Pulmonary Medicine

Mesothelioma

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What every physician needs to know:

Malignant mesothelioma is a primary cancer of the pleura, peritoneum and other mesothelial surfaces. In most cases, it is caused by asbestos exposure.

The incidence of mesothelioma has risen dramatically in the last few decades as a result of asbestos use in the mid to late twentieth century. In the US the incidence is now in decline, whereas in the UK it is predicted to continue rising until at least 2015.

Most patients present with breathlessness or chest pain and a unilateral pleural effusion. A history of asbestos exposure is typical but not universal.

Mesothelioma has no cure, and it responds poorly to currently available treatments. Median survival is 9-12 months from diagnosis. Those with sarcomatoid histology and poor performance status do worse. 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 but is often asymptomatic. Palliation of symptoms is of paramount importance in mesothelioma, and care is best delivered by a specialist multidisciplinary team.

Classification:

Site

Primary pleural mesothelioma accounts for over 90 percent of cases. Sixty percent occur in the right pleural cavity and 40 percent in the left. Primary peritoneal mesothelioma (<10%) is less common. Mesothelioma can rarely arise on other serosal surfaces, such as the pericardium (<1%) and the tunica vaginalis (<0.5%).

Histology

Epithelioid mesothelioma (60%) has the best prognosis, and sarcomatoid mesothelioma (10%) has the poorest prognosis. Mixed/biphasic mesothelioma (30%) has an intermediate prognosis.

Stage

Mesothelioma is not a solitary tumor; it grows as multi-focal pleural nodules. As such, staging systems like the TNM classification are difficult to perform and have little clinical relevance in most cases.

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

Symptoms present insidiously in mesothelioma. The average time from onset to diagnosis is 2-3 months. Occasionally, mesothelioma may be detected incidentally on chest x-ray. Although extrapleural spread is found in up to 80 percent of cases at post-mortem, most symptoms and signs result from local tumor effects.

Symptoms

Breathlessness occurs in 40-70 percent of cases. Pleural effusion occurs in more than 90 percent of patients with mesothelioma, causing breathlessness through impairment of diaphragmatic function and compression of the underlying lung. Trapped lung occurs in advanced disease when the lung becomes encased by tumor rind, restricting ventilation. Pericardial effusion occurs in less than 10 percent of cases and can lead to pericardial tamponade. Pericardial disease may also cause cardiac arrhythmias. Pneumonia is common in mesothelioma. Pulmonary embolus should be considered in anyone with an acute increase in breathlessness or breathlessness disproportionate to the extent of his or her disease.

Chest pain occurs in 25-60 percent of cases. Pain is an early feature in mesothelioma resulting from tumor invasion of the innervated parietal pleura and rib periosteum. The pain is usually a constant, dull ache, but it can be pleuritic and it is often severe. It may be located in the chest wall or upper abdomen, but with diaphragmatic involvement it radiates to the shoulder and upper arm. Neuropathic pain, which can result from invasion of intercostal or brachial plexus nerves, has a burning, shooting, or gnawing quality.

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

Cough occurs in 20-40 percent of cases, and weight loss/anorexia/fatigue occurs in 20-30 percent of cases. Fevers and sweats occur in 20 percent of cases.

Signs

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

Volume loss and asymmetrical chest expansion may be seen in advanced disease because of 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.

Clubbing is not associated with mesothelioma; when present, it usually reflects underlying asbestosis.

Paraneoplastic syndromes

Paraneoplastic syndromes are rare in malignant mesothelioma, so other causes should first be excluded. However, the following conditions have been reported to occur in the context of mesothelioma:

  • Nephrotic syndrome/membranous nephropathy

  • Neurological syndromes, including polyneuropathy and paraneoplastic cerebellar degeneration

  • Hypercoagulability

  • Hypercalcaemia

  • Autoimmune hemolytic anemia

  • Disseminated intravascular coagulation

Beware: there are other diseases that can mimic mesothelioma:

Mesothelioma must be differentiated from other diseases that cause unilateral pleural effusions or pleural thickening.

