Civil litigation

The first lawsuits against asbestos manufacturers were brought in 1929. Since then, many lawsuits have been filed. As a result of the litigation, manufacturers sold off subsidiaries, diversified, produced asbestos substitutes, and started asbestos removal businesses. In June 1982, a retired boiler-maker, James Cavett, won a record award of $2.3 million compensatory and $1.5 million in punitive damages.

The Manville Corporation, formerly the Johns-Manville Corporation, filed for reorganization and protection under the United States Bankruptcy Code in August 1982. At the time, it was the largest company ever to file bankruptcy, and was one of the richest. Manville was then 181st on the Fortune 500, but was the defendant of 16,500 lawsuits related to the health effects of asbestos.

Johns-Manville was described by Ron Motley, a South Carolina attorney, as "the greatest corporate mass murderer in history." Court documents show that the corporation had a long history of hiding evidence of the ill effects of asbestos from its workers and the public. One of many examples is a memo from Johns-Manville's medical director to corporate headquarters:

The fibrosis of this disease is irreversible and permanent so that eventually compensation will be paid to each of these men. But, as long as the man is not disabled it is felt that he should not be told of his condition so that he can live and work in peace and the company can benefit by his many years of experience.

By the early 1990s, "more than half of the 25 largest asbestos manufacturers in the US, including Amatex, Carey-Canada, Celotex, Eagle-Pitcher Industries, Forty-Eight Insulations, Manville Corporation, National Gypsum, Standard Insulation, Unarco, and UNR Industries had declared bankruptcy. Filing for bankruptcy protects a company from its creditors.".

One of the major issues relating to asbestos in civil procedure is the latency of asbestos-related diseases. Most countries have limitation periods to bar actions that are taken long after the cause of action has lapsed. For example, in Malaysia the time period to file a tort action is six years from the time the tort occurred. Due to several asbestos-related actions, countries such as Australia have amended their laws relating to limitations to accumulate starting from time of discovery rather than time when the cause of action accrued.

Asbestos and the law

This article concerns asbestos-related legal and regulatory issues. Litigation related to asbestos injuries and property damages has been claimed to be the longest-running mass tort in U.S. history. Since asbestos-related disease has been identified by the medical profession in the late 1920s, workers' compensation cases were filed and resolved in secrecy, with a flood of litigation starting in the United States in the 1970s, and culminating in the 1980s and 1990s. A massive multi-district litigation (MDL) complex filing has remained pending in the Eastern District of Pennsylvania for over 20 years. As many of the scarring-related injury cases have been resolved, asbestos litigation continues to be hard-fought among the litigants, mainly in individually-brought cases for terminal cases of asbestosis and cancers.

Background

In the late 19th century and early 20th century, asbestos was considered an ideal material for use in the construction industry. It was known to be an excellent fire retardant, to have high electrical resistance, and was inexpensive and easy to use.

The problem with asbestos arises when the fibers become airborne and are inhaled. Because of the size of the fibers, the lungs cannot expel them. They are also sharp and penetrate tissues.

Health problems attributed to asbestos include

1. Asbestosis - A lung disease first found in textile workers, asbestosis is a scarring of the lung tissue from an acid produced by the body's attempt to dissolve the fibers. The scarring may eventually become so severe that the lungs can no longer function. The latency period (meaning the time it takes for the disease to develop) is often 10–20 years.
2. Mesothelioma - A cancer of the mesothelial lining of the lungs and the chest cavity, the peritoneum (abdominal cavity) or the pericardium (a sac surrounding the heart). Unlike lung cancer, mesothelioma has no association with smoking. The only established causal factor is exposure to asbestos or similar fibers.The latency period for mesothelioma may be 20–50 years. The prognosis for mesothelioma is grim, with most patients dying within 12 months of diagnosis.
3. Cancer - Cancer of the lung, gastrointestinal tract, kidney and larynx have been linked to asbestos. The latency period for cancer is often 15–30 years.
4. Diffuse pleural thickening

Considerable international controversy exists regarding the perceived rights and wrongs associated with litigation on compensation claims related to asbestos exposure and alleged subsequent medical consequences. Some measure of the vast range of views expressed in legal and political circles can perhaps be exemplified by the two quotes below, the first from Prof. Lester Brickman, an American legal ethicist writing in the Pepperdine Law Review, and second, Michael Wills, a British Member of Parliament, speaking in the House of Commons on July 13. 2006:

"A review of the scholarly literature indicates a substantial degree of indifference to the causes of this civil justice system failure. Many of the published articles on asbestos litigation focus on transactional costs and ways in which the flow of money from defendants to plaintiffs and their lawyers can be expeditiously and efficiently prioritized and routed. The failure to acknowledge, let alone analyze, the overriding reality of specious claiming and meritless claims demonstrates a disconnect between the scholarship and the reality of the litigation that is nearly as wide as the disconnect between rates of disease claiming and actual disease manifestation".

"Many of those who I see in my surgeries have worked in a number of workplaces and they could have been exposed to asbestos in each of them, but medical science is such that no one can identify which of them it is. As a result, there has been a long and complex history of legal discussion on how to apportion liability. The lawyers and the judiciary have wrestled, rightly and valiantly, with complex and difficult law, but it has created despair for the families whom we represent. Many of my constituents’ families have been riven by the consequences of litigation in trying to get some compensation for a disease that has been contracted through no fault of theirs. That is cruel and unacceptable."

Regulation and government action

Worldwide, 60 countries (including those in the European Union) have banned the use of asbestos, in whole or in part. Some examples follow.

Australia

A nationwide ban on importing and using all forms of asbestos took effect on 31 December 2003. Reflecting the ban, the National Occupational Health and Safety Commission (NOHSC) revised asbestos-related material to promote a consistent approach to controlling exposure to workplace asbestos and to introduce best-practice health and safety measures for asbestos management, control and removal. The ban does not cover asbestos materials or products already in use at the time the ban was implemented.

Although Australia has only a third of the UK's population, its asbestos disease fatalities approximate Britain's of more than 3,000 people per year.

Brazil

The São Paulo State law 12.684/07 prohibits the use of any product which utilizes asbestos, this legislation having been formally upheld by the Brazilian Supremo Tribunal Federal.

Canada

The only asbestos mines still operating in Canada are in the Province of Quebec. They are owned by the Quebec government who expropriated the Asbestos Corporation Limited in 1981 from its American parent, General Dynamics. Quebec is the second largest producer in the world behind Russia and the world's largest exporter of asbestos. Quebec exports 95 percent of its chrysotile production, mostly to Asian and other poor countries. In 1999 the government of Canada went before the World Trade Organization to challenge, unsuccessfully, the ban on asbestos in France.

France

France banned the use of asbestos in 1997, and the WTO upheld France's right to the ban in 2000. In addition, France has called for a worldwide ban.

Italy

Italy fully banned the use of asbestos in 1992 and set up a comprehensive plan for asbestos decontamination in industry and housing.

Japan

Japan did not fully ban asbestos until 2004, and so its government has been held responsible for related diseases.

New Zealand

In 1984 the import of raw amphibole (blue and brown) asbestos into New Zealand was banned. In 2002 the import of chrysotile (white) asbestos was banned.

United Kingdom

The British Government's Health and Safety Executive (HSE) has promoted rigorous controls on asbestos handling, based on reports linking exposure to asbestos dust or fibres with thousands of annual deaths from mesothelioma and asbestos-related lung cancer.

• "At least 3500 people in Great Britain die each year from mesothