Mesothelioma Treatment & Management

Treatment options for the management of malignant mesothelioma include surgery, chemotherapy, ^{[2, 3]} radiation, and multimodality treatment. Surgery in patients with disease confined to the pleural space is reasonable. 

The histopathological 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.

For more information, see Malignant Pleural Mesothelioma Treatment Protocols.

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

Currently, ipilimumab plus nivolumab is the most effective treatment for metastatic malignant pleural mesothelioma (MPM) that is unresectable. The other active agents are anthracycline, platinum, and alkylating agents; each produces a response rate of 10-20%. ^[24]

Ipilimumab/nivolumab

In the open-label, randomized, phase III CheckMate 743 study (n=605), nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care platinum doublet chemotherapy (cisplatin or carboplatin plus pemetrexed). Two-year overall survival rates were 41% in the nivolumab plus ipilimumab group and 27% in the chemotherapy group. Overall survival benefit was seen predominantly in the patients with non-epithelioid histology, who comprised 25% of participants. Progression-free survival and response rates were comparable with nivolumab/ipilimumab and chemotherapy. ^[24]

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 B-12 were given routinely to prevent the adverse effects of pemetrexed. This trial established the regimen as the standard of care for this disease. ^[25]

Santoro et al reported that chemonaive patients with malignant pleural mesothelioma who received either pemetrexed/cisplatin or pemetrexed/carboplatin 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. ^[26]

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%). ^[27]

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 cisplatin. 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 6 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%). ^[28]

Single-agent pemetrexed

Single-agent pemetrexed therapy 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 chemo-naive patients. Of the pretreated patients, the response rate was 12.1% and median time to progressive disease was 4.9 months. ^[29]

Cisplatin/gemcitabine

A 1999 phase II study by Byrne et al using cisplatin (100 mg/m²) on day 1 and gemcitabine (1000 mg/m²) administered intravenously on days 1, 8, and 15 of a 28-day cycle for 6 cycles showed response rates of 47.6% (complete and partial response), 42.8% (stable disease), and 9.5% (progressive disease). The median response duration was 25 weeks, progression-free survival was 25 weeks, and the overall survival was 41 weeks. Toxicity was mainly gastroenterologic and hematologic in nature. ^[30]

Durvalumab plus chemotherapy

In unresectable malignant pleural mesothelioma, tThe 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. ^{[31, 32]}  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. ^[31]  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). ^[32]

A phase III study of durvalumab plus chemotherapy, DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM3R) is currently recruiting. ^[33]

Additional drug combinations

Several other combinations have been found to be active, including cisplatin/doxorubicin (Adriamycin)/mitomycin C, bleomycin/intrapleural hyaluronidase, cisplatin/doxorubicin, carboplatin/gemcitabine, and cisplatin/vinblastine/mitomycin C. ^[34] The cisplatin/gemcitabine combination has yielded the best results.

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. ^[35] 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%. ^[36]  

Numerous trials of chemotherapeutic agents have been performed. Until recently, however, the studies were small and used different staging systems and inaccurate measurements of disease.

In 2013, the cancer stem cell inhibitor defactinib (VS-6063) received an orphan drug designation from the US Food and Drug Administration (FDA) for treatment of mesothelioma. The drug's manufacturer agreed to conduct a double-blind, placebo-controlled trial in patients with malignant pleural mesothelioma. However, the trial was terminated when interim analysis showed a good safety profile but lack of efficacy. ^[37]

In 2020, the FDA approved nivolumab in combination with ipilimumab for first-line treatment of unresectable metastatic pleural mesothelioma. Approval was based on the phase III CheckMate-743 clinical trial (n = 605), a randomized, open-label study in which the combination of nivolumab and ipilimumab yielded superior overall survival (OS) compared with platinum-based standard of care chemotherapy. Patients who received nivolumab in combination with ipilimumab survived a median of 18.1 months, while patients who underwent chemotherapy survived a median of 14.1 months. ^[38]

Trimodality therapy involves a combination of all 3 standard strategies: surgery, chemotherapy, and radiation. In a 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. ^[39]

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.

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. ^[40] 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%). ^[41]  

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%. ^[42] 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. ^[43]

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.

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. ^[44]

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. ^[45]  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. ^{[45, 46]}  

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. ^{[47, 48]}   

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. ^[49]

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. ^{[44, 46]}

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. ^{[50, 51, 52, 53]}

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. ^{[50, 51, 52, 53]}

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. ^[54]  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. ^[55]

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. ^[55]

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.