Mesothelioma in Australia: a review

Malignant mesothelioma (MM) is a form of invasive cancer that arises in the mesothelial cells of the pleural or peritoneal cavities (and occasionally in the tunica vaginalis of the scrotum). MM is almost exclusively caused by the inhalation of asbestos. In this article we concisely review the Australian experience of this disease, discussing the epidemiology, diagnosis, prognosis and management of mesothelioma from an historical Australian perspective, and review the most recent advances (2000–2017) in the understanding and clinical aspects of MM.

Epidemiology of mesothelioma

The high incidence of MM and of all other asbestos-related diseases in Australia and the United Kingdom is the direct result of the use of asbestos in industry and building construction during the 20th century. As a consequence of this heavy clinical burden, both countries have contributed significantly to the investigation of MM over the past 40 years.

Australia has one of the highest rates of death from MM in the world (Box 1). Western Australia has the highest incidence of MM in Australia because of the mining of crocidolite (blue asbestos) at Wittenoom Gorge from 1937 until 1966 and its widespread use in asbestos-cement and other products. Exposure to imported amosite (brown asbestos) and the contamination of most chrysotile (white asbestos) deposits by more pathogenic amphibole asbestos varieties (including crocidolite, amosite and tremolite) also contributed to the disease burden.

In 2015, the Australian Mesothelioma Registry (AMR) received 650 notifications of newly diagnosed MM; most patients (78%) were men, and 82% were over 65 years of age.1 The age-standardised incidence rate for mesothelioma in Australia in 2015 was 23 cases per million population. Allowing for a lag time in notifications to the AMR and a change in data source in 2010 from the Australian Cancer Database to the AMR, the numbers of new cases and the age-standardised incidence rates (Box 2) have probably now reached their peak values in Australia, as in other most affected countries. The incidence of MM commenced rising here in the 1960s, but the long latency between exposure to asbestos and the onset of disease (the risk increases continuously and exponentially after 10–15 years, with a mean latency of 30–40 years)2,3 means that the peak has only now been reached. Given the continuing legacy of asbestos-containing materials in many Australian homes and buildings, there is increasing concern about people being exposed to asbestos when performing domestic tasks and renovations,3 and it is likely that the elevated prevalence of MM in Australia will persist for some decades.

In Australia, the first wave of MM cases involved the miners and millers of crocidolite and workers involved in the transport and processing of asbestos for manufacturing asbestos-cement products. The second wave of disease affected people working with asbestos-cement products in buildings or with asbestos used for insulation in industry. A recently described third wave includes people exposed to asbestos in situ (occupationally, environmentally, or domestically), including those undertaking home renovations.3 Similar waves of exposure and disease have been described in other countries,4 although Australia is notable both for having mined raw asbestos as well as employing it widely in industry and construction. Blue asbestos production at Wittenoom (Western Australia) ceased in 1966, white asbestos production at Woodsreef in New South Wales ended in 1983, and importing or using any form of asbestos was banned from 2004. However, it is estimated that in 2015 about two million tonnes of chrysotile were mined elsewhere in the world and exported (particularly from Russia and China), with India, Indonesia, China and Brazil currently consuming nearly two-thirds of all asbestos produced.5

Risk of mesothelioma

MM is rare in people who have never been exposed to asbestos. The exact pathogenesis and biological mechanisms of the interactions between asbestos fibres and mesothelial cells that result in MM are unknown. The risk of developing MM is determined by the type and amount of asbestos to which an individual is exposed, and by the time since first exposure; there is a clear dose–response relationship, with no threshold below which there is no risk of disease.6 Crocidolite is five times as potent as amosite for causing MM, which in turn is ten times as potent as chrysotile.7 The risk of developing MM continues after first exposure to asbestos for at least 50 years, with no difference in latency or MM subtype associated with different fibre types.8

One clinical implication of these observations is that the risk of developing MM is extremely low (unmeasurable) for individuals transiently exposed to asbestos (eg, during a weekend renovating a house, but with no other exposure), but it is not possible to exclude risk altogether. In contrast, 10% of deaths among Wittenoom workers, who had extremely high exposure to crocidolite, have been attributed to mesothelioma (with a similar proportion dying of lung cancer2). Almost all asbestos that remains in Australian homes and the environment is a mixture of fibre types, the exact ratios of which vary by manufacturer and the market price of the different forms at the time of mixing and construction. It is therefore not possible to draw general conclusions about the exact nature of ongoing exposure to asbestos in Australia today.

