Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is an aggressive cancer of the pleural mesothelium, strongly linked to asbestos exposure. It usually presents with a unilateral pleural effusion and chest pain, is rarely curable, and has a median survival of about 12 months.

Incidence is about 1 to 3 cases in 100,000 people each year in countries with past heavy asbestos use, and it is rising where use continues. It is four times commoner in men. Median age at diagnosis is about 70, with a latency of 20 to 60 years from first exposure.

Risk factors are occupational or environmental asbestos exposure (all fibre types, amphiboles most carcinogenic), erionite in some rural regions, prior thoracic radiotherapy and germline BAP1 variants (BAP1 tumour predisposition syndrome, which also carries risk of uveal and cutaneous melanoma and renal cell carcinoma). Smoking does not raise risk.

Pathophysiology. Asbestos fibres cause chronic inflammation, oxidative injury and release of HMGB1, which drives transformation of mesothelial cells. Loss of BAP1, CDKN2A (with MTAP) and NF2 is frequent.

Histological subtypes. Epithelioid (60% to 70%) has the best prognosis, with a median survival of 14 to 18 months. Biphasic (20% to 30%) and sarcomatoid (10% to 20%) subtypes have median survival of 4 to 10 months and respond poorly to chemotherapy.

Prognostic factors. Non-epithelioid histology, male sex, older age, poor performance status, raised white cell count and platelets, low haemoglobin, chest pain and extensive disease worsen survival.

• Dyspnoea (most common) and dull, constant chest or shoulder pain, often non-pleuritic.
• Cough, weight loss, night sweats and fatigue.
• Recurrent unilateral pleural effusion; later a contracted, fixed hemithorax.
• Tumour seeding along biopsy or drain tracts, chest wall masses, and superior vena cava obstruction.
• Pericardial involvement, transdiaphragmatic spread to the peritoneum, and thrombocytosis. Distant metastases are late.

Red flags.

• Rapidly increasing dyspnoea from tense effusion or contralateral disease.
• Superior vena cava obstruction, spinal cord compression from tumour invasion, or pericardial tamponade.

• Chest radiograph then CT of the chest and upper abdomen with contrast: pleural thickening of over 1 cm, nodularity, mediastinal pleural involvement and fissural disease, with unilateral effusion. FDG-PET-CT assists staging.
• Pleural fluid cytology has a sensitivity of about 30% to 50%, so tissue is needed. Video assisted thoracoscopic biopsy with several deep samples is preferred, with image directed core biopsy when the patient cannot have thoracoscopy.
• Immunohistochemistry: positive mesothelial markers (calretinin, WT1, cytokeratin 5/6, D2-40) with negative adenocarcinoma markers (TTF-1, Ber-EP4, MOC31, claudin-4, CEA). Loss of nuclear BAP1 staining or MTAP loss, or homozygous CDKN2A deletion on FISH, confirms malignancy in difficult cases.
• Staging by tumour, node and metastasis categories using CT, PET-CT and endobronchial ultrasound with sampling of mediastinal nodes. Laparoscopy when peritoneal spread is suspected before surgery.
• Pulmonary function with a perfusion scan, echocardiography and cardiopulmonary testing when surgery is considered.
• Germline testing for BAP1 variants in younger patients or with a family history of related tumours.

Differential diagnosis.

• Metastatic adenocarcinoma of lung, breast, ovary or kidney
• Lung adenocarcinoma invading the pleura
• Epithelioid haemangioendothelioma and pleural sarcoma
• Solitary fibrous tumour of the pleura
• Benign asbestos related pleural effusion, plaques and diffuse pleural fibrosis
• Tuberculous or parapneumonic pleural disease and empyema
• Lymphoma and thymoma with pleural spread

Treatment is multidisciplinary and mostly palliative. Treatment choice depends on histology, stage, performance status and comorbidity.

Systemic therapy for unresectable disease.

