Malignant Pleural Mesothelioma

What every physician needs to know

Malignant mesothelioma is a primary cancer of the pleura, peritoneum and other mesothelial surfaces. It is caused by asbestos exposure in the majority of cases.

The incidence of mesothelioma has risen dramatically in the last few decades as result of asbestos use in the mid to late 20^th century. The global consumption of asbestos has continued to increase especially in developing countries where asbestos use is often remains unregulated. The incidence of asbestos-related mesothelioma and lung cancer is expected to rise exponentially.

The most common presentation is breathlessness and/or chest pain and a unilateral pleural effusion. A history of asbestos exposure is typical but not universal.

Mesothelioma has no cure and responds poorly to currently available treatments. Median survival is between 9-12 months from diagnosis. Those with sarcomatoid histology and poor performance status have a worse prognosis. The only treatment that has been shown to improve survival is combination chemotherapy with Pemetrexed and Cisplatin, although the benefits are modest. Surgery has no proven role.

As the disease progresses symptoms arise from pleural effusions and progressive infiltration of tumor around the hemithorax, with invasion of adjacent structures. Extra-thoracic spread is common at advanced stages. Palliation of symptoms is of paramount importance in mesothelioma and care is optimal when delivered by a specialized, multidisciplinary team.

Classification:

Site

Primary pleural mesothelioma comprises >90% of cases. Sixty percent occur in the right pleural cavity and 40% in the left.

Primary peritoneal mesothelioma contributes <10% to the incidence. Direct invasion of pleural mesothelioma through the diaphragm can also lead to peritoneal disease.

Mesothelioma can occur on other serosal surfaces such as the pericardium (<1%) and the tunica vaginalis (<0.5%).

Histopathology

Histological (LINK to histology) classification of mesothelioma is into 3 main subtypes:

Epithelioid mesothelioma (60%) – has the best prognosis

Sarcomatoid mesothelioma (10%) – has the poorest prognosis

Mixed or biphasic mesothelioma (30%) – has an intermediate prognosis

Staging

Accurate staging of mesothelioma is difficult and does not influence clinical management in the majority of cases. It is usually only performed if radical treatment is being considered, or in the context of clinical trial. A number of different staging systems have been proposed. However, the TNM based system is recommended by the International mesothelioma interest group: refer to Table I (Scherpereel, Astoul et al. 2010). This system is designed for surgical tumor staging and imaging may underestimate the extent of T- and N- disease.

Table I.

Are you sure your patient has mesothelioma? What should you expect to find

Symptoms

Symptoms are insidious in mesothelioma. The average time from onset to diagnosis is around 2-3 months. Occasionally mesothelioma may be detected incidentally on chest radiographs. Although extra-pleural spread is found in up to 80% of cases at post mortem, most symptoms and signs result from local tumor effect.

Breathlessness (40-70%)

Pleural effusion occurs in >90% of patients with mesothelioma, causing breathlessness through impairment of diaphragmatic function and compression of underlying lung.

In advanced disease the lung becomes encased by tumor rind resulting in trapped lung. The resultant restrictive defect can cause hypoxemia and dyspnea.

Pericardial effusion occurs in <10% of cases and can lead to pericardial tamponade. Pericardial disease may also cause cardiac arrhythmias.

Pneumonia can occur with mesothelioma. Weight loss, sarcopenia and deconditioning may also contribute to breathlessness during the disease course.

Pulmonary embolus should be suspected in anyone with an acute increase in breathlessness or breathlessness disproportionate to the extent of disease.

Chest pain (25-60%)

Pain is an early feature in mesothelioma due to tumor invasion of the innervated parietal pleura and rib periosteum. The pain is usually a constant, dull ache but can be pleuritic and is often severe. It may be located in the chest wall or upper abdomen but with diaphragmatic involvement radiates to the shoulder and upper arm.

Neuropathic pain can result from invasion of intercostal or brachial plexus nerves and has a burning, shooting or gnawing quality.

Pain may also result from treatments for mesothelioma. Post thoracotomy pain is a neuropathic pain occurring in the region of the scar, often associated with hyperesthesia of the skin. Treatment with cisplatin can cause painful peripheral neuropathies.