Attempts to identify genetic risk for developing MM (or genes that confer protection) have been disappointing, although there is evidence of familial aggregation not entirely explained by shared exposure;2,6 mutations in the BAP1 gene have been implicated as predisposing to disease, but are very rare in most case series.9,10

Secondary prevention of mesothelioma

There is no evidence that any agents are effective in the secondary prevention of MM (ie, subsequent to asbestos exposure). A large study of individuals exposed to asbestos detected no benefit from vitamin supplementation (β-carotene, retinol).11 While there is no evidence that tobacco smoking influences the risk of MM (in contrast to that of lung cancer),10 individuals exposed to asbestos should be strongly encouraged to avoid tobacco smoke, to mitigate their increased risk of lung cancer and other smoking-related diseases.

Early detection and screening

Given the poor response to treatment and the toxic effects of treatments currently employed, there is little medical justification for screening people for MM until symptoms that may respond to treatment are present. For instance, attempts at radical surgery to remove apparently limited disease have not been useful, even after extensive disease staging.12 In a clinical (non-randomised) trial, the survival of patients considered potentially operable after clinical staging was similar for those who proceeded to surgery and those who did not.13

Low dose computed tomography (CT) screening of an asbestos-exposed Western Australian population for early stage lung cancer identified four cases of asymptomatic MM (0.44% of the cohort) during the first year of the program.14 The presence of asbestos-related pleural plaque is not an independent additional risk for MM,15 and, except in research studies, follow-up surveillance of people exposed to asbestos according to whether pleural plaques are present or absent is not justified. Blood levels of biomarkers such as mesothelin, osteopontin and fibulin-3 can be elevated prior to the diagnosis of MM,16-18 but their utility as screening tools remains limited, partly because of the marked biological heterogeneity of MM.

Individuals with a history of minor exposure, such as during small renovations at home, should be reassured that their risks are immeasurably low, and advised to avoid further exposure to asbestos and tobacco smoking.

Diagnosis of mesothelioma

MM affects the pleura (in more than 90% of cases), the peritoneum, and, very rarely, the tunica vaginalis. Pleural MM usually causes insidious onset of chest pain, breathlessness, and loss of weight. People with peritoneal MM usually experience abdominal distension (caused by ascites) and pain. A thorough history of occupational and environmental exposure to asbestos is vital for diagnosis, and subsequently for supporting claims for compensation; this may require the expertise of an industrial hygienist. Radiological changes, particularly pleural effusion or pleural thickening evident in plain film, CT, or ultrasound imaging, are typical (Box 3).

Cytological examination of pleural or peritoneal fluid or a fine needle aspiration biopsy sample may be sufficient in experienced pathology laboratories for establishing the diagnosis of epithelioid mesothelioma,19 and is the investigation of first choice. Core biopsies or surgical biopsies obtained by video-assisted thoracoscopy or laparoscopy may be required for diagnosing biphasic and sarcomatoid pathological subtypes (epithelioid, sarcomatoid and biphasic are by far the three most common subtypes of MM). Open biopsies are no longer needed for diagnosing MM.

Immunohistochemical staining is used to establish the presence of malignancy and to determine the mesothelial origin of the affected cells. Fluid or circulating biomarkers can assist diagnosis, but there is no objective evidence supporting their predictive value in the clinical setting and for following the progress of disease. Mesothelin assays and ONCOblot tissue of origin cancer detection tests are available in some laboratories, but have important limitations; they are not used for clinical diagnosis, although they may contribute to monitoring progression or response to therapy. Electron microscopy is not usually indicated for determining the type of malignancy.