Other malignant diseases of the pleura

Metastatic cancers from extrapleural 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, cancers of unknown primary, ovarian cancer, and stomach cancer.

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

Unless an extrapleural primary site can be readily identified elsewhere, clinical and radiological assessment cannot reliably distinguish secondary malignancy from mesothelioma. Histocytology 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 percent of cases may be of a malignant form. They are usually asymptomatic, but they may cause chest pain, dyspnea, and cough. They are usually well defined, they are often pedunculated, and they are rarely associated with a pleural effusion.

Non-malignant causes of an exudative pleural effusion

Non-malignant causes of an exudative pleural effusion include benign asbestos pleural effusion, parapneumonic effusion, tuberculous effusion, and pulmonary embolus.

Non-malignant causes of pleural thickening

Asbestos - related pleural thickening

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

Diffuse benign pleural thickening often involves the costophrenic angles, fissures, and apices. Appearance on a chest X-ray is of a continuous opacity covering at least a quarter of the chest wall. The paravertebral regions are commonly involved. In contrast to mesothelioma, diffuse benign pleural thickening is usually smooth in appearance on CT. Around 20 percent 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 pleurodizing agent, calcification helps to identify the pleural thickening as benign.

How and/or why did the patient develop mesothelioma?

The majority of cases of malignant mesothelioma are associated with a prior history of asbestos exposure. The mid to late twentieth 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 cases, the latent period is much longer, with a median of 30-40 years. The incidence of mesothelioma is predicted to peak in 2015 in Europe, but it has already peaked in the US, where asbestos was regulated earlier.

Current incidence of mesothelioma is around 3300 cases per year in the US and 2000-2500 cases per year in the United Kingdom.

In many developing countries, asbestos usage is still on the increase and is often poorly regulated, so a second global wave of asbestos-related disease is predicted.

Asbestos

Asbestos is a naturally occurring fibrous mineral. The carcinogenicity of asbestos fibers relates in part to their needle-like structure, which 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.

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 damage, production of oxygen-free radicals, and increased expression of oncogenes.

Non-asbestos causes of mesothelioma

Other substances with fiber structures similar to that of 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 those of 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.

Smoking is not associated with mesothelioma.

Sporadic mesothelioma

The background rate of mesothelioma in those with little or no asbestos exposure is estimated to be 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.

Which individuals are at greatest risk of developing mesothelioma?

Mesothelioma most commonly presents between the ages of 60-79, although this age range is likely to increase as the cohort of occupationally exposed workers ages. Mesothelioma rarely presents in those under the age of 40, but when it does, it is usually because of childhood asbestos exposure.

Over 80 percent of mesotheliomas occur in males because of differences in asbestos exposure, rather than susceptibility to disease.

Asbestos exposure

Up to 20 percent of patients with mesothelioma have no discernable asbestos exposure, so 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 with exposure to crocidolite (compared to chrysotile) asbestos.

Occupational asbestos exposure

Those involved in the manufacture and use of asbestos products have the highest individual mesothelioma risk. Occupations with high levels of exposure include those of asbestos miners, shipbuilders, railway workers, heating/boiler engineers, foundry workers, construction workers, and garage mechanics. A large number of cases now also occur in the group exposed incidentally to asbestos present in the workplace, such as plumbers and electricians.

Calculating 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 the duration of that work.

Non-occupational asbestos exposure

Many have been incidentally and often unknowingly exposed to asbestos present in buildings in their work or home environments. Spouses and children of asbestos workers have an increased risk of developing mesothelioma as a result of exposure to asbestos fibers carried home on their family member's work clothes.

Risks of mesothelioma in other asbestos-related diseases

Pleural plaques are a marker of previous asbestos exposure. Pleural plaques, which are benign, are found in around 5 percent of the total population at autopsy. The risk of mesothelioma in an individual with pleural plaques is related to his or her underlying asbestos exposure.

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

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

Blood test, pleural fluid tests and biomarkers, including mesothelin (soluble mesothelin-related peptide, or SMRP), can help make the diagnosis of mesothelioma.

