Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma is a rare tumor with a dismal prognosis that originates in the mesothelial surfaces of the pleura. The main risk factor is exposure to asbestos. Worldwide, especially in developed countries, occupational asbestos exposure has decreased significantly. Due to the long latency between exposure and development of mesothelioma, the disease is still very relevant and cases are seen sporadically. Despite advances in diagnostic imaging and clinical research, early and prompt diagnosis is challenging. Some serum tumor markers are promising but not incorporated to guidelines yet. Current treatments have been evolving very slowly in recent years; treatment focus in the use of chemotherapy, radiation and surgery. This chapter aims to present a review of malignant pleural mesothelioma to assist the practicing physician in the early recognition and evaluation of patients presenting with suspected pleural mesothelioma.

1. Introduction

Malignant mesothelioma (MM) is a rare, highly aggressive and fatal disease which originates in the mesothelial surfaces of pleura or, rarely, in other serosal membranes such as peritoneum, pericardium, and tunica vaginalis [1]. Most cases of MM have been linked to asbestos exposure. Some studies confirmed asbestos exposure in up to 80% to −86% of patients with MM; latency period between first between the first exposure and tumor development, is long and ranges from 15 to 60 years [2, 3].

Malignant pleural mesothelioma (MPM) is the most common type seen in up to 70% of cases, followed by peritoneal and pericardial mesothelioma in 30% and 1–2% respectively.

The survival of patients with mesothelioma is the worst compared with all the other types of cancer; this is related to the stage at diagnosis which is usually advanced and lack of new more effective therapies for treatment. Reported survival for mesothelioma is a 5-year survival rate of less than 10% and a median survival time of less than 1 year. In patients with early stage of MPM, overall survival is better compared with those diagnosed at a late stage; 5-year survival ranges between 7% and 24% [4, 5, 6, 7, 8].

2. Epidemiology and pathogenesis

The incidence of malignant pleural mesothelioma (MPM) is low and it has been reported to be less than 5/100,000 inhabitants in Europe [9]. The World Health Organization estimates that as many as 92,250 people die annually per year worldwide due to asbestos-related disease with around 43,000 dying of mesothelioma; more than 80% are related to occupational exposure [4, 5]. The continued use of asbestos products in developing countries raises concern of an increased incidence of MPM in the future and there are predictions that incidence will continue increasing until 2030 [10].

Other factors linking to predisposition for MM includes a germline mutation in the BAP1 gene, somatic mutations, ionizing radiation such as in patients previously treated with radiotherapy, exposure to erionite (which may be found in travel roads). Smoking has not been reported to be a risk factor for MM [11].

Several report suggest an increased risk for MPM in people exposed to asbestos who develop benign asbestos pleural diseases like pleural plaques; other investigators did not find same relationship in people with asbestos related pleural thickening [12, 13, 14].

Detailed review of the potential molecular mechanisms underlying the pathogenesis of asbestos-related diseases and mesothelioma is out of the scope of this review. Several studies suggest that asbestos fibers deposited in lungs and translocated to the pleura could have direct genotoxic effects on epithelial and mesothelial cells.

Generation of reactive oxygen and nitric species leading to oxidative stress and chronic inflammation is the main molecular mechanism linking asbestos exposure with the development of fibroplasia and neoplasia. Reactive oxygen species can be generated directly by the asbestos fibers or indirectly by inflammatory cell which will lead to release of cytokines that will potentiate the inflammatory response [15, 16]. Asbestos fibers have been shown to induce chromosomal and genetic damage in mammalian cells; mesothelioma is characterized by multiple chromosomal alterations [17, 18].

Studies suggest that the main mechanisms in the development of fibrosis and malignant cell transformation in patients exposed to asbestos are chronic inflammation, oxidative stress, genetic and epigenetic changes and direct cellular toxicity and genotoxicity [19].

3. Diagnosis and clinical presentation

Diagnosis of MPM is challenging as usually symptoms are non-specific, they can develop slowly over a period of months and many times information regarding asbestos exposure is not readily available. Patients tend to present with advanced disease and at advanced age, the average age for a MPM presentation is 72.

Symptoms are usually related to the extension of the disease and ranges from dyspnea, thoracic pain and constitutional symptoms to life threatening conditions like superior vena cava syndrome or pericardial tamponade due to malignancy [20, 21]. See Table 1 for details of symptoms [25].

Symptoms	Comments
Constitutional symptoms	Weight loss, fatigue, anorexia, low grade-fever
Dyspnea-usually chronic	Due to pleural effusion
Cough-dry	Reported in up to 10% of patients [22, 23]
Thoracic pain	Unilateral, constant, dull, irradiation to shoulder or upper abdomen due to pleural irritation
Dysphagia	Due to esophageal compression
Neurological symptoms	Sympathetic nerve involvement of the arm with neuropathic pain and Pancoast tumor symptoms, Horners’s syndrome, recurrent laryngeal nerve palsy due to tumor invasion
Intermittent hypoglycemia	Multifactorial—secretion of insulinase inhibitor [24], secretion of leucine like substance stimulating insulin release

Table 1.

Clinical presentation of malignant pleural mesothelioma.

Due to the vague symptoms diagnosis delays are not unusual as symptoms can be attributed to other pathologies. A very detailed occupational and medical history is necessary to identify exposure to asbestos and other potential predisposing risk factors.

