Understanding Malignant Pleural Mesothelioma: Causes, Treatments, and New Hope

Table of Contents

• Introduction: What is Malignant Pleural Mesothelioma?
• Causes of Mesothelioma
• Types and Molecular Features of Mesothelioma
• Symptoms and Diagnosis
• Staging and Prognosis
• Current Treatment Options
• The Future of Mesothelioma Treatment
• Clinical Implications for Patients
• Limitations of Current Knowledge
• Recommendations for Patients
• Source Information

Introduction: What is Malignant Pleural Mesothelioma?

Malignant pleural mesothelioma is an aggressive cancer that develops in the lining of the lungs (pleura). It accounts for 90% of all mesothelioma cases and is usually diagnosed at advanced stages. Tragically, only 5-10% of patients survive 5 years after diagnosis. While asbestos exposure is the primary cause, other risk factors like genetic mutations are emerging.

The United States has seen a decline in deaths from 14 per 1 million people in 2000 to 11 per 1 million in 2015 due to safer work practices. However, the UK still reports 77 deaths per 1 million. Despite prevention progress, treatment advances have lagged. This review examines why current therapies have limited impact and explores promising new approaches like immunotherapy.

Causes of Mesothelioma

Asbestos exposure causes most mesothelioma cases. A landmark 1960s study in South Africa found all 33 examined patients had significant asbestos exposure. Asbestos was widely used because it's fire-resistant and durable, but many countries now ban it due to cancer links. Mining continues in Russia (710,200 metric tons in 2017), Kazakhstan (192,700 tons), and Brazil (135,000 tons), with exports to high-use countries like India (318,000 tons) and China (235,000 tons).

The disease has a 20- to 50-year latency period. While asbestos fibers and chronic inflammation trigger cancer, the exact mechanisms remain unclear. Reactive oxygen species damage DNA, creating mutations. Genetic factors also play a role:

• Germline mutations (inherited DNA changes) occur in >10% of patients
• BAP1 gene mutations accelerate mesothelioma in mice and humans
• PALB2 and BRCA1/2 DNA repair gene defects increase risk

Types and Molecular Features of Mesothelioma

Three main subtypes exist, with distinct prognoses:

1. Epithelioid mesothelioma (50-60% of cases): Best survival outlook
2. Sarcomatoid mesothelioma (10%): Highly invasive and treatment-resistant
3. Biphasic mesothelioma (30-40%): Mix of both subtypes

Recent research shows these subtypes exist on a spectrum rather than as separate categories. Molecular analysis reveals frequent tumor-suppressor gene mutations:

• BAP1 (lost in 60% of epithelioid cases)
• CDKN2A
• NF2
• SETD2

BAP1 loss is linked to premalignant changes, suggesting early intervention opportunities.

Symptoms and Diagnosis

Most patients seek help late due to slow early growth. Key symptoms include:

• Breathlessness (from fluid buildup or lung encasement)
• Chest pain (indicates tumor invasion)
• Fatigue, weight loss, and night sweats

Diagnosis involves imaging and tissue tests:

Step 1: Chest CT scan, sometimes with PET-CT or MRI for detail.
Step 2: Fluid analysis (pleural effusion) or biopsy. Biopsy is more reliable for sarcomatoid types.
Step 3: Immunohistochemistry tests using markers like:

• Positive: Calretinin, Wilms’ tumor 1 antigen
• Negative: Thyroid transcription factor 1 (rules out lung cancer)

BAP1 nuclear staining loss helps confirm diagnosis in 60% of epithelioid cases.

Staging and Prognosis

The latest International Association for the Study of Lung Cancer TNM system (8th edition) stages cancer based on:

1. Tumor size/invasion (T)
2. Lymph node involvement (N)
3. Metastasis (M)

However, staging has limitations. Autopsy studies reveal hidden spread to:

• Lymph nodes (53% of cases)
• Liver (32%)
• Bone (14%)
• Brain (3%)

Histologic subtype greatly affects survival but isn't considered in TNM staging. Epithelioid patients typically outlive sarcomatoid patients.