Blood tests

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

Pleural fluid tests

Pleural fluid is usually sero-sanguinous in appearance, but it may be bloody in around a quarter of cases. Protein and LDH levels in pleural fluid usually confirm 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 poor overall survival and unsuccessful pleurodesis than are those with a higher pleural fluid pH, its predictive accuracy is inadequate to guide patient care. Pleural fluid glucose correlates with pH and has similar clinical implications. Both of these parameters probably reflect pleural tumor burden.

Pleural fluid should be sent for cytology.

Biomarkers

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

Mesothelin (soluble mesothelin related peptide, SMRP)

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 it can occur in other malignancies, especially adenocarcinoma. False negatives occur in early-stage disease and in sarcomatoid subtypes, so mesothelioma cannot be excluded on the basis of a negative test alone.

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, so it may also have a role in monitoring disease progression and response to treatment.

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

Chest X-ray, CT, ultrasound, PET/PET-CT, and MRI can be helpful in making or excluding the diagnosis of mesothelioma.

Chest X-ray

Chest X-ray usually shows unilateral pleural effusion (>80%) that is 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 they often do not cause mediastinal shift because of encasement of the lung or mediastinal infiltration with tumor. Pleural plaques may be present, but their absence does not help exclude mesothelioma.

Computed tomography (CT)

CT detects pleural thickening in more than 90 percent of patients at presentation. The pleural thickening is often nodular in appearance, it can extend onto the mediastinum and/or diaphragm, and it 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 thoracocentesis. Findings suggestive of malignancy include pleural thickening larger than 1cm and pleural or diaphragmatic nodules.

PET/PET-CT

Positive emission tomography combined with CT has a high sensitivity for mesothelioma and detects extrapleural disease not seen on CT, upstaging around a third of patients undergoing pre-surgical assessment. However, PET-CT cannot accurately differentiate mesothelioma from pleural inflammation, from post-pleurodesis effects, or from metastatic carcinoma. Therefore, its role as a diagnostic tool is limited.

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 does, and it may also be of use in evaluating response to chemotherapy.

Magnetic resonance imaging (MRI)

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

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 they 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. 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, a sample should be sent for biochemical and cytological analysis. The yield of pleural fluid cytology in mesothelioma is generally low; however, needle thoracentesis is relatively non-invasive, and it should be the first diagnostic procedure in most patients.

Thoracentesis should be performed under ultrasound 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 percent sensitive, so a negative result does not exclude mesothelioma.

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

Tissue can be obtained by closed (blind) percutaneous biopsy, image-guided percutaneous biopsy, thoracoscopy, and thoracotomy. Closed (Abrams needle) pleural biopsy has a lower diagnostic yield and an increased risk of complications compared to image-guided techniques, which are preferable.

Where pleural thickening is visible (>1cm), CT-guided biopsy is diagnostic in 85-90 percent cases of mesothelioma. Pleural biopsy can also be performed under direct USS guidance if suitable sites can be identified. In one series, USS-guided core needle biopsy was diagnostic in 77 percent of cases of mesothelioma.

Thoracoscopy allows pleural biopsy under direct vision of the pleura. It can be performed as a "medical" thoracoscopy (pleuroscopy) or as a "surgical" VATS (video-assisted thoracic surgery) procedure under general anesthetic. The sensitivity of thoracoscopy in mesothelioma is over 90 percent, but false negatives do occur. Therefore, patients without a definitive diagnosis after thoracoscopy still require close follow-up.

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 and laparoscopy have been included in staging protocols prior to surgical resection of malignant mesothelioma. These procedures are not justified in routine clinical care.

What pathology/cytology 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.

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

Cytology

Cytological diagnosis of mesothelioma is not straightforward. The sensitivity (32-76%) is dependent on the tumor subtype, the extent of disease, and the experience of the examining cytologist. For these reasons, cytological suspicion often requires confirmation with tissue histology.

Histology

Mesothelioma is classified histologically into three subtypes: epitheloid mesothelioma (60%), sarcomatoid mesothelioma (10%), and mixed or biphasic mesothelioma (30%).

Epithelioid mesothelioma consists of oval or cuboidal cells, which 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 patterns.