• Cisplatin with pemetrexed: cisplatin 75 mg/m2 IV over 1 to 2 hours with pre-hydration and post-hydration, and pemetrexed 500 mg/m2 IV over 10 minutes, both on day 1 of a 21-day cycle for up to 6 cycles; supplementation: folic acid 400 micrograms orally once daily starting 7 days before the first dose and continuing until 21 days after the last, vitamin B12 1000 micrograms IM starting 1 week before the first dose and repeated every 9 weeks, dexamethasone 4 mg orally twice daily on the day before, the day of and the day after each pemetrexed dose; maximum cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 each cycle; monitoring: FBC, creatinine and electrolytes before each cycle, audiometry, neuropathy symptoms; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (substitute carboplatin AUC 5 IV on day 1 when it is lower), give pemetrexed only when clearance is 45 mL/min or more, stop NSAIDs from 2 days before to 2 days after each pemetrexed dose, hold for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L and resume at 75% of the dose
• Nivolumab with ipilimumab (preferred for non-epithelioid histology, and an option for epithelioid disease): nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks, for up to 24 months or until progression or unacceptable toxicity; maximum nivolumab 360 mg each 3-week dose and ipilimumab 1 mg/kg each 6-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks
• Carboplatin AUC 5 IV on day 1 of a 21-day cycle with pemetrexed 500 mg/m2 IV on day 1, for up to 6 cycles, replaces cisplatin in patients who are unfit or have creatinine clearance of 45 to 59 mL/min; maximum carboplatin dose about 750 mg each cycle; monitoring: FBC (nadir around days 14 to 21), creatinine, folic acid 400 micrograms orally once daily from 7 days before the first dose until 21 days after the last, vitamin B12 1000 micrograms IM every 9 weeks; adjustment: recalculate carboplatin with each creatinine (GFR capped at 125 mL/min), hold for neutrophils under 1.0 x 10^9/L or platelets under 75 x 10^9/L.

Surgery. Extended pleurectomy with decortication is considered in selected fit patients with early epithelioid disease, as part of multimodality therapy, in specialised centres. Extrapleural pneumonectomy is not advised because of high morbidity without benefit in survival.

Radiotherapy. Palliative radiotherapy for chest wall pain or localised masses (20 Gy in 5 fractions). Hemithoracic intensity modulated radiotherapy (about 50 Gy) after pleurectomy is an option only in specialised centres. Prophylactic irradiation of drain or biopsy tracts is not routine.

Pleural effusion and symptom control.

• Pleurodesis or indwelling catheter once the lung has re-expanded: sterile graded talc 4 to 5 g instilled once into the pleural space, by thoracoscopic poudrage or as a slurry in 50 mL of saline through a chest drain, after the lung has re-expanded; maximum 5 g in one procedure; monitoring: pain, fever, oxygen saturation, chest radiograph, drain output below 150 mL in 24 hours before removal; adjustment: avoid when the lung cannot expand (use an indwelling pleural catheter), give analgesia before instillation, use a smaller dose in markedly reduced reserve
• Specialist palliative care early for dyspnoea, pain and psychological support. Cordotomy is an option for severe localised pain.

Second line and beyond. Re-treatment with a platinum doublet or immunotherapy if the first response was durable, or palliative single agent chemotherapy, in patients with good performance status.

Monitoring. CT every 8 to 12 weeks during treatment. Weekly review for toxicity. Thyroid, cortisol and liver monitoring during immunotherapy.

Referral and escalation.

• Referral to a mesothelioma multidisciplinary team on suspicion.
• Urgent admission for tense effusion with respiratory compromise, superior vena cava syndrome, cord compression or severe immune related toxicity.
• Occupational and compensation advice, with notification of the exposure history to the relevant authority where required.

Special groups.

• Older adults and poor performance status: single agent therapy or best supportive care.
• Renal impairment: carboplatin replaces cisplatin, and pemetrexed is avoided under 45 mL/min.
• Autoimmune disease: immunotherapy risks flare, so decide with a specialist.
• Pregnancy: very rare, and managed by a multidisciplinary team with chemotherapy avoided in the first trimester.