Unexplained pleural pain associated with pleural effusion in subjects with asbestos exposure should raise concern for MPM; more than 70% of patients with MPM develop malignant pleural effusion [26].

An accurate and expedited diagnosis is important. Diagnostic investigation include initial non-invasive investigation with chest radiographs, high resolution computed tomogram of the chest (HRCT), occasionally Magnetic Resonance Imaging (MRI), Positron emission tomography computed tomogram (PET-CT) among others [27]. Cytological and tissue diagnosis is needed for diagnosis and management. Several serum tumor markers have been investigated to help in early diagnosis but their diagnostic role is still under investigation [3, 28, 29, 30]. Another promising diagnostics technique are the analysis of exhaled breath of patients with mesothelioma to evaluate volatile organic compounds and circulating tumor cells test (liquid biopsy [31, 32]. See Table 2 for details.

Modality	Common findings	Advantages	Disadvantages
Non-invasive evaluation
Chest radiograph	Pleural effusion; Nodular pleural thickening or masses; Pneumothorax (rare); Pericardial effusion	Inexpensive; Readily available	Poor sensitivity to detect small pleural effusion or pleural disease
HRCT (high resolution computed tomography) chest	Pleural effusion/thickening/masses; Interlobular, lobular, mediastinal and parietal pleural thickening; Involvement of interlobar fissure; Chest wall involvement; Pneumothorax (rare); Pericardial effusion	Sensitive to detect pulmonary and pericardial disease
MRI (Magnetic Resonance Imaging)	As HRCT of chest with better resolutions to evaluate neurological and soft tissue involvement	Good to evaluate tumor expansion and superior soft tissue contrast; Good to evaluate neurological complications of tumor	Expensive, not readily available, radiology reading expertise needed
PET-CT (Positron Imaging Tomography Scan) chest	Unilateral circumferential pleural and fissural thickening with ^18F-FDG avidity	Useful for staging and treatment response	Cannot differentiate between MPM versus other malignant pleural effusion
Serum tumor markers	Mesothelin; Fibulin-3; Osteopontin; HMGB-1 (high mobility group box 1)	Potential to support diagnosis	Studies are not consistent; Under investigation
Volatile organic compounds in exhaled breath ; Liquid biopsy		Non invasive	Still investigational
Invasive evaluation
Pleural fluid analysis/cytology	Usually negative or inconclusive	Immediate therapeutic relief in cases of large volume effusions	Low sensitivity
Pleural biopsy	Histopathology showing cells characteristic of the type of mesothelioma	High sensitivity and specificity	Longer hospital length of stay post procedure and post op pain

Table 2.

Diagnosis of malignant pleural mesothelioma.

Definitive diagnosis of MPM requires histopathology, supported by clinic-radiological findings.

3.1 Imaging modalities

3.1.1 X-ray

Chest X-rays are the primary imaging method used to detect suspicious features indicative of malignant pleural mesothelioma.

Pleural effusion is observed in 70% of cases [26], along with pleural plaques, pleural thickening, and interstitial lung disease, which are suggestive of asbestosis. Additionally, blunting of the costophrenic angle due to small effusions or pleural thickening, as well as a reduction in hemithorax size, may also be present.

3.1.2 Computed tomography

Computed tomography (CT) plays a pivotal role in the diagnosis and management of MPM. CT imaging provides detailed anatomical information and is crucial for assessing the extent of disease involvement, guiding treatment decisions, and monitoring response to therapy. By delineating the characteristic features of MPM, such as pleural thickening, effusion, and other associated findings, CT scans are essential for accurate diagnosis and staging of this challenging disease. Main radiological findings in patients with MPM are described in Table 2, parietal pleural thickening exceeding 1 cm, and circumferential pleural thickening are highly suggestive of MPM. In one study of 219 cases, pleural thickening was observed in 90%, diffuse in 63%, nodular in 22%, and mass-type in 7%. Interesting, pleural effusion was present in 79% of cases, and mediastinal lymphadenopathy in 25% [33].

3.1.3 Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) has emerged as a valuable imaging tool in the assessment of MPM, offering unique advantages over other modalities such as CT and PET. By providing detailed soft tissue contrast and multiplanar imaging capabilities, MRI can enhance the detection, characterization, and staging of MPM, aiding in treatment planning and prognostication. When MRI was compared with chest CT in patients with MPM, MRI was better in patients with small foci, and to differentiate malignant from benign disease [34, 35]. MRI is an important study to evaluate loco-regional involvement of MPM due to the high soft tissues contrast and resolution [36]. MRI is important to investigate the resectability of pleural tumors and to plan surgery in selected patients. Studies have shown that peak tumor enhancement on MRI occurs between 150 and 300 seconds following intravenous (IV) contrast administration and hence delayed phase MRI imaging is recommended [37].

3.1.4 Positron Imaging Tomography Scan

PET scanning has emerged as a valuable tool in the diagnosis and management of MPM. By detecting metabolic activity in tissues, PET scans provide functional information that complements the anatomical details obtained from other imaging modalities like CT scans and MRI. This non-invasive imaging technique allows for more accurate staging, assessment of treatment response, and monitoring of disease progression in MPM patients. FDG PET has diagnostic and prognostic importance, it can identify metabolically active areas which can be correlated with imaging information, it may locate best areas for tissue biopsies and may predict prognosis in patients during treatment. A higher FDG uptake has been associated with shorter survival [38, 39].