Sarcomatoid mesothelioma contains spindle cells and collagenous stroma. The desmoplastic variant is collagen-rich and paucicellular, and it can sometimes be mistaken for benign fibrous pleuritis or a pleural plaque. Other subtypes include the lymphohistiocytoid pattern, which contains a lymphocytic infiltrate that may resemble lymphoma.

Mixed or biphasic mesothelioma (30%) demonstrates both epithelioid and sarcomatoid differentiation; at least 10 percent of both components must be present to make the diagnosis.

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.

The choice of markers and their interpretation varies depending on what other tumors are being considered in the differential diagnosis. No markers are 100 percent specific, but using a panel that contains 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.

Markers helpful for identifying lung adenocarcinoma include MOC-31, BG8, CEA, TTF-1, B72.3, and Ber-EP4. Markers helpful for identifying squamous lung carcinoma include p63, MOC-31, BG8, and Ber-EP4.

Electron microscopy

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

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

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

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 many have multiple comorbidities. In these patients, the best available 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 no proven role, but it is practiced in some centers. At present, all treatment options in mesothelioma are palliative, and treatment should be undertaken only following a full and frank discussion with the patient, taking into account his or her specific wishes and concerns.

Treatments for breathlessness

Pleural effusion occurs in over 90 percent of mesothelioma patients. Repeated hospitalizations can be minimized by providing early, definitive management of pleural effusions. The choice of management strategy depends on factors like 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. 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 for talc slurry administered via a chest drain and talc poudrage, performed at thoracoscopy, are similar.

  • Indwellling pleural catheters (IPC) - Indwelling pleural catheters, which offer an alternate to pleurodesis, are of particular use if pleurodesis has failed or if the lung has become trapped.

Trapped lung occurs when the visceral pleura becomes encased with tumor rind, restricting ventilation and preventing lung re-expansion following drainage of pleural fluid. Trapped lung patients who gain symptomatic relief from therapeutic aspiration of pleural fluid can benefit from an indwelling pleural catheter. Surgical decortication of tumor is controversial, and little published evidence supports its routine use, so it should be considered only in selected patients with persistent breathlessness unresponsive to other treatments.

Breathlessness in mesothelioma is often multifactorial. Pneumonia, pulmonary embolism, pericardial disease, and atelectasis are common causes of breathlessness in patients with mesothelioma. These diagnoses should be considered and actively excluded. Opiates and benzodiazepines are useful adjuncts for symptomatic relief, especially if the underlying cause is not reversible. Oxygen can be beneficial in hypoxemic patients.

Pain management

Pain, which occurs early in mesothelioma, can be the first presenting symptom. Pain management should not wait until the diagnosis is confirmed since uncontrolled pain makes investigations more unpleasant and clouds subsequent discussions and care planning. Both pharmacological and non-pharmacological strategies can be valuable.

Opiates

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

Palliative radiotherapy

Pain caused by localized chest wall invasion can be treated with palliative radiotherapy.

Nerve blocks/ablation

Strategies that target 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. It has been used successfully in mesothelioma patients.

Palliative chemotherapy

Mesothelioma is relatively insensitive to chemotherapy. A combination of a multi-targeted folate antagonist (pemetrexed or raltitrexed) and cisplatin has demonstrated a survival advantage in randomized controlled trials in patients with good performance status. This is now considered standard first-line chemotherapy for mesothelioma. Other chemotherapy agents have been studied in non-randomized trials with generally poor responses.

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

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.

Targeted therapies

Agents that target vascular endothelial growth factor (VEGF), epidermal growth factor (EGFR) pathways, and histone deacetylase are the subject of ongoing clinical trials.

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 that cause symptoms such as pain, esophageal obstruction, and SVC syndrome can provide symptomatic relief in 50-70 percent 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 and can ulcerate. The risk of tract metastasis increases with increasing size of pleural puncture: fine-needle aspiration and image-guided needle biopsy both carry a risk of 4 percent, chest drain has a risk of 9 percent, thoracoscopy a risk of 16 percent, and thoracotomy a risk of 24 percent. Not all tract metastases cause symptoms.

