What is the recommended first‑line systemic treatment for a medically fit adult (≥ 18 years, ECOG 0‑2) with stage III‑IV malignant mesothelioma, and what alternative or second‑line options are available?

Advanced Malignant Mesothelioma: First-Line Systemic Treatment

For medically fit adults with stage III-IV malignant pleural mesothelioma (ECOG 0-2), the recommended first-line treatment is platinum-based chemotherapy combined with pemetrexed (with mandatory folic acid and vitamin B12 supplementation), with consideration of adding bevacizumab or using immunotherapy based on histologic subtype. 1

First-Line Treatment Algorithm by Histologic Subtype

For Nonepithelioid Histology (Sarcomatoid or Biphasic)

• Ipilimumab plus nivolumab is the preferred first-line regimen, administered for up to 2 years regardless of PD-L1 status 2
• This represents the strongest recommendation for this aggressive histologic subtype

For Epithelioid Histology

Primary option:

• Pembrolizumab combined with pemetrexed plus platinum-based chemotherapy for up to 2 years 2

Alternative options include:

• Nivolumab plus ipilimumab 2
• Pemetrexed 500 mg/m² plus cisplatin (AUC 5) on day 1 of a 21-day cycle, with median overall survival of 12.1 months 1, 3, 2
• Pemetrexed plus carboplatin (preferred for patients with poor performance status or significant comorbidities unable to tolerate cisplatin), with median overall survival of 12.7-14 months 3, 2
• Bevacizumab added to cisplatin/pemetrexed if patient is fit for bevacizumab and cisplatin, but not planned for macroscopic complete resection 1

Mandatory Vitamin Supplementation Protocol

Critical to prevent toxicity:

• Vitamin B12 1000 μg intramuscularly starting at least 1 week before first pemetrexed dose, then every 9 weeks throughout treatment 3
• Folic acid 0.4-1.0 mg orally daily, starting at least 1 week before first dose and continuing throughout treatment 1, 3

Treatment Duration and Monitoring

• Administer 4-6 cycles for front-line therapy 3
• Patients with stable or responding disease should take a treatment break rather than continuing maintenance therapy 3
• Performance status evaluation before each cycle 3
• Complete blood counts to assess nadir timing during cycle (days 8 and 15) 3
• Response evaluation using CT scan after 2-3 chemotherapy cycles using modified RECIST criteria 1

Second-Line Treatment Options

For patients previously treated with chemotherapy who are immunotherapy-naïve:

• Single-agent nivolumab is the standard second-line option 2

For patients who received first-line immunotherapy:

• Pemetrexed plus platinum-based chemotherapy can be reintroduced in patients with durable response (>6 months) to first-line pemetrexed-based therapy 1, 2

For patients with performance status 2:

• Single-agent pemetrexed, vinorelbine, or gemcitabine may be considered, though response rates are low 1, 2

Important Contraindications and Special Considerations

Absolute contraindications:

• Severe renal impairment is an absolute contraindication for pemetrexed 3

Performance status considerations:

• ECOG 0-2: eligible for standard combination regimens 1, 2
• ECOG 3-4: best supportive care is recommended; chemotherapy is not recommended 3, 2

Asymptomatic patients with low disease burden:

• May be considered for observation before initiating systemic therapy, with chemotherapy planned at time of symptomatic or radiographic progression 3

Role of Surgery in Advanced Disease

Surgery is NOT recommended as standard treatment for stage III-IV disease:

• Patients with sarcomatoid or sarcomatoid-predominant histology, N2 disease (8th edition TNM staging system), and/or stage IV should not be considered for radical surgery other than in the context of research 1
• Radical surgery should only be performed in highly selected patients within prospective randomized controlled clinical trials or national/international surgical registries 1
• If surgery is considered, pleurectomy/decortication is preferred over extrapleural pneumonectomy due to lower respiratory postoperative morbidity and preservation of quality of life 1

Palliative Radiotherapy

• Palliative radiotherapy for pain relief should be considered in cases of painful sites of disease caused by local infiltration of normal structures 1
• Prophylactic drain site radiotherapy is NOT recommended in routine clinical care (this represents a change from older 2001 guidelines that recommended routine prophylactic irradiation) 1

Clinical Trial Enrollment

• Inclusion of patients in clinical trials is highly encouraged, particularly for immunotherapy combinations and multimodal approaches 1
• Novel insights in immunotherapy are promising but need further development and results from ongoing phase III trials before definitive recommendations 1