3.2 Biomarkers

In recent years, there has been growing interest in the use of biomarkers as valuable tools for improving the early detection, prognostication, and monitoring of MPM. Biomarkers are measurable indicators of biological processes or responses to treatment, and their identification and validation hold promise for enhancing the clinical management of MPM. Currently, three blood biomarkers have potential for the diagnosis of MPM and include soluble mesothelin related proteins (SMRP), Osteopontin and Fibulin-3.

3.2.1 Soluble mesothelin related peptides

Soluble mesothelin-related peptides (SMRPs) are normally present in mesothelin cells but show increased expression in various cancer types. These peptides are associated with the cell membrane and undergo processing to produce both megakaryocyte-potentiating factor (MPF) and mesothelin. Mesothelin contributes to the survival and growth of tumor cells by activating the NF-kB pathway [40]. Studies by Hollevoet and colleagues conducted on a population of 4491 participants of which 1026 had a diagnosis of MPM and 3465 were controls (healthy, healthy asbestos exposed, benign asbestos related disease, benign respiratory disease and lung cancer) [41] have demonstrated that mesothelin, when used as a diagnostic marker, exhibits a high specificity of 96% but a relatively lower sensitivity of 47%. Importantly, levels of SMRPs have been found to inversely correlate with overall survival, as reported in their research. While it could be elevated in ovarian, pancreatic adenocarcinoma and parenchymal lung tumors a study by Creany et al. [42] reinforced its sensitivity by showing that SMRP was positive in only 2.8% and 1.6% in other malignancies and non malignant lung and pleural diseases respectively.

3.2.2 Osteopontin

Osteopontin is an extracellular cell adhesion protein known for its role in mediating cell-matrix interactions and cell signaling through interaction with integrin and CD44 receptors. It has been found to be elevated in a wide range of malignancies including neurological, gastrointestinal, lung, breast and bladder cancer. In a seminal study by Pass et al. [43], it was found that serum levels of osteopontin were significantly elevated in patients diagnosed with pleural mesothelioma compared to individuals with a history of asbestos exposure (P < 0.001). Specifically, using a cutoff value of 48.3 ng/mL, the receiver operating characteristic (ROC) curve analysis revealed a sensitivity of 77.6% and a specificity of 85.5% when comparing the group exposed to asbestos with the group diagnosed with mesothelioma.

3.2.3 Fibulin-3

Fibulin-3, a conserved member of the fibulin family of extracellular glycoproteins encoded by the EFEMP1 gene, has been the focus of recent research. In a study conducted by Pass et al. comparing patients with malignant pleural mesothelioma (MPM) and those with only asbestos exposure, higher levels of plasma fibulin-3 were observed in the MPM group. The causes of non-mesothelioma effusions ranged from congestive heart failure, adenocarcinoma and squamous cell carcinomas of the lung and also lymphoma. High levels of fibulin-3 have been found in pleural effusions of patients with MPM when compared to those patients with pleural effusion unrelated to MPM. A cutoff value of 52.8 ng/mL for levels of plasma fibulin-3 showed a sensitivity of 96.7% and a specificity of 95.5% in distinguishing patients with MPM from those without [29].

3.2.4 HMGB1

HMGB1, a well-known damage-associated molecular pattern (DAMP), plays a crucial role in inflammation. Studies have revealed that the total level of HMGB1 in the blood was notably elevated in both MPM patients and individuals exposed to asbestos, in comparison to healthy controls [44]. It is also found in lymphomas and lung cancers. Patients with MPM had higher levels of HMGB1 when compared to asbestos-exposed individuals and healthy controls. A cutoff value of 2.0 ng/mL for serum hyperacetylated HMGB1 showed a sensitivity and specificity of 100% in distinguishing patients with MPM from controls or exposed to asbestos [44].

3.3 Invasive modalities

3.3.1 Thoracentesis

Thoracentesis serves as the primary invasive diagnostic and therapeutic intervention, albeit offering only symptomatic relief, for patients presenting with a large pleural effusion as the primary symptom of MPM. Its sensitivity ranges between 16% and 30.8% [45] due to the challenge of differentiating between reactive mesothelial cells and malignant cells. Furthermore, in addition to its pivotal role in diagnosing malignant pleural effusion (MPE), thoracentesis plays a central role in palliative treatment by facilitating the drainage of a substantial volume of pleural fluid.

3.3.2 Video Assisted Thoracoscopic Surgery

With its minimally invasive nature, Video Assisted Thoracoscopic Surgery (VATS) offers several advantages over traditional open surgery, including reduced postoperative pain, shorter hospital stays, and quicker recovery times. In the context of MPM, VATS plays a crucial role in both diagnosis and treatment, allowing for precise tissue sampling and the performance of various therapeutic procedures.