Cough (20-40%)

Weight loss / Anorexia / Fatigue (20-30%)

Fevers/sweats (20%)

Signs

Pleural effusion is detectable clinically as stony dullness to percussion with reduced breath sounds. Massive pleural effusion occurring without tracheal deviation to the contralateral side, due to a fixed mediastinum or trapped lung, is highly suggestive of malignant disease.

Volume loss and asymmetrical chest expansion may be seen in advanced disease due to tumor encasement of the hemithorax.

Chest wall masses can arise from direct chest wall invasion or tumor seeding through needle tracts.

Neurological invasion can manifest as Horner’s syndrome, sympathetic nerve involvement of the arm, recurrent laryngeal nerve palsy and spinal cord compression. Superior vena cava syndrome may result from mediastinal invasion. Arrhythmias can occur with cardiac involvement.

Clubbing is not associated with mesothelioma. When present it usually reflects underlying asbestosis.

Paraneoplastic syndromes

Although rare, a number of paraneoplastic conditions have been reported to occur in the context of malignant mesothelioma.

• Nephrotic syndrome / membranous nephropathy

• Hypercoagulability

• Neurological syndromes including polyneuropathy and paraneoplastic cerebellar degeneration

• Hypercalcemia

• Autoimmune hemolytic anemia

• Disseminated intravascular coagulation

Beware: there are other diseases that can mimic mesothelioma:

Other malignant diseases of the pleura

Metastatic cancers from extra-pleural sites are the most common cause of a malignant pleural effusion. Lung cancer accounts for over a third of cases, followed by breast cancer (25%), lymphoma (10%), cancers of unknown primary (7%), ovarian (5%) and stomach cancer (2%).

Pleural thickening from metastatic disease is macroscopically indistinguishable from mesothelioma. In addition, sarcomas can be similar in appearance and behavior to sarcomatoid mesothelioma.

Unless an extra-pleural primary site can be readily identified elsewhere, clinical and radiological assessment cannot reliably distinguish secondary malignancy from mesothelioma. Histopathology is usually required.

Solitary fibrous tumor of the pleura (SFTP)

Solitary fibrous tumors of the pleura are mesenchymal in origin and are usually benign, although approximately 12% of cases may be of a malignant form. They are usually asymptomatic but may cause chest pain, dyspnea and cough. They are usually well defined and often pedunculated and are rarely associated with a pleural effusion.

Non-malignant causes of an exudative pleural effusion –

Benign asbestos pleural effusion

Parapneumonic effusion

Tuberculosis

Pulmonary embolus

Non-malignant causes of pleural thickening

Asbestos related pleural thickening

Localized areas of parietal pleural thickening due to asbestos (pleural plaques) usually occur bilaterally in the lower chest adjacent to rib contours. When calcified, these can be readily distinguished from malignant disease.

Diffuse benign pleural thickening often involves the costophrenic angles, fissures and apices. Chest radiograph appearances are of a continuous opacity covering at least a quarter of the chest wall. The paravertebral regions are commonly involved. In contrast to mesothelioma, it is usually smooth in appearance on CT.

Around 20% of patients with mesothelioma will have concomitant areas of benign asbestos related pleural thickening.

Non-asbestos related pleural thickening

Any intense inflammatory insult to the pleura can heal by fibrosis, resulting in pleural thickening. Causes include empyema, hemothorax, pleural tuberculosis and thoracotomy.

Pleural thickening may also be seen post pleurodesis. Where talc has been used as the pleurodesing agent, calcification helps to identify this as benign.

How and/or why did patient develop mesothelioma?

Epidemiology of mesothelioma

The majority of cases of malignant mesothelioma are associated with a prior history of asbestos exposure. The mid to late 20^th century saw a boom in the manufacture and use of asbestos products. In most developed countries asbestos usage peaked in the early 1970s and has been banned since the 1980s.

Mesothelioma does not occur until at least 10-20 years after asbestos exposure and in most patients the latent period is much longer, with a median of 30-40 years.