Prognosis of mesothelioma

MM is inevitably fatal: the median survival time for patients with pleural mesothelioma is 9–12 months, while patients with peritoneal mesothelioma often die within 6 months of diagnosis.20 However, the specific prognosis varies widely between patients.21 The factors most consistently found to be independently predictive of poor survival for patients with pleural MM include higher age, being male, and sarcomatoid histological features.22 The effects of these variables were determined in clinical trial populations, which may limit the generalisability of the findings. More recently, a regression tree model has been developed and validated for a broader Australian population of patients with pleural MM, taking into account the interaction of clinical variables such as weight loss, Eastern Cooperative Oncology Group (ECOG) performance status, haemoglobin and serum albumin levels, and tumour histological subtype.23 Genetic and immunohistochemical studies continue to report advances in tumour biology, but no clinically useful prognostic factors have yet been identified. Nuclear mitotic and atypia grading systems may provide useful prognostic information, but further evaluation is required.22

Management of patients with mesothelioma

Multidisciplinary management is important from the outset for establishing the diagnosis and instituting appropriate care. Palliation of pain and dyspnoea is imperative, as poorly controlled pain ultimately requires more medication than pain adequately treated from its onset. Therapeutic pleural aspiration, drainage with talc pleurodesis, and inserting indwelling pleural or peritoneal catheters are simple and effective procedures for controlling fluid accumulation and reducing dyspnoea.23 Weight loss may require dietary intervention or oral corticosteroid therapy. Evidence that surgery (pleurectomy or radical pleuro-pneumonectomy) benefits disease control is limited; it does not improve survival, and may cause significant complications.24,25

Combination chemotherapy with cisplatin or carboplatin and pemetrexed improved survival in clinical trial patients (by about 3 months),26 and these medications are currently first line agents. There is no clear evidence base that informs the use of second line agents, and clinical trials of novel agents would be desirable. The clinical utility of radiological staging of MM (in contrast to that of lung cancer) is limited; most patients are offered chemotherapy because of their general fitness and expected tolerance of the treatment, rather than because of tumour stage.

Immunotherapy directed against cytotoxic T cell lymphocyte antigen 4 and programmed cell death protein 1 may offer hope; efficacy of the immune checkpoint inhibitors tremelimumab and nivolumab has been reported after initial phase 2 studies.27,28 Larger trials and further early phase immunotherapy studies are underway in Australia and elsewhere.

Radiotherapy has a limited role in MM treatment, as the disease is typically widely disseminated, but it is indicated for palliating localised disease causing symptoms such as local chest wall pain, metastatic disease, or bulky disease that compresses mediastinal structures (oesophagus, vena cava, subclavian vein). The role of prophylactic radiotherapy for reducing procedure tract metastases is unclear.29 Publication of the results of two large randomised studies in the UK is pending.

Multidisciplinary palliative care is vital throughout the course of the disease; patients with MM and their families need the support of community care organisations for managing life at home for as long as possible. The results of a large international randomised study (including Australia) that examined the utility of early palliative care in patients with pleural MM should be published soon.30

Medico-legal questions

Questions of compensation and litigation are important for patients with MM, especially for relatively young patients, who may have dependents. It is therefore vital that the history of exposure to asbestos be recorded accurately and as early as possible in the course of the disease, and that competent legal advice be sought before the patient is terminally ill. Community asbestos support organisations can assist with access to sources of such advice.

In Australia, damages claims based on liability in common law have now been legally established, so that about 95% of patients with MM and documented exposure to asbestos are compensated. However, there are still disparities between jurisdictions in awarding general damages (for pain and suffering), with workers’ compensation schemes for different asbestos-related diseases varying between states. The patterns of workforce and domestic exposure in Australia have changed since the prohibition of the production and importation of asbestos, with an increasing number of claims related to domestic exposure in homes containing asbestos-cement building materials.

Conclusion

Malignant mesothelioma is a universally fatal, preventable disease, the incidence of which is projected to decline in Australia over coming decades as exposure to asbestos continues to fall. Response to currently available anti-tumour treatments is usually minimal, so that early multidisciplinary management is of key importance. Further information about malignant mesothelioma can be found in the Asbestos Diseases Research Institute guidelines for the diagnosis and treatment of mesothelioma on the website of Lung Foundation Australia.31

Box 1 – Age-standardised mortality attributed to mesothelioma per million men aged 15 years or more, 2013

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Source: World Health Organization mortality database (http://www-dep.iarc.fr/WHOdb/WHOdb.htm). * 2012 data cited, as 2013 data are not available.

Box 2 – Age-standardised incidence rates of mesothelioma in Australia, 1982–2014, by sex

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Source: .

Box 3 – Malignant pleural mesothelioma. A. Computed tomography (CT) imaging of the chest, showing diffuse right-sided pleural thickening. B. Positron emission tomography–computed tomography (PET-CT) imaging of the same patient, showing high metabolic activity (marked [¹⁸F]-fluorodeoxyglucose uptake)