Current Treatment Options

Treatment depends on cancer stage, subtype, and patient health. All approaches include symptom management.

Pleural Fluid Management

Draining fluid (pleural effusion) relieves breathlessness. Options:

• Temporary drainage + talc administration (success rate similar to surgery)
• Indwelling catheters
• Surgery (higher complication risk)

Surgery

Surgery aims to remove visible tumor but isn't curative. Four approaches:

1. Partial pleurectomy: Removes part of the pleura
2. Pleurectomy-decortication: Removes affected pleura
3. Extended pleurectomy-decortication: Adds diaphragm/pericardium removal
4. Extrapleural pneumonectomy: Removes lung, pleura, diaphragm, and pericardium

The MARS trial showed shorter survival with radical surgery (14.4 vs. 19.5 months without surgery). The ongoing MARS2 trial is testing less radical surgery combined with chemotherapy.

Radiotherapy

No survival benefit proven. The SAKK 17/04 trial found no improvement in relapse-free survival after surgery. Radiotherapy is sometimes used to prevent tumor track invasion, but two major trials (PIT and SMART) showed no benefit.

Tumor-Treating Fields

This FDA-approved device uses electric fields with chemotherapy. Approved based on a phase 2 study (no comparison group), so true effectiveness remains uncertain.

Systemic Therapy

First-line chemotherapy: Cisplatin + pemetrexed improves survival to 12.1 months vs. 9.3 months with cisplatin alone (EMPHACIS trial). Adding bevacizumab (MAPS trial) extended survival to 18.8 months but increased side effects.

Immunotherapy breakthrough: Nivolumab + ipilimumab improved survival to 18.1 months vs. 14.1 months with chemotherapy (2020 FDA approval). For relapsed disease, nivolumab alone improved survival by 3 months vs. placebo (CONFIRM trial).

The Future of Mesothelioma Treatment

Key research areas include:

• Immunotherapy combinations (e.g., checkpoint inhibitors)
• Maintenance therapies after initial chemotherapy
• Vinorelbine chemotherapy trials (results expected 2021)
• Targeting BAP1 and other genetic pathways

Understanding mesothelioma's molecular heterogeneity may enable personalized treatments.

Clinical Implications for Patients

These findings mean:

• Immunotherapy (nivolumab + ipilimumab) is now a first-line option with survival benefits
• Surgery's role is uncertain—seek second opinions for surgical recommendations
• Genetic testing may reveal inherited risks (BAP1 mutations)
• Clinical trials offer access to emerging therapies

Always discuss treatment toxicity; for example, bevacizumab combined with chemotherapy increases side effects despite modest survival gains.

Limitations of Current Knowledge

Critical gaps remain:

• No asbestos-specific mutational signature identified
• Staging systems miss hidden metastases found in autopsies
• Surgery trials underpowered (MARS had only 50 participants)
• Immunotherapy long-term data pending
• Biomarkers like PD-L1 don't predict treatment response

Molecular heterogeneity makes "one-size-fits-all" treatments ineffective.

Recommendations for Patients

Based on current evidence:

1. Confirm diagnosis with biopsy and BAP1 testing
2. Discuss immunotherapy as first-line treatment if eligible
3. Seek high-volume centers for accurate staging
4. Consider clinical trials for novel therapies
5. Address symptoms early: Manage breathlessness and pain proactively
6. Genetic counseling: If family history suggests BAP1 syndrome

For relapsed disease, options include platinum-pemetrexed rechallenge or vinorelbine.

Source Information

Original Article Title: Perspectives on the Treatment of Malignant Pleural Mesothelioma
Authors: Sam M. Janes, M.D., Ph.D., Doraid Alrifai, M.D., Ph.D., and Dean A. Fennell, M.D., Ph.D.
Journal: The New England Journal of Medicine
Publication Date: September 23, 2021
DOI: 10.1056/NEJMra1912719
This patient-friendly article is based on peer-reviewed research from the original publication.