One study showed a reduction in occurrence of metastases following thoracoscopy, whereas two others have shown no benefit. There is insufficient evidence to support the routine use of prophylactic radiotherapy to all pleural puncture sites. In all cases, patients should be closely observed for signs of metastasis and treated promptly if it occurs.

Adjuvant radiotherapy

High-dose radiotherapy has been employed following extrapleural 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

Surgical approaches in mesothelioma are limited and are applicable only to small numbers of selected patients. Mesothelioma is not a solitary tumor; it grows as multifocal pleural nodules, so it is not amenable to complete resection. Tumor almost always relapses, even after resection of all macroscopic disease.

Tumor debulking through pleurectomy/decortication may be beneficial in selected patients with symptomatic trapped lung. Removal of tumor rind allows lung re-expansion and establishes pleurodesis. This is the subject of an ongoing clinical trial, but no data so far suggest a survival benefit even in large observational series.

Extrapleural pneumonectomy (EPP) involves the removal of the entire visceral and parietal pleura, along with the lung, hemidiaphragm, and pericardium. Less than 10 percent of mesothelioma patients meet the criteria for EPP: those with good performance status and early-stage disease. Perioperative mortality following EPP is around 5 percent, significant morbidity is 25 percent, and quality of life measures may remain impaired for up to six months after surgery. EPP is not generally recommended, as there is no evidence that it is superior to other treatment modalities, and there are no significant survival benefits to justify its high mortality and morbidity.

Novel approaches in mesothelioma

Numerous other approaches, including gene therapy, photodynamic therapy, intrapleural chemotherapy, immunotherapy, and intensity-modulated radiotherapy, have been applied to malignant mesothelioma but have had little proven success. Many of these are still active areas of research.

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

The median length of survival after a diagnosis of mesothelioma is 9-12 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. The clinical course after diagnosis is determined primarily by progressive local invasion. However, metastatic disease is found in over three-quarters of patients at post-mortem.

Factors associated with a poor prognosis include:

  • Sarcomatoid or mixed histology

  • Male

  • Poor performance status

  • The presence of chest pain

  • Age greater than 75 years

  • 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 that correlate with a poor prognosis include high white blood cell count, neutrophil:lymphocyte ratio greater than 5, raised platelet count, and raised serum LDH.

Two prognostic scoring systems, CALGB and EORTC, have been validated in mesothelioma, but they are rarely used outside the research setting.

In a randomized controlled trial of 456 patients with a good performance status (Karnofsky score >70), treatment with pemetrexed and cisplatin was found to improve median survival from 9.3 to 12.1 months compared to single-agent cisplatin. Raltitrexed, another anti-folate, confers similar survival benefit to pemetrexed and maintains quality of life measures. Many other agents have been tried in phase II trials in mesothelioma with some evidence of objective individual responses. However, the effects of these drugs on prognosis cannot be determined in the absence of randomized controlled trials.

The effects of radical surgery on prognosis are uncertain. Retrospective series of EPP and pleurectomy/decortication, with or without adjuvant chemotherapy/radiotherapy, report median survival rates of 12-23 months with five-year survival rates of 10-15 percent. These patients are highly selected with good performance status and favorable prognostic indices. Whether prognosis is altered by surgery can only be definitively determined by randomized controlled trials.

One non-randomized trial compared outcomes in patients who underwent EPP in addition to chemotherapy/radiotherapy to patients who met selection criteria for EPP but did not proceed to surgery. Median (20.4 vs. 20.7 months) and one-year survival rates (76% vs. 78%) were almost identical between the two groups.

What other considerations exist for patients with mesothelioma?

Patients who know they have been exposed to asbestos may have had a fear of developing mesothelioma for many years, and some know ex-colleagues who contracted the disease. Fears of a protracted painful death need to be dispelled by providing palliative support and attention to symptom control from the outset. Obtaining a firm diagnosis can be difficult--patients with mesothelioma sometimes require multiple diagnostic and therapeutic interventions--so it is important for the clinician to gain the patient's trust during this period.