Performing pleural biopsy via VATS provides the advantage of visualizing and precisely sampling representative areas from different sites within the pleural cavity. This approach allows for the retrieval of larger tissue samples, significantly enhancing the probability of confirming the diagnosis [46]. Additionally, VATS enables thorough drainage of any pleural effusion and comprehensive exploration of the entire thoracic cavity, facilitating the assessment of disease extent. Additionally, positive-pressure ventilation under direct observation after the procedure enables the evaluation of lung re-expansion following effusion drainage, informing subsequent management strategies [47]. VATS pleural biopsy is generally well-tolerated, with patients typically experiencing minimal post operative painƒ and a short hospital stay.

VATS pleural biopsies demonstrate a sensitivity of 95%, specificity of 100%, and negative predictive value of 94% [48]. These diagnostic performance metrics are comparable to those of medical thoracoscopy, although no randomized trial has directly compared the two procedures. Notably, VATS also offers the advantage of facilitating more invasive surgical interventions, such as lung resection and tumor debulking, concurrently with the diagnostic procedure.

3.4 Histopathology

MPM shows diverse histological subtypes: epithelioid (60–80%), sarcomatoid (<10%), and biphasic/mixed (10–15%) [49]. Epithelioid MPM displays various histological patterns with polygonal, oval, or cuboidal cells resembling reactive mesothelial cells. Mitotic activity is generally low but can be higher in poorly differentiated cases [46]. Sarcomatoid MPM is rare but aggressive, characterized by spindle-shaped cells with varying nuclear atypia and mitotic activity [50]. Heterologous differentiation, such as osteoid or bone formation, is uncommon. Biphasic MPM contains both epithelioid and sarcomatoid components, each comprising at least 10% of the tumor. If one component is less than 10%, the tumor may be predominantly classified as either sarcomatoid or epithelioid [51]. While metastatic lesions also present with atypical features, the histopathology depends on primary site of origin and diagnosis is mainly dependent on Immunohistochemical (IHC) staining.

3.4.1 Role of BRCA associated protein 1 (BAP-1) immunohistochemistry

Differentiating between malignant mesothelioma and reactive mesothelial proliferation can pose significant challenges in both histology and cytology. The loss of the BAP1 protein is a common occurrence in mesothelioma, particularly in the epithelioid/biphasic subtypes, often linked to homozygous BAP1 deletion. BAP1 immunostaining from pleural fluid serves as an outstanding biomarker, exhibiting a 100% specificity in distinguishing between benign and malignant mesothelial proliferations [52, 53], making it a valuable rule in test.

4. Staging

Staging helps classify the cancer based on the size of the tumor, its spread to nearby tissues and lymph nodes, as well as its potential metastasis to distant organs. This classification system provides valuable information that guides treatment decisions, such as whether surgery is a viable option, the potential benefits of chemotherapy or radiation therapy, and the overall prognosis for the patient. Historically, two staging systems were used for MPM following which the currently used TNM staging came into existence.

4.1 Butchart staging

Developed in 1976, the Butchart System consisting of four stages stands as the oldest formal staging system for mesothelioma and is exclusively utilized for staging pleural mesothelioma. This system relies solely on the location of the primary tumor mass to determine the stage and does not take into account factors such as tumor size or the overall extent of cancer present. This system had its limitations as the observations were based of a small study consisting of only 29 patients [54] and its ability for survival prediction is further limited by lack of inclusion of lymph node and chest wall involvement. The staging is described in Table 3.

Stage	Butchart Staging	Brigham Staging
1	Tumor confined to the parietal pleura	Tumor confined to the capsule of the parietal pleura, including ipsilateral pleura, lung, pericardium and diaphragm, or chest wall disease. Tumor is resectable
2	Invasion of the chest wall, esophagus, heart or contralateral pleura, with or without thoracic lymph node involvement	All Stage 1 disease with positive intrathoracic lymph nodes. Tumor is resectable
3	Invasion into diaphragm or extrathoracic lymph nodes	Local extension of disease into the chest wall or mediastinum, heart or through diaphragm into peritoneum, with or without extrathoracic or contralateral lymph node involvement. Tumor is unresectable
4	Distant extrathoracic metastatic disease	Distant extrathoracic metastatic disease. Tumor is unresectable

Table 3.

Butchart & Brigham Staging.

4.2 Brigham Staging

Dr. David Sugarbaker of Boston’s Brigham and Women’s Hospital and colleagues introduced a staging system for malignant mesothelioma in 1993 [55], which was later revised in 1998. The system is based on two key factors: the operability of the mesothelioma through surgery and the involvement of lymph nodes. Derived from an analysis of 52 patients, It comprises of four stages as shown in Table 3.

4.3 TNM staging

In 1994, the International Mesothelioma Interest Group (IMIG) published the initial widely recognized tumor, node, and metastasis (TNM) classification for MPM [56]. This classification emerged from a consensus meeting held in June 1994 during the Seventh World Conference of the International Association for the Study of Lung Cancer (IASLC).

This has been the most widely used staging system and has been adopted by multiple societies like the International Union Against Cancer (UICC), the American Joint Committee on Cancer (AJCC), and the European Society for Radiotherapy and Oncology (ESTRO), among others. The latest version is the eighth TNM classification for MPM which was published in 2018.

As any of the other TNM classifications, the T descriptors (T1, T2, T3, and T4) define the local extent of the primary tumor. The N descriptors (N0, N1, N2, and N3) define nodal involvement and M represents evidence of metastasis.

Based on the TNM classification a staging system for this tumor was derived; stage I to IV. Some of the revisions of the latest version of the TNM classification for MPM includes removal of the N3 category and only M1 involvement is considered stage IV. Readers interested in detailed description are directed to review the eighth TNM classification for malignant pleural mesothelioma published in the journal of Translational Lung Cancer Research [57].

5. Treatment

Multimodality treatment is the foundation of therapy for MPM. Surgical therapy is a valued part of this approach.

5.1 Surgical

Surgical management for MPM is a part of a multimodal approach, which also includes chemotherapy and/or radiation therapy. The choice of surgery and overall management depends on factors such as the stage of the disease, the patient’s overall health status, and potential for improved quality of life.

Patient selection for surgery is a critical step in the preoperative process. There are no absolute contraindications for surgery with respect to any comorbid condition.

Components of assessment include:

1. Functional status: understanding the patient’s daily activity levels and physical capabilities is essential in predicting postoperative recovery and potential complications. Patient’s functional status is generally assessed by ECOG performance scale [58].

2. Cardiac assessment: this is vital to determine the risk of cardiac complications during the peri-operative period. The revised cardiac risk index (RCRI) is typically used for cardiac assessments, identifying patients who need further cardiac evaluation due to high risk of complications [59]. Echocardiograms are conducted to exclude pulmonary hypertension.

3. Pulmonary function assessment: this testing is crucial, considering that thoracic surgery may impact respiratory function and help to identify patients with pre-existing pulmonary conditions. Preoperative pulmonary function tests are essential. Although there are no specific criterial regarding MPM, criteria for pneumonectomy in lung cancer includes a forced expiratory volume (FEV₁) > 2 L and diffusing capacity for carbon monoxide (DLCO) > 80%. If FEV₁ and DLCO fall below 80%, additional testing is mandated [60].

Considerations regarding surgical role include:

1. The surgical management of MPM demands careful preoperative staging with imaging and proper selection of patients based in performance status and cardiopulmonary reserve to evaluate those patients candidates for extra pleural pneumonectomy (EPP).

2. Aim for surgery is cytoreductive. Goal of surgical resection is macroscopic resection as this a diffusely growing tumor [61].

3. Results of isolated surgical therapy are poor and a multimodal approach with chemotherapy and/or radiation is necessary.

4. Type of surgery depends on factors such as the extent of disease, overall health of the patient, surgical risk, and potential for improved quality of life.

5. All patients with the diagnosis of MPM should be initially evaluated in a multidisciplinary setting, including medical and radiation oncology, and surgery.

6. Histological subtype by biopsy should precede therapy [61].

Procedures typically fall under one of two categories—aggressive surgery or palliative measures. Advanced stages of the disease (Stages II, III, and IV) often necessitate symptomatic treatment, which can include drainage of effusions or other measures to improve comfort and quality of life.

5.1.1 Aggressive surgery

While more extensive, aims at maximal removal of the disease. Median survival after the most radical surgery EPP is 18 months with a median survival of 14% at 5 years [62]. There are two major types of surgery used in the treatment of malignant mesothelioma.

5.1.1.1 Pleurectomy/decortication (P/D)

This is a lung-sparing surgery that involves removal of the pleura (the lining of the lung and chest wall) and any other visible tumor masses. This is often performed when the disease is more localized and the patient is otherwise in good health. This procedure can help to improve symptoms such as shortness of breath and chest pain. Subsequent to the surgical intervention, adjuvant therapies like radiation therapy, chemotherapy, and targeted therapy may serve a role in enhancing prognosis and managing the disease.

5.1.1.2 Extra pleural pneumonectomy

EPP involves the removal of the diseased lung, part of the pericardium, the diaphragm, and the parietal pleura. While this procedure can provide a more substantial disease reduction, it also comes with significantly more risk and potential for complications.

The choice between these procedures often depends on numerous factors such as the extent of disease, overall health of the patient, surgical risk, and potential for improved quality of life. However, it is crucial to factor the significant morbidity associated with these procedures. Patient selection is the key to successful outcomes and a multidisciplinary team often determines the optimal approach. In cases where the disease progression is advanced and cure is not feasible, the focus shifts towards palliative care, prioritizing the management of symptoms and improving the patient’s quality of life.

Although there is controversy as to which procedure is better, lung sparing macroscopic resection was associated with comparable long-term outcomes with lower perioperative mortality [63]. P/D is associated with better long term survival for resectable MPM however post operative complications were higher in this group [64].

In a feasibility study on mesothelioma patients treated with standard care, those randomized to surgery and radiotherapy had a median survival of 14.4 months, contrasted with 19.5 months in the observation-only group [65]. However, due to a high dropout rate, the study lacked sufficient power. The forthcoming MARS 2 study is expected to provide more definitive insights [66].

