Malignant Pleural Mesothelioma Treatment Protocols

Treatment protocols for malignant pleural mesothelioma are provided below, including the following:

• General approaches
• Surgical resection
• Chemotherapy ^[1]
• Radiotherapy
• Trimodality therapy ^[2]

General treatment approach

Stages I-III resectable, with epithelial histology:

• Induction chemotherapy (cisplatin and pemetrexed) followed by surgical exploration or

• Pleurectomy/decortication (P/D) with adjuvant chemotherapy, optionally followed by radiation therapy or

• Extrapleural pneumonectomy (EPP) with sequential chemotherapy plus hemithoracic radiation therapy

​Stages I-III unresectable:

• Chemotherapy is recommended

• Radiation for palliation and positive margins

Stage IV or sarcomatoid or mixed histology :

• Chemotherapy plus bevacizumab

• Radiation post chemotherapy for palliation

• Surgery is not recommended for patients with stage IV disease

Surgical resection

The 2 surgical procedures commonly used in malignant mesothelioma are P/D and EPP.  P/D 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; this procedure has a morbidity of 25% and a mortality of 2%

P/D is a good option for patients with early-stage disease with favorable histology and fpr good-risk patients. In addition, P/D is appropriate for patients with advanced disease and mixed histology and/or high risk. ^{[3, 4]}

EPP is a more extensive procedure than P/D; it involves dissection of the parietal pleura and division of the pulmonary vessels, as well as en bloc resection of the lung, pleura, pericardium, and diaphragm, followed by reconstruction. EPP provides the best local control, because the entire pleural sac is removed along with the lung parenchyma. Mortality is higher with EPP than with P/D, although in recent years, the mortality in EPP has been lowered to 3.8%

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. In patients with the epithelioid type, if the patient is fit to tolerate a thoracotomy, the best option is still a thoracotomy and macroscopic clearance of the tumor as part of multimodality therapy

Chemotherapy

See the list below:

• Chemotherapy alone is recommended for patients with stage I-IV disease who are not candidates for surgery and for patients with sarcomatoid histology

• The mainstay of treatment is combination chemotherapy with pemetrexed and cisplatin ^[5]

• Other combination therapies that have also been used are carboplatin and pemetrexed, which is beneficial in patients with poor performance status or who have comorbidities

• Combination cisplatin and gemcitabine may be used if patients cannot take pemetrexed

• Hyperthermic intrathoracic chemotherapy (HITHOC) with cisplatin alone or combined with doxorubicin or gemcitabine has demonstrated benefit ^[6]

First-line combination chemotherapy:

• Pemetrexed 500 mg/m² IV plus cisplatin 75 mg/m² IV plus bevacizumab 15 mg/kg IV every 3 weeks for six cycles, with bevacizumab maintainence until progression ^[3]  or

• Pemetrexed 500 mg/m² IV plus carboplatin AUC 5 IV plus  bevacizumab 15 mg/kg IV every 3 weeks for six cycles, with bevacizumab maintainence until progression ^[3]  or

• Pemetrexed 500 mg/m² IV plus  cisplatin 75 mg/m² IV every 3 weeks ^{[7, 8, 9]}  or

• Pemetrexed 500 mg/m² IV plus  carboplatin AUC 5 IV every 3 weeks ^{[7, 10, 11]}  or

• Gemcitabine 1000-1250 mg/m² IV on Days 1, 8, and 15 plus  cisplatin 80-100 mg/m² IV on Day 1 every 3-4 weeks ^{[12, 13]}  or

• Nivolumab 360 mg IV q3Weeks plus ipilimumab 1 mg/kg IV q6Weeks; continue combination until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression  ^{[14, 15]}

Second-line chemotherapy:

• Pemetrexed 500 mg/m² IV on day 1 every 3 weeks (if not used as first-line therapy) ^{[16, 17]} or

• Vinorelbine 30 mg/m² IV weekly ^{[18, 19]}

Radiation therapy

Radiation therapy is recommended after surgery and/or in conjunction with chemotherapy. Generally, adjunctive radiation therapy should be given to patients after EPP.

Preoperative radiation therapy ^[3] :

• Total dose: 45-50 Gy
• Fraction size: 1.8-2 Gy
• Treatment duration: 4-5wk

Postoperative radiation therapy or negative margins ^[3] :

• Total dose: 50-54 Gy
• Fraction size: 1.8-2 Gy
• Treatment duration: 4-5wk

Microscopic-macroscopic positive margins ^[3] :

• Total dose: 54-60 Gy
• Fraction size: 1.8-2 Gy
• Treatment duration: 5-6wk

Palliative radiation therapy or chest wall pain from recurrent nodules ^[3] :

• Total dose: 20-24 Gy
• Fraction size: 4 Gy or greater
• Treatment duration: 1-2wk

Multiple brain or bone metastases ^[3] :

• Total dose: 30 Gy
• Fraction size: 3 Gy
• Treatment duration: 2wk

Prophylactic radiation to help prevent surgical tract recurrence ^[3] :

• Total dose: 21 Gy
• Fraction size: 7 Gy
• Treatment duration: 1-2wk

Trimodality therapy

Trimodality therapy involves a combination of all 3 standard strategies (ie, surgery, chemotherapy, radiation) and is recommended for stage II-III disease that is medically operable and has epithelial histology. ^{[3, 2]}

Chemotherapeutic regimens found to be useful in the trimodality treatment include the following: 

• CAP - Cyclophosphamide/ doxorubicin (Adriamycin)/cisplatin
• CP - Carboplatin/ paclitaxel 
• CMV - Cisplatin/ methotrexate/ vinblastine