Patients may direct anger toward previous employers. Compensation is usually available when employers have negligently exposed them to the risks of asbestos. However, the process of acquiring compensation is not always straightforward, and the litigation process can be time-consuming and stressful at a time when preservation of quality of life is a primary concern.

What’s the evidence?

"BTS statement on malignant mesothelioma in the UK, 2007". Thorax. vol. 62. 2007. pp. ii1-ii19.

(Guidelines from the British Thoracic Society, covering all aspects of mesothelioma care.)

Scherpereel, A, Astoul, P, Baas, P. "Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma". Eur Respir J. vol. 35. 2010. pp. 479-95.

(Guidelines from the European Respiratory Society and the European Society of Thoracic Surgeons, covering all aspects of mesothelioma care.)

Hodgson, JT, McElvenny, DM, Darnton, AJ, Price, MJ, Peto, J. "The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050". Br J Cancer. vol. 92. 2005. pp. 587-93.

(This study describes trends in mesothelioma incidence in the UK.)

Teta, MJ, Mink, PJ, Lau, E, Sceurman, BK, Foster, ED. "US mesothelioma patterns 1973-2002: indicators of change and insights into background rates". Eur J Cancer Prev. vol. 17. 2008. pp. 525-34.

(This study describes trends in mesothelioma incidence in the UK.)

Robinson, BW, Creaney, J, Lake, R. "Mesothelin-family proteins and diagnosis of mesothelioma". Lancet. vol. 362. 2003. pp. 1612-6.

(First study to identify mesothelin as a useful biomarker for mesothelioma.)

Husain, AN, Colby, TV, Ordonez, NG. "Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group". Arch Pathol Lab Med. vol. 133. 2009. pp. 1317-31.

(Guidelines from the International Mesothelioma Interest Group on the histocytological diagnosis of mesothelioma.)

Abrahm, JL. "Palliative care for the patient with mesothelioma". Semin Thorac Cardiovasc Surg. vol. 21. 2009. pp. 164-71.

(A review article covering all aspects of palliative care in patients with malignant pleural mesothelioma.)

Vogelzang, NJ, Rusthoven, J, Symanowski, J. "Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma". J Clin Oncol. vol. 21. 2003. pp. 2636-44.

(This study and the following study are randomized controlled trials that show a survival advantage with pemetrexed and raltitrexed in combination with cisplatin in patients with mesothelioma.)

van Meerbeeck, JP, Gaafar, R, Manegold, C. "Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada". J Clin Oncol. vol. 23. 2005. pp. 6881-9.

Boutin, C, Rey, F, Viallat, JR. "Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma: a randomized trial of radiotherapy". Chest. vol. 108. 1995. pp. 754-8.

(This study and the following study show conflicting results on the benefits of prophylactic radiation to sites of pleural interventions in patients with mesothelioma.)

O' Rourke, N, Garcia, JC, Paul, J, Lawless, C, McMenemin, R, Hill, J. "A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma". Radiother Oncol. vol. 84. 2007. pp. 18-22.

Flores, RM, Pass, HI, Seshan, VE. "Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients". J Thorac Cardiovasc Surg. vol. 135. 2008. pp. 6 e1-3 -6.

(A large multicenter series that describes outcomes following extrapleural pneumonectomy and pleurectomy/decortication.)

Hasani, A, Alvarez, JM, Wyatt, JM. "Outcome for patients with malignant pleural mesothelioma referred for trimodality therapy in Western Australia". J Thorac Oncol. vol. 4. 2009. pp. 1010-6.

(A study that compares the effects on prognosis of radical surgery against a matched (but non-randomized) group of patients who did not undergo surgery.)

Herndon, JE, Green, MR, Chahinian, AP, Corson, JM, Suzuki, Y, Vogelzang, NJ. "Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B". Chest. vol. 113. 1998. pp. 723-31.

(This study and the following study look at prognostication in mesothelioma and derive the CALGB and EORTC prognostic scoring systems.)

Curran, D, Sahmoud, T, Therasse, P, van Meerbeeck, J, Postmus, PE, Giaccone, G. "Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience". J Clin Oncol. vol. 16. 1998. pp. 145-52.

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