, 59]}

In 2019, the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation issued an expert opinion recommending the use of RT for MPM in the following scenarios^[61] :

• Before or after extrapleural pneumonectomy
• As an adjuvant to lung-sparing procedures (ie, without pneumonectomy)
• As palliative therapy for focal symptoms caused by the disease

ESMO recommendations regarding RT for MPM are as follows^[29] :

• RT can be considered for palliation of pain related to local infiltration of thoracic structures
• The use of prophylactic RT of tracts after diagnostic or therapeutic pleural procedures to prevent chest wall metastases is not recommended.
• RT can be considered in an adjuvant setting after macroscopic complete resection to reduce the local failure rate; however, no evidence is available for its use as a standard treatment.
• When postoperative RT is applied, strict dose constraints for thoracic critical organs must be adhered to in order to avoid toxicity to organs at risk.

Palliative and supportive care and surveillance

ESMO recommendations are as follows^[29] :

• Early access to specialist palliative care at the time of diagnosis does not improve quality of life
• Pleurodesis is useful in preventing recurrent effusions
• For recurrent pleural effusions, an indwelling pleural catheter  can provide good clinical benefit.
• For patients with indwelling pleural catheters, aggressive draining is not superior to symptomatic drainage for controlling breathlessness.
• For surveillance, imaging to evaluate response is best carried out with contrast-enhanced computed tomography scanning.

• References

Medication Summary

Treatment options for the management of malignant mesothelioma include surgery, chemotherapy, radiation, and multimodality treatment. Currently, no therapy is considered standard. The standard methods of surgery, radiation, or chemotherapy alone have not improved survival. At present, the first choice for treatment of metastatic malignant pleural mesothelioma is the combination of ipilimumab and nivolumab.

The US Food and Drug Administration (FDA) has approved the following regimens for treatment of malignant pleural mesothelioma:

• Pemetrexed in combination with cisplatin, for initial treatment in patients whose disease is unresectable or who are not candidates for curative surgery
• Nivolumab in combination with ipilimumab, for first-line treatment of unresectable malignant pleural mesothelioma^[30]
• Pembrolizumab in combination with pemetrexed and platinum chemotherapy, for first-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma^[36]

• References

Gemcitabine (Gemzar)

• Dosing, Interactions, etc.

Clinical Context:  Gemcitabine is a cytidine analogue that, after being metabolized intracellularly to an active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into deoxyribonucleic acid (DNA). It is cell-cycle specific for the S phase.

• References

Pemetrexed disodium (Alimta)

• Dosing, Interactions, etc.

Clinical Context:  This agent disrupts folate-dependent metabolic processes essential for cell replication. It specifically inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed disodium is indicated for use in combination with cisplatin to treat patients with malignant pleural mesothelioma in unresectable disease, as well as patients who are not candidates for curative surgery.

• References

Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  Cisplatin is a platinum-based alkylating agent. It inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of the double helix. Cisplatin is indicated for use in combination with pemetrexed disodium to treat patients with malignant pleural mesothelioma in unresectable disease and those who are not candidates for curative surgery.

• References

Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxorubicin is an anthracycline antibiotic that causes DNA strand breakage through effects on topoisomerase II and direct intercalation into DNA, which causes DNA polymerase inhibition. This drug is both mutagenic and carcinogenic.

• References

Class Summary

These agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis is also a potential mechanism of many antineoplastic agents.

• References

Nivolumab (Opdivo)

• Dosing, Interactions, etc.

Clinical Context:  Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Combination therapy with ipilimumab is indicated for first-line treatment of adults with unresectable malignant pleural mesothelioma.

• References

Ipilimumab (Yervoy)

• Dosing, Interactions, etc.

Clinical Context:  Ipilimumab is a targeted a recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody. It binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 augments T-cell activation and proliferation. The proposed mechanism of action is indirect, possibly through T-cell–mediated antitumor immune responses. Combination therapy with nivolumab is indicated for first-line treatment of adults with unresectable malignant pleural mesothelioma.

• References

Bevacizumab (Avastin)

• Dosing, Interactions, etc.

Clinical Context:  Recombinant humanized monoclonal antibody to VEGF; blocks the angiogenic molecule VEGF thereby inhibiting tumor angiogenesis, starving tumor of blood and nutrients. Bevacizumab has orphan drug designation for treatment of mesothelioma.

• References

Pembrolizumab (Keytruda)

• Dosing, Interactions, etc.

Clinical Context:  Monoclonal antibody to programmed cell death-1 protein (PD-1); indicated for treatment of unresectable or metastatic melanoma and for adjuvant treatment of adults with stage IIB, IIC, or III melanoma following complete resection.

• References