The global incidence of mesothelioma is expected to continue to rise despite a predicted decrease in developed countries. In the USA the incidence is now in decline, and that in Australia has plateaued. Current incidence of mesothelioma is around 3300 cases per year in the US and 2000-2500 cases per year in the United Kingdom. However, the global consumption of asbestos has continued to rise especially in developing countries where asbestos use is often unregulated. Data from the WHO predicts there will be a major rise in asbestos-related mesothelioma and lung cancers in the coming decades (World Health Organization 2017), often termed by the media as the ‘Asian tsunami of asbestos deaths’.

Asbestos

Asbestos is a naturally occurring fibrous mineral. The carcinogenicity of asbestos fibers partly relates to their needle-like structure that hinders their clearance following inhalation. Amphiboles, including crocidolite (blue asbestos) and amosite, have a higher length to width ratio and are more carcinogenic than the curly ‘serpentine’ fibers of chrysotile (white) asbestos.

How does asbestos cause mesothelioma

A number of different mechanisms have been postulated to contribute to asbestos induced malignant transformation, including chronic pleural inflammation, disruption of the mitotic spindle, chromosomal changes, production of oxygen free radicals and increased expression of oncogenes.

Non-asbestos causes of mesothelioma

Other substances with fiber structures similar to asbestos can cause mesothelioma. Erionite, a non-asbestos mineral present in the environment, is responsible for many cases in Turkey. Carbon nanotubes have similar physical properties to asbestos and their safety is the subject of ongoing research.

Simian virus 40 has been postulated to be a causative agent or cofactor in mesothelioma development but the evidence is inconclusive and its role remains controversial.

Sporadic mesothelioma

The background rate of mesothelioma in those with little or no asbestos exposure is around 1 per million.

Genetic associations

It is unclear why only a proportion of those exposed to asbestos develop mesothelioma. Whether some people may be genetically predisposed is still the subject of investigation.

Smoking is not associated with malignant mesothelioma.

Which individuals are of greatest risk of developing mesothelioma?

Age

Mesothelioma most commonly presents between the ages of 60-79, although this is likely to increase as the cohort of occupationally exposed workers ages. Mesothelioma can rarely occur in those under the age of 40, usually due to childhood asbestos exposure.

Gender

Over 80% of mesotheliomas occur in males. This is due to differences in asbestos exposure rather than susceptibility to disease.

Asbestos exposure

Up to 20% of patients with mesothelioma have no discernible asbestos exposure. Therefore, the absence of an asbestos history does not exclude a diagnosis of mesothelioma.

The risk of developing mesothelioma increases with cumulative asbestos exposure with time since first exposure and is higher with exposure to crocidolite (compared to chrysotile) asbestos.

Occupational exposure

Those involved in the manufacture and use of asbestos products have the highest individual mesothelioma risk. However, a large number of cases now occur in the group exposed incidentally to asbestos present in the workplace, such as plumbers and electricians.

Measuring exposure

Estimating asbestos exposure is of little clinical value but is of importance as a research tool and in medico-legal assessments. The level of exposure and its associated risk is estimated by considering the fiber type, the nature of the work being performed and its duration.

Non-occupational exposure

Many have been incidentally, and often unknowingly, exposed to asbestos present in buildings in their work or home environment.

Spouses and children of asbestos workers have an increased risk of developing mesothelioma as a result of exposure to asbestos fibers carried home on work clothes.

Risks of mesothelioma in other asbestos related diseases

Pleural plaques are a marker of previous asbestos exposure. They are benign and are found in around 5% of the population at autopsy. The risk of mesothelioma in an individual with pleural plaques is related to the underlying asbestos exposure.

Asbestos related pulmonary fibrosis (asbestosis) is usually associated with high levels of asbestos exposure and as a consequence those with asbestosis have an increased risk of developing mesothelioma.

Genetic predisposition

As only a small percentage of asbestos exposed subjects develop mesothelioma, the search for any underlying genetic predisposition of affected individuals is a topic of interests. Germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) have recently been found in families with a high incidence of mesothelioma and in sporadic cases of mesothelioma. In some cases development of mesothelioma was also associated with uveal melanoma.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Routine blood tests

Hematology/ Biochemistry

Routine blood tests may show non-specific changes due to malignancy such as anemia, thrombocytosis and raised inflammatory markers but have little discriminatory value.