5.1.2 Palliative surgery

When MPM is advanced and curative intent is not an option, surgery is helpful is symptom control and palliation. Pleural drainage reduces volume of effusion, dyspnea and cough in patients with trapped lung. Therapeutic options depend on patients’ overall clinical status, ability to tolerate general anesthesia and presence of trapped lung. In high-risk patients, talc slurry under local anesthesia is an option, where as in patients who can tolerate general anesthesia, thoracoscopy with talc insufflation is an option as the procedure can be performed under direct vision [67]. A randomized control trial (RCT) compared VATS pleurodesis versus talc pleurodesis showed that talc pleurodesis might be preferable considering improved overall survival, fewer complications and shorter length of stay [68]. However, this included all patients with suspected malignant mesothelioma who had a pleural effusion and excluded patients with who has previous attempted pleurodesis and previous primary treatment for mesothelioma. VATS pleurodesis or partial pleurectomy (PP) is effective in management of recurrent effusions and entrapped lung.

As always, a comprehensive personalized discussion with the patient and a multidisciplinary team regarding treatment is paramount (Table 4).

Recommendations regarding surgical therapy as per ESMO clinical practice guidelines [25]*

1. Surgery: primarily advised for diagnosis, staging, and palliative purposes

2. Pleurodesis: talc poudrage via thoracostomy is the recommended procedure

3. Treatment in selected MPM patients: macroscopic resection, often combined with other treatments, is best performed at specialized, experienced centers

4. Surgical preference: Extended Pleurectomy and Decortication (EPD) is preferred over Extrapleural Pneumonectomy (EPP)

Table 4.

Recommendations regarding surgical therapy.

^*

Readers are encouraged to refer to the detailed recommendations. The table summarizes key features.

5.2 Chemotherapy

Chemotherapy for MPM is used as a part of a multimodal treatment approach that may also include surgery and radiation therapy. It can be utilized in the neoadjuvant setting, adjuvant setting, in addition to palliative care. The aim is to reduce tumor volumes, improve symptom control, and enhance patient survival. Systemic therapy is based on staging and whether the disease is resectable or not (Table 5).

Therapeutic options	Pharmacologic group	Agents used
First line agents	Alkylating agents	Cisplatin
	plus
	Cytotoxic agents	Pemetrexed
	Nucleoside analogue	Gemcitabine
	plus
	Alkylating agents	Cisplatin, carboplatin, oxaliplatin
Immunotherapy	Anti-Programmed Death-1 (PD-1) Antibody	Pembrolizumab, nivolumab ipilimumab
	Antiangiogenic therapy	Bevacizumab, sorafenib, sunitinib, cediranib, dovitinib

Table 5.

Chemotherapy/immunotherapy options for patients with MPM.

5.2.1 Resectable disease

In patients with resectable disease, standard practice consists of 4 cycles of neoadjuvant or adjuvant cisplatin-pemetrexed therapy. Bevacizumab is not recommended because of the high risk of bleeding during surgical resection.

5.2.2 Unresectable disease

The most common regimen for MPM is a combination of cisplatin and pemetrexed. Vogelzang et al. randomized 448 patients to cisplatin monotherapy vs. cisplatin- pemetrexed doublet therapy. This combination demonstrated an increased survival benefit compared to cisplatin alone in studies. Doublet therapy showed improved median survival 12.8 vs. 9 months, longer median time for disease progression (5.7 vs. 3.9 months) with a higher response rates (41.3% vs. 16.7%). Hematological toxicity (neutropenia) was higher in doublet arm and addition of folic acid and vitamin B12 resulted in significant reduction [69].

Gemcitabine, when combined with a platinum compound like cisplatin, carboplatin, or oxaliplatin, has undergone extensive testing in numerous phase II studies, showing variable response rates with acceptable toxicity levels [70, 71, 72]. Arrieta et al. [52] highlighted its efficacy, safety, and cost-effectiveness, particularly noting that Gemcitabine plus cisplatin is a viable and safe treatment for patients with unresectable MPM [47]. Carboplatin is an alternative when cisplatin is unsuitable.

In the refractory or second-line setting, agents such as gemcitabine or vinorelbine can be considered. It is important to consider patient’s performance status, tumor histology, prior treatments, and side-effect profiles before deciding treatment. Chemotherapeutic agents have associated side effects, which include nausea, fatigue, neutropenia, and kidney toxicity.

5.3 Immunotherapy

5.3.1 Anti-Programmed Death-1 (PD-1) antibody

For patients with PDL-1 positive status, Pembrolizumab therapy is recommended. Specifically, in patients with previously treated PDL-1 positive malignant mesothelioma (MM), characterized by expression in 1% or more tumor cells, Pembrolizumab treatment up to 2 years, or until confirmed progression or unacceptable toxicity, demonstrated a 20% objective response rate, 72% disease control, and a median overall survival (OS) of 18 months [73].

The FDA approved Nivolumab plus Ipilimumab as a first-line treatment for adult patients with unresectable MPM, citing significant and clinically meaningful improvements in overall survival compared to standard-of-care chemotherapy [74]. Conversely, Pembrolizumab is not recommended as a stand-alone treatment for advanced, pretreated MPM [75].

5.3.2 Antiangiogenic therapy

Angiogenesis plays a crucial role in the development of malignant mesothelioma (MM). Bevacizumab, an angiogenesis inhibitor, has been investigated as a potential treatment option. The Mesothelioma Avastin Cisplatin Pemetrexed Study evaluated the impact of adding Bevacizumab to a first-line treatment regimen of cisplatin and pemetrexed for advanced MPM. This addition significantly enhanced overall survival in MPM patients, albeit with anticipated, manageable toxic effects [76].

