What is the recommended treatment approach for patients with epithelioid Pleural Mesothelioma?

Treatment Approach for Epithelioid Pleural Mesothelioma

For patients with epithelioid pleural mesothelioma, pembrolizumab combined with pemetrexed plus platinum-based chemotherapy should be offered as first-line systemic therapy for up to 2 years, with lung-sparing surgical cytoreduction (pleurectomy/decortication) reserved for highly selected patients with early-stage disease (T1-3N0) who meet strict cardiopulmonary criteria and can receive multimodality treatment. 1

First-Line Systemic Therapy

Primary Recommendation for Epithelioid Subtype

• Pembrolizumab with pemetrexed (500 mg/m²) plus platinum (cisplatin 75 mg/m² or carboplatin AUC 5) every 3 weeks may be offered as first-line therapy for up to 2 years in the absence of disease progression or intolerable toxicity. 1
• This regimen is specifically recommended for the epithelioid subtype, as the survival benefit of dual immunotherapy (ipilimumab + nivolumab) is most significant in nonepithelioid subtypes. 1, 2

Alternative First-Line Options

• Pemetrexed plus platinum-based chemotherapy (with folic acid and vitamin B12 supplementation) remains a robust treatment option for epithelioid mesothelioma, particularly for patients not candidates for immunotherapy. 1, 3
• Bevacizumab may be added to cisplatin/pemetrexed in select patients with no contraindications (excluding those with PS 2, substantial cardiovascular comorbidity, uncontrolled hypertension, age >75, or bleeding/clotting risk). 1, 3

Duration and Monitoring

• Administer 4-6 cycles of pemetrexed-based chemotherapy; for patients with stable or responding disease, a break from chemotherapy is recommended. 1
• Maintenance pemetrexed is not recommended. 1

Surgical Cytoreduction

Patient Selection Criteria

Surgery should only be considered for highly selected patients who meet ALL of the following criteria: 1

• Clinical early-stage disease (T1-3N0) with epithelioid histology
• No evidence of extrathoracic disease on PET-CT
• Meet specific preoperative cardiopulmonary functional criteria
• Able to receive multimodality treatment (adjuvant or neoadjuvant)
• Performance status 0-1

Surgical Approach

• Lung-sparing options (pleurectomy/decortication or extended P/D) are the primary choice over extrapleural pneumonectomy (EPP). 1
• This recommendation reflects lower respiratory postoperative morbidity and preservation of quality of life with P/D compared to EPP. 1
• Surgery must be performed at specialized centers by board-certified thoracic surgeons with mesothelioma experience. 1, 3

Contraindications to Surgery

Do not offer maximal surgical cytoreduction to patients with: 1

• Sarcomatoid histology
• Transdiaphragmatic disease
• Multifocal chest wall invasion
• Contralateral mediastinal (N3) or supraclavicular lymph node involvement
• N2 disease (8th edition TNM staging)
• Stage IV disease

Multimodality Treatment Protocol

Neoadjuvant Approach

• For highly selected patients with early-stage epithelioid tumors, neoadjuvant immunotherapy may be offered; however, adjuvant immunotherapy is not recommended. 1
• Neoadjuvant chemotherapy (4-6 cycles of pemetrexed/platinum) can be administered before surgery. 1, 3

Adjuvant Therapy

• After surgical cytoreduction, patients should receive additional antineoplastic treatment based on multidisciplinary discussion. 1
• Adjuvant radiotherapy (50-60 Gy in 1.8-2.0 Gy fractions) may be offered to patients with good performance status after EPP to improve local control, though it does not provide clear survival benefit. 1

Special Populations

Asymptomatic Patients with Minimal Disease

• In asymptomatic patients with epithelioid mesothelioma and minimal pleural disease who are not surgical candidates, a trial of close observation may be offered before initiating systemic therapy. 1

Patients Not Candidates for Maximal Cytoreduction

• Offer surgical cytoreduction with additional antineoplastic treatment based on multidisciplinary discussion. 1
• For symptomatic pleural effusion, perform talc pleurodesis via thoracoscopy or place an indwelling pleural catheter. 1, 3

Second-Line Treatment

After First-Line Immunotherapy

• If disease progresses after completing immunotherapy with initial disease control, retreatment with immunotherapy may be offered. 1
• Discontinue immunotherapy if severe immunotherapy-related toxicities occur. 1

After First-Line Chemotherapy

• Patients who achieved durable response (>6 months) with first-line pemetrexed-based chemotherapy may be offered retreatment with the same regimen. 1
• Vinorelbine or gemcitabine switch maintenance chemotherapy may be offered. 1
• Given the limited activity of second-line chemotherapy, participation in clinical trials is strongly recommended. 1

Critical Prognostic Factors

Favorable prognostic characteristics include: 3, 4

• Epithelioid histology
• Early-stage disease (Stage I-II)
• Performance status 0-1
• Absence of lymph node involvement (pN0)

In the subgroup of epithelioid MPM patients without positive lymph nodes (pN0) after EPP, 5-year disease-free survival reaches 27%. 4

Essential Multidisciplinary Approach

• All treatment decisions must be made by a multidisciplinary team including thoracic surgeons, pulmonologists, medical oncologists, radiation oncologists, and diagnostic imaging specialists. 1, 3
• Patient-centered communication is essential, recognizing that some patients prioritize extending survival while others emphasize symptom management and quality of life. 1

Common Pitfalls to Avoid

• Never proceed with surgical resection without thorough preoperative staging including PET-CT and mediastinal evaluation. 1, 5
• Do not offer maximal surgical cytoreduction to patients with sarcomatoid histology or N2 disease outside of clinical trials. 1
• Avoid maintenance pemetrexed after completing first-line chemotherapy. 1
• Do not perform surgery as single-modality treatment; additional antineoplastic therapy is mandatory. 1, 3