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 results obtained with radiation therapy have been disappointing.  Radiation has had no effect on survival, but it has provided significant palliation in 50% of patients treated for chest pain and chest wall metastasis.
However, investigators evaluating the feasibility of the Surgery for Mesothelioma After Radiation Therapy (SMART) approach for resectable malignant pleural mesothelioma reported that preoperative radiation therapy may improve survival. [21, 22, 23] In a study of 25 patients with resectable malignant pleural mesothelioma, a 1-week course of high-dose hemithoracic intensity-modulated radiation therapy (IMRT) before extrapleural pneumonectomy 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 it was 13% among those with biphasic subtypes. No grade 3 or higher toxicities were associated with IMRT. [21, 22]
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.
Regular follow-up visits with an internist, pulmonary specialist, medical oncologist, and radiation oncologist are recommended.
Currently, cisplatin as a single drug has been used as the standard drug for phase III clinical trials. None of the standard treatment options has improved survival. The most active agents are anthracycline, platinum, and alkylating agents; each produces a response rate of 10-20%. 
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. 
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. 
In a phase III study, Zalcman et al reported improved overall survival with the addition of bevacizumab to the cisplatin/pemetrexed regimen as first-line treatment of advanced malignant pleural mesothelioma. Median survival increased from 16.1 months to 18.8 months with the addition of bevacizumab; however, patients receiving bevacizumab experienced more grade 3 or higher hypertension and thrombotic events. 
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%). 
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. 
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. 
Additional drug combinations
Several other combinations have been found to be active, including cisplatin/doxorubicin (Adriamycin)/mitomycin C, bleomycin/intrapleural hyaluronidase, cisplatin/doxorubicin (Adriamycin), carboplatin/gemcitabine, and cisplatin/vinblastine/mitomycin C.  The cisplatin/gemcitabine combination has yielded the best results.
Ranpirnase (Onconase) is a novel cytotoxic ribonuclease. It is a nonmyelosuppressive agent with minimal apparent toxicity to vital organs. It binds to the cell surface and penetrates the cell's interior through the energy-dependent endocytotic process. In the cytosol, it degrades transfer ribonucleic acid (tRNA); this damage constitutes a signal for apoptosis (ie, programmed cell death) and contributes to inhibition of cell growth and proliferation. 
The dose-limiting toxicity was renal; it was manifested by proteinuria, azotemia, peripheral edema, flushing, myalgia, dizziness, and decreased appetite.
In a phase II study by Miluski et al, 105 patients with 0-2 performance status were treated with ranpirnase. Median survival time was 6 months for the intent to treat group and 8.3 months for the treatment target group. Among the 81 patients assessable for tumor response, 4 had partial response, 2 had minor regressions, and 35 experienced stabilization of previously progressive disease. 
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.  These data suggest that apoptosis is not a key phenomenon in mesothelioma development and histologic differentiation.
Numerous trials of chemotherapeutic agents have been performed; until recently, however, the studies were small, the staging systems used were different, and the measurements of disease were inaccurate.
In July 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. 
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. 
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.
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.  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%). 
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%.  It is a difficult procedure because the tumor encases the whole pleura, and the local recurrence rate is high.
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. 
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.
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.
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