Other anti-angiogenic therapies, including Sorafenib, Sunitinib, Cediranib, and Dovitinib, have not shown promising results in treating Malignant Pleural Mesothelioma (MPM) [77, 78, 79, 80]. Currently, there is no consensus on treatment for patients who progress after cisplatin-based chemotherapy. Available options range from single-agent or combination immunotherapy, platinum-doublet immunotherapy, to Bevacizumab with Pemetrexed and Cisplatin therapy, depending on local expertise.

Ongoing advances in understanding MPM’s pathogenesis aim to optimize traditional treatments like chemotherapy and integrate new molecular targeted therapies into treatment protocols for this aggressive disease (Table 6).

Recommendations regarding systemic therapy as per ESMO clinical practice guidelines [25]*

First line therapy for malignant pleural mesothelioma (MPM); Pemetrexed and platinum-based chemotherapy Standard: pemetrexed combined with cisplatin. Alternative: pemetrexed with carboplatin. Addition: vitamin supplementation. Bevacizumab combination therapy Composition: bevacizumab combined with platinum (cisplatin or carboplatin) and pemetrexed.

Recommendations for Unresectable MPM; Nivolumab Plus Ipilimumab; Criteria: recommended for unresectable MPM regardless of histologies or PD-L1 status.

Maintenance therapy in non-progressive MPM; Gemcitabine maintenance Guideline: not routinely recommended in non-progressive MPM. Pemetrexed maintenance Guideline: not routinely recommended after first-line therapy in non-progressive MPM.

Table 6.

Systemic therapy as per ESMO guidelines.

*

Readers are encouraged to refer to the detailed recommendations. The table summarizes key features.

5.3.3 Systemic therapy for second line and beyond

5.3.3.1 Options for systemic therapy for second line and beyond

Treatment options for immunotherapy-naïve malignant pleural mesothelioma (MPM) patients

1. Immunotherapy options

   • Pembrolizumab: an option for immunotherapy-naïve patients.

   • Nivolumab: demonstrated superiority over best supportive care

   • Nivolumab-Ipilimumab combination: considered as a third or fourth line of treatment.

2. Subsequent treatment strategies

   1. Reintroduction of chemotherapy

      • Options include platinum-pemetrexed or pemetrexed chemotherapy.

   2. Gemcitabine-ramucirumab combination

      • An alternative treatment option.

   3. Post-failure strategy

      • No routine third-line therapy recommended after failure of initial options.

   4. Clinical trial participation

      • Considered as a last resort for treatment exploration.

5.3.3.2 Future directions

A wide array of clinical trials is ongoing, targeting various aspects of MPM pathophysiology. While many trials have been completed, others are actively recruiting participants. These trials are expected to provide critical insights and potentially more effective therapeutic options for MPM patients and results may significantly enhance our understanding and management of MPM.

5.3.3.3 Recommended reading for future perspectives

Pezzoli et al.’s Special Article: Titled “A Glimpse in the Future of Malignant Mesothelioma Treatment,” this article offers valuable insights into prospective developments in MPM treatment [81].

5.4 Radiation therapy

For malignant mesothelioma, radiation therapy (RT) has been explored as both a primary and ancillary intervention. This can be delivered in the adjuvant, neoadjuvant and palliative settings.

In terms of primary intervention, external beam radiotherapy (EBRT) may be employed for curative intent, palliative pain relief, or control of symptoms like dyspnea. Pros and cons are, however, at balance. While EBRT has failed to show definitive overall survival benefit, recent advances such as Intensity-Modulated Radiation Therapy (IMRT) have demonstrated potential by enabling a more targeted irradiation and reducing toxicity to surrounding organs.

Adjuvant radiotherapy following surgical procedures [like extra pleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)] has been another domain of interest. Traditionally, prophylactic irradiation of procedure sites was used to prevent tract seeding, based on earlier studies [82, 83]. Subsequent trials have revealed no benefit of prophylactic radiotherapy to diagnostic or therapeutic procedure tracks [84, 85].

There is also the strategy of trimodality therapy—combining surgery, chemotherapy, and RT. Stahel et al. reported that high-dose hemi-thoracic radiotherapy after neoadjuvant chemotherapy and EPP in patients with MPM. The study observed an increase in relapse-free survival from 7.6 months in patients who did not receive RT to 9.4 months in the group that underwent RT post-chemotherapy and EPP [86]. Despite the demonstrated safety, the ideal criteria for selecting patients who would most benefit from this aggressive trimodal therapy (surgery, chemotherapy, and RT) are not well-defined [87]. The findings underscore the need for further research to establish clear guidelines for selecting patients for trimodal therapy, aiming to maximize benefits while minimizing risks. Existing evidence on trimodal therapy is equivocal and it may be best suited for select patients with good performance status and limited disease spread.

5.4.1 Palliative RT

Radiotherapy can be used in palliation of pain, SVC syndrome, metastatic lesions and obstructive symptoms. Mcleod et al. assessed the role of RT for the treatment of pain in MPM. Complete case analysis of the 30 patients assessable at week 5, revealed improvement of pain in 47% of patients alive at week 5 [88]. SYSTEMS-2 is a randomized study of RT dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20 Gy/5#) or dose escalated treatment (36 Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM [89].