Pleural fluid

Appearances

Pleural fluid is usually serosanguinous in appearance but may be bloody in around a quarter of cases.

Biochemistry

Pleural fluid is usually an exudate.

Pleural fluid pH is often low in mesothelioma. Although patients with a low pleural fluid pH (pH<7.3) are more likely to have a poorer overall survival and unsuccessful pleurodesis, its predictive accuracy is poor and should not be used to guide patient care. Pleural fluid glucose correlates with pH and has similar clinical implications. Both of these parameters probably reflect pleural tumor burden.

Cytology

For cytopathological assessment of pleural fluid see pathology section.

Other tests

Other tests may be helpful if non-malignant diagnoses are suspected, such as adenosine deaminase in cases of possible pleural TB.

Biomarkers

Biomarkers have been well studied in mesothelioma as an aid to diagnosis and to identify early disease in asbestos exposed individuals. Mesothelin is the most promising of all currently available biomarkers.

Mesothelin

Mesothelin is a useful adjunct test but it does not replace the need for histological confirmation. An elevated serum or pleural fluid mesothelin is strongly suggestive of mesothelioma, but can occur in other malignancies, e.g., adenocarcinoma especially of the ovaries. False negatives occur in early stage disease and in sarcomatoid subtypes, meaning mesothelioma cannot be excluded on the basis of a negative test alone. Serum mesothelin level can also be elevated from renal failure.

Although mesothelin levels can sometimes be elevated before mesothelioma presents, current evidence does not support its use for screening purposes.

Mesothelin levels increase with tumor burden, meaning it may also have a role in monitoring disease progression and treatment response.

What imaging studies will be helpful making or excluding the diagnosis of mesothelioma?

Chest Radiograph

Chest x-ray usually shows unilateral pleural effusion (>80%) often associated with pleural thickening/pleural based mass (~40%). Pleural thickening without an effusion is less common (10-20%). Pleural effusions may be massive but often do not cause mediastinal shift due to encasement of the lung or mediastinal infiltration with tumor. Pleural plaques may be present but their absence does not help exclude mesothelioma.

CT

CT detects pleural thickening in >90% of patients at presentation. This is nodular in appearance, extends onto the mediastinum and/or diaphragm in most cases and can cause volume loss. However these appearances do not differentiate mesothelioma from metastatic pleural disease and malignancy cannot be excluded by their absence.

Fissural extension, lymph node involvement and invasion of the chest wall, diaphragm and mediastinum can be detected in more advanced disease.

Ultrasound

Thoracic ultrasound detects small volumes of pleural fluid with high sensitivity and identifies safe sites for thoracentesis. Findings suggestive of malignancy include pleural thickening >1cm and pleural or diaphragmatic nodules.

PET/PET-CT

Positive emission tomography combined with CT has a high sensitivity (94-100%) for mesothelioma and detects extrapleural disease not seen on CT, upstaging around a third of patients undergoing pre-surgical assessment.

The degree of metabolic activity seen on PET correlates with prognosis. Combining FDG activity with volumetric analysis of tumor burden predicts survival more accurately than TNM staging and may also be of use in evaluating response to chemotherapy.

MRI

MRI provides similar information to CT and is not widely used in the diagnosis of mesothelioma, although it better delineates chest wall and diaphragmatic invasion.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of mesothelioma?

Lung function tests may show a restrictive pattern but are generally not helpful in making a diagnosis of mesothelioma.

What diagnostic procedures will be helpful in making or excluding the diagnosis of mesothelioma?

Histocytological diagnosis of mesothelioma is often difficult (see PATHOLOGY). More invasive procedures to obtain larger or multiple biopsies are required when pleural fluid cytology and percutaneous biopsy fail to yield a diagnosis.

Pleural fluid sampling (thoracentesis)

If pleural fluid is present then a sample should be sent for biochemical and cytological analysis. The yield of pleural fluid cytology in mesothelioma has traditionally been regarded as having a low yield. However, advances in immunostaining (especially epithelial membrane antigen) and cytogenetics (egg loss of BAP-1) have significantly improved the accuracy. Guidelines from several international cytologist bodies have all confirmed that pleural fluid cytology is adequate in diagnosing the majority of cases with epithelioid mesothelioma cells. This was further supported by a study of over 500 cases of MPM confirming the high (99%) predictive value of pleural fluid cytology as validated against post-mortem results. (Segal, Sterrett et al. 2013) Cytological diagnosis however does depend on the expertise of the reporting pathologists.

Thoracentesis and pleural tissue aspiration should be performed under imaging guidance, which increases the chance of obtaining fluid and reduces the risk of solid organ puncture.

Tissue biopsy

Confirmation of a diagnosis of mesothelioma through demonstration of tumor infiltration of deeper tissues requires a tissue biopsy. Larger biopsy specimens may also be needed to determine subtypes. No biopsy techniques are 100% sensitive, meaning a negative result does not exclude mesothelioma.

Tissue can be obtained in the following ways:

Percutaneous pleural biopsies

Percutaneous pleural biopsies are best performed prior to complete drainage of pleural fluid to reduce the risk of lung puncture and pneumothorax.

Closed (blind) biopsy

Closed (Abrams needle) pleural biopsy has a lower diagnostic yield and an increased risk of complications compared to image guided techniques, which are preferable.

Image guided biopsy

Where pleural thickening is visible, CT guided biopsy is diagnostic in around 85-90% cases of mesothelioma. Ideally >1cm pleural thickening should be present, diagnostic yield may be lower for thickening <5mm.

Pleural biopsy can also be performed under direct US guidance if suitable sites can be identified. In one series, US guided core needle biopsy was diagnostic in 77% of cases of mesothelioma.

Targeting areas that are FDG-avid on PET scans may be useful especially in patients with diffuse pleural thickening.

Thoracoscopy

Thoracoscopy allows pleural biopsy under direct vision of the pleura. It can be performed as a ‘medical’ thoracoscopy (pleuroscopy) under sedation and local anesthetic, or as a ‘surgical’ VATS (video assisted thoracic surgery) procedure under general anesthetic.

The sensitivity of thoracoscopy in mesothelioma is over 90%. However false negatives do occur, hence those patients without a definitive diagnosis after thoracoscopy still require close follow up.

Thoracotomy

The use of thoracotomy and open surgical biopsy has declined with the advent of thoracoscopic techniques. However where other tests have failed to provide a definitive diagnosis, open surgical biopsies may be required.

Other staging procedures

Mediastinoscopy can be performed to stage nodal involvement prior to consideration of surgical resection of mesothelioma. Laparoscopy may be required to assess for sub-diaphragmatic extension in the same setting. With the rapid decline of radical surgery in mesothelioma, invasive staging procedures are seldom required.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of mesothelioma?

Mesothelioma cells are often difficult to distinguish from benign reactive mesothelial proliferations and from metastatic pleural malignancies, particularly adenocarcinoma. Sarcomatoid mesothelioma often does not shed malignant cells into the pleural effusion and may instead induce an overlying reactive mesothelial proliferation.

Cytology

Cytological diagnosis of mesothelioma is not straightforward. The sensitivity (32-76%) is dependent on tumor subtype, extent of disease and the experience of examining cytologist. (See above.)

Histology

Examination of larger biopsy specimens at multiple levels to confirm invasion of deep structures may be required to distinguish mesothelioma from benign pleural disease.

Histological classification falls into 3 subtypes:

Epithelioid mesothelioma (60%)

Epithelioid subtype consists of oval or cuboidal cells that can look similar to benign, reactive mesothelial cells or other epithelioid carcinomas. Common secondary patterns of epithelial mesothelioma include tubulopapillary, acinar (glandular), adenomatoid (microglandular) and solid mesothelial pattern. Epithelioid mesothelioma has the best prognosis of all the subtypes.

Sarcomatoid mesothelioma (10%)

Sarcomatoid subtype contains spindle cells and collagenous stroma. The desmoplastic variant is collagen rich and paucicellular and can sometimes be mistaken for benign fibrous pleuritis or a pleural plaque. Other subtypes include the lymphohistiocytoid pattern, containing a lymphocytic infiltrate which may resemble lymphoma. Sarcomatoid mesothelioma has the poorest prognosis and responds poorly to treatment.

Mixed or biphasic mesothelioma (30%)

Biphasic disease demonstrates both epithelioid and sarcomatoid differentiation – at least 10% of both components need to be present to make the diagnosis. Biphasic disease has an intermediate prognosis.

Immunohistochemistry

Immunohistochemistry adds important information to standard cytological and histological analysis. If malignant cells are seen, staining for markers that are differentially expressed by mesothelial cells can help distinguish mesothelioma from other carcinomas. However no single marker can differentiate mesothelioma from benign mesothelial proliferations with certainty.

Immunohistochemical markers

The choice of markers and their interpretation will vary depending on what other tumors are being considered in the differential diagnosis. No markers are 100% specific but using a panel containing both mesothelial and epithelial markers increases the overall specificity.

• Calretinin, cytokeratins and Podoplanin (D2-40) are positive in the majority of mesotheliomas and WT-1 is a useful marker for epithelioid mesothelioma. However calretinin, cytokeratin 5/6 and podoplanin can be positive in squamous lung carcinoma and cytokeratins do not differentiate mesothelioma from sarcoma. Epithelial membrane antigen (EPA) staining is particularly useful though negative staining occurs in up to 15% of cases.

• Markers helpful for identifying lung adenocarcinoma include MOC-31, BG8, CEA, TTF-1, B72.3, Ber-EP4

• Markers helpful for identifying squamous lung carcinoma include p63, MOC-31, BG8, Ber-EP4

Electron microscopy

Epithelioid mesotheliomas display characteristic ultrastructural features. Electron microscopy can occasionally be useful where immunohistochemical results are equivocal.

Molecular diagnosis

Advanced molecular technology is increasingly applied to aid the diagnosis of mesothelioma. Two tests in particular are now available for clinical use and can be used to support the diagnosis in selected cases. Loss of BAP-1 expression can now be performed by immunostaining. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions of 9p21, is a good marker of mesotheliomas and can be detected using fluorescence in situ hybridization.

If you decide the patient has mesothelioma, how should the patient be managed?

General principles of management

Mesothelioma is incurable and responds poorly currently available treatments. Palliation of symptoms and preservation of quality of life are of paramount importance.

Mesothelioma presents many challenges that are best managed by a multidisciplinary team with experience in mesothelioma care. Nurses, chest physicians, oncologists, palliative care specialists, surgeons, dieticians, occupational therapists, psychologists and social workers may all be required.

Many patients with mesothelioma are elderly and may have multiple comorbidities. In these patients best supportive care with active symptom control is usually the most appropriate strategy. Chemotherapy can provide a small survival advantage in patients with a good performance status. Radical surgery has been shown to prove no survival benefits in randomized clinical trials. At present all treatment options in mesothelioma are palliative and should only be undertaken following a full and frank discussion with the patient, taking into account their specific wishes and concerns.

Active symptom control

Breathlessness

Pleural effusion

Pleural effusion occurs in over 90% of mesothelioma patients. Early, definitive management of pleural effusions can minimize repeated hospitalization. The choice of management strategy depends on factors such as the presence of a trapped lung, life expectancy and patient preference.

Thoracentesis

Repeated therapeutic aspiration of fluid may be appropriate in patients for whom life expectancy is short or who accumulate pleural fluid slowly, such that very few procedures would be anticipated to be required during their remaining life. In most cases a more definitive strategy is preferred.

Pleurodesis

Where the lung fully re-expands following drainage of pleural fluid, pleurodesis can be attempted. Success rates are similar for talc slurry administered via a chest drain and talc poudrage, performed at thoracoscopy. A study of 320 mesothelioma patients found that surgical or bedside chemical pleurodesis both had a high failure rates; about one-third of patients required further invasive pleural drainages before death.

Indwelling pleural catheters (IPC)

Indwelling pleural catheters offer an alternative to pleurodesis and provide as good symptomatic relief as talc slurry pleurodesis. They are of particular use if pleurodesis has failed or the lung has become trapped. Complications of IPC includes infection and symptomatic loculation of effusion. In the case of mesothelioma, catheter tract metastases develop in about 14% of patients and can be managed with local radiotherapy.

Trapped lung

Trapped lung occurs when the visceral pleura becomes encased with tumor rind, restricting ventilation and preventing lung re-expansion following drainage of pleural fluid.

Those patients who gain symptomatic relief from therapeutic aspiration of pleural fluid can benefit from an IPC.

Surgical decortication of tumor is controversial and little published evidence supports its routine use. At present it should be considered only in selected patients with persistent breathlessness unresponsive to other treatments.

Other causes

Breathlessness in mesothelioma is often multifactorial. Pneumonia, pulmonary embolism, pericardial disease, sarcopenia and deconditioning are common causes of breathlessness in patients with mesothelioma. These diagnoses need to be considered and actively excluded.

Non-specific treatments for breathlessness

Opiates and benzodiazepines are useful adjuncts for symptomatic relief, especially if the underlying cause is not reversible. Oxygen may be beneficial in hypoxemic patients.

Pain

Pain occurs early in mesothelioma and can be the first presenting symptom. Pain management should not wait until the diagnosis is confirmed. Uncontrolled pain makes investigations more unpleasant and clouds subsequent discussions and care planning.

Opiates

Opiates are often required in mesothelioma, doses should be titrated according to response. Most patients will require a long acting background opiate plus short acting doses for breakthrough pain.

Misconceptions some patients may harbor about opiate addiction or other stigmas need to be addressed. Prevention and treatment of opiate induced side effects, such as constipation and nausea, should be proactive.

Non-opiates

Other pharmacological agents including non-steroidal anti-inflammatory drugs are of value in relieving acute pain.

Treatments for neuropathic pain

Neuropathic pain, arising from neurological invasion by tumor, can respond to anticonvulsants, tricyclic antidepressants and corticosteroids.

Nerve blocks/ablation

Strategies targeting pain transmission at the level of the spinal cord include epidural and intrathecal catheters and cordotomy. Cordotomy involves ablation of the spino-thalamic tract within the spinal cord, leading to contralateral loss of pain sensation.

Palliative radiotherapy

See palliative RT section.

Palliative chemotherapy

Mesothelioma is relatively insensitive to chemotherapy. A large number of chemotherapy agents (and their combinations) have been studied in cohort studies or randomized trials with generally poor responses and could not provide a cure. Many new agents are currently under trial.

First line chemotherapy

A combination of Pemetrexed plus cisplatin, administered intravenously every 3 weeks for up to 6 cycles, has been considered standard first line chemotherapy for mesothelioma after a randomized trial showed that it could prolong survival over cisplatin alone by a median of around 12 weeks.

Daily oral folate supplementation should be administered with pemetrexed/ raltitrexed to limit the risk of toxicity. Grade 3 or 4 neutropenia occurs in 16-27%. Nausea, vomiting and fatigue are the most common clinical side effects. If co-morbidities preclude the use of cisplatin, carboplatin may be substituted. Data from non-randomized studies suggests that outcomes are comparable.

Recently a randomized trial of 448 mesothelioma patients showed that the addition of bevacizumab (15mg/kg) to pemetrexed/cisplatin can further improve the median survival by 2.7 months with acceptable toxicity. (Zalcman, Mazieres et al. 2016)

Second line chemotherapy

Mesothelioma inevitably progresses even in those who respond to first line therapy. Limited data exist for second line chemotherapy. The role of retreatment with pemetrexed in those who responded initially is under investigation. Gemcitabine and vinorelbine are also reported to have activity in mesothelioma.

Immunotherapies

Immunotherapy agents, alone or with standard chemotherapy, are the subject of many ongoing clinical trials in mesothelioma.

Radiotherapy

Mesothelioma is relatively sensitive to radiotherapy, however toxicity to underlying lung and other adjacent organs precludes the use of curative doses over the entire pleural surface.

Palliative radiotherapy

Radiotherapy to localized areas of disease causing symptoms such as pain, esophageal obstruction or SVC syndrome can provide symptomatic relief in up to 50-70% of patients.

Prophylactic needle tract irradiation

Mesothelioma has a propensity to metastasize down tracts of pleural interventions, causing chest wall masses that can become painful. The risk of tract metastasis increases with increasing size of pleural puncture: fine needle aspiration (4%), image guided needle biopsy (4%), chest drain (9%), thoracoscopy (16%), and thoracotomy (24%). Not all tract metastases will cause symptoms.

Three small studies have shown conflicting results on the role of prophylactic radiotherapy to procedural sites in mesothelioma patients. (Boutin, Rey et al. 1995, Bydder, Phillips et al. 2004, O’Rourke, Garcia et al. 2007, Chapman, Mulrennan et al. 2008, Davies, Musk et al. 2008). A recent large multi-centered randomized trial found that the incidence of procedural tract metastases was significantly lower than what was reported in prior studies. (Clive, Taylor et al. 2016) Subjecting all patients to post procedural prophylactic radiotherapy was not justified. However, in all cases patients should be observed for signs of metastasis and treated if procedural tract metastases develop.

Adjuvant radiotherapy

High dose radiotherapy has been employed following extra-pleural pneumonectomy to reduce the risk of local recurrence, however the dosing strategy is complex and toxicities can be severe. This approach has not been evaluated in randomized controlled trials.

Surgery in mesothelioma

Mesothelioma is not a solitary tumor but grows as multifocal pleural nodules. As a consequence it is not amenable to complete resection. Tumor almost always relapses, even after resection of all macroscopic disease. No quality data exist to support the use of radical surgery.

Pleurectomy/Decortication

Tumor debulking through pleurectomy /decortication was evaluated in a multi-centered clinical trial which failed to show any survival advantage over patients who received pleurodesis for pleural fluid control. (Rintoul, Ritchie et al. 2014)

Extra-pleural pneumonectomy (EPP)

Extra-pleural pneumonectomy involves the removal of the entire visceral and parietal pleura along with the lung, hemidiaphragm and pericardium. Less than 10% of mesothelioma patients meet criteria for EPP, these are patients with good performance status and early stage disease.

Perioperative mortality following EPP is around 5% and significant morbidity is 25%. Quality of life measures may remain impaired for up to 6 months after surgery.

The Mesothelioma And Radical Surgery (MARS) multi-centered trial found that EPP produces significant harm. Patients randomized to receive EPP had a significantly shorter median survival (by five months) compared with those who did not have surgery. Serious adverse events were more common with EPP.

Multi-modality treatment in mesothelioma

As individual treatment modality has failed to make significant impact on survival, numerous combinations of the above treatment modalities have been attempted. None are supported by comparison trials and existing literature is difficult to interpret due to selection bias.

What is the prognosis for patients managed in the recommended way?

The median length of survival from diagnosis of mesothelioma is between 6-12 months. However, considerable individual variations exist. In a small proportion of cases the disease appears to be far less aggressive and survival of a few patients (<5%) for several years without treatment is reported in some series.

The clinical course during this time is mostly determined by progressive local invasion however metastatic disease is found in over three quarters at post mortem.

Prognostic factors

Clinical parameters predicting prognosis have been examined in a number of studies. Factors associated with a poor prognosis include:

• Sarcomatoid or mixed histology

• Male

• Poor performance status

• The presence of chest pain

• Age >75

• Advanced stage of disease

The only two parameters that routinely inform clinical care are performance status and histology. Those with good performance status and epithelioid histology have the best prognosis and may be candidates for more aggressive treatment.

Other laboratory parameters which correlate with a poorer prognosis include high white blood cell count, neutrophil: lymphocyte ratio >5, raised platelet count and raised serum LDH.

Two prognostic scoring systems have been validated in mesothelioma – CALGB and EORTC. These are rarely used outside the research setting. Another approach using data collected in routine clinical care was recently published. (Brims, Meniawy et al. 2016)

What other considerations exist for patients with mesothelioma?

Patients who know they have been exposed to asbestos may have harbored a fear of developing mesothelioma for many years and some will have witnessed ex-colleagues contract the disease. Fears of a protracted painful death or fears of ‘drowning’ need to be dispelled through provision of palliative support and attention to symptom control from the outset. Obtaining a firm diagnosis can be difficult and patients with mesothelioma sometimes require multiple diagnostic and therapeutic interventions. It is important the clinician gains the patients trust during this period.

Anger against former employers is common. Compensation is available for patients where employers have negligently exposed them to the risks of asbestos. However this is not always straightforward and the litigating process can be time consuming and stressful at a time where preservation of quality of life is a primary concern.

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