Radiation therapy is an evolving field in mesothelioma management. As clinical experience with newer radiation modalities grows, radiation therapy may provide benefit for these patients (Table 7).

Recommendations regarding radiation therapy as per ESMO clinical practice guidelines [25]*

1. Palliation of pain due to local infiltration; RT serves as a treatment option for alleviating pain associated with local tumor infiltration.

2. Discontinued use of prophylactic RT; Prophylactic radiotherapy to tracts post-diagnostic or therapeutic pleural procedures is no longer recommended for preventing chest wall metastases.

3. RT in adjuvant setting post-resection; Consideration of RT as an adjuvant therapy is viable following complete tumor resection.

4. Minimizing toxicity in postoperative RT; Emphasis on avoiding toxicity to adjacent organs at risk when applying postoperative radiotherapy.

Table 7.

Recommendations for radiation therapy.

*

Readers are encouraged to refer to the detailed recommendations. The table above summarizes key features.

6. Prognosis

The prognosis for MPM depends on several factors, including age, gender, stage at diagnosis, patient’s performance status, and the effectiveness of treatment [8, 90, 91, 92].

Stage: The stage of the disease at the time of diagnosis is a critical factor in determining prognosis. Mesothelioma is typically staged from I to IV, with stage I being localized and easier to treat, while stage IV indicates advanced disease that has spread to distant organs. Early-stage mesothelioma generally has a better prognosis than advanced-stage disease.

Treatment: Mesothelioma treatment options may include surgery, chemotherapy, RT and immunotherapy. The effectiveness of treatment and the patient’s response to it can significantly affect prognosis. Some patients may undergo multimodal treatment approaches.

Age and overall health: A patient’s age and overall health play a role in determining their prognosis. Younger, healthier individuals may have a better chance of tolerating aggressive treatments and achieving longer-term survival.

Mesothelioma cell type: Of three primary cell types of mesothelioma: epithelioid, sarcomatoid, and biphasic (a combination of both), epithelioid mesothelioma generally has a better prognosis than the other two cell types [93, 94].

Genetic and molecular factors: Recent research has identified specific genetic mutations and molecular markers associated with mesothelioma. Recently GOLT1B and MAD2L1 expression was reported as the best predictor of survival [95]. Three promising emerging therapeutic targets include STAT3, KDM4A, heparanase [96].

6.1 Prognostic scoring systems

6.1.1 Multimodality prognostic score

Multimodality prognostic score (MMPS) was reported by Opiz et al. [97]. These include

1. Tumor volume pretreatment greater than 500 ml

2. Non-epithelioid histology

3. Serum C-reactive protein value greater than 30 mg/L

4. Progression after induction chemotherapy assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1 are standardized criteria that can be used at different time points to classify response into the categories of complete response, partial response, stable disease, or disease progression).

The score identified group of patient not benefitting from multimodality treatment (Score ≤ 2 vs. ≥2) 21 (15–28) vs. 4 (3–5) months P ≤ 0.0005). The MMPS (using three or four variables) showed that patients with score 0 had the longest overall survival compared with those with a score of 3 or higher.

In patients with MPM, pretreatment serum albumin level is a marker of prognostic significance [98]. In a subsequent publication, adding albumin to the initial MMPS score showed improved performance in comparison to the original score [99]. Using a classification and regression tree (CART) model Harris et all reported the group of patients with no weight loss, hemoglobin >15 g/L and serum albumin >4.3 g/L at time of referral to the surgical center has the best survival [100]. Several gene markers have looked at prognosis in patients with MM [17, 101, 102]. In newly diagnosed patients with MPM, use of pretreatment parameters may help to prognosticate outcomes after surgery and also enhance stratification on clinical trials [103].

6.1.2 Cancer and leukemia group B (CALGB) index

CALBG index was developed retrospectively using clinical characteristics of 337 patients [7]. Six prognostic groups can be determined with median survival ranging between 29.9 months in the most favorable group to 1.8 for the least favorable one. Pleural disease involvement, LDH level > 500 lUlL, poor PS, chest pain, platelet count >400,000/f.LL, nonepitheloid histology, and increasing age older than 75 years independently predict poorer survival. These findings were confirmed by a subsequent study [104].

6.1.3 European Organization for Research and Treatment of Cancer experience (EORTC) index

ORTC index was also developed retrospectively during a 9-year period from October 1984 to October 1993. 204 eligible adult patients with MPM were entered into five consecutive prospective EORTC phase II clinical trials designed to assess the efficacy of various anticancer drugs (mitoxantrone, epidoxorubicin, etoposide, and paclitaxel) [6]. Patients with poor functional status, elevated WBC counts, mesothelioma as a probable/possible diagnosis, male gender and sarcomatous histological subtype had a poor prognosis.

7. Conclusion

It is important to note that MPM is often diagnosed at an advanced stage, which can make it challenging to treat effectively. As a result, the overall prognosis for mesothelioma is generally poor, with a median survival of around 12–21 months for pleural mesothelioma. However, advancements in treatment options, such as immunotherapy and targeted therapies, have provided some hope for improved outcomes, particularly for those with earlier-stage disease or specific molecular markers. Early suspicion and aggressive diagnosis is recommended to improve outcomes.

Conflict of interest

“The authors declare no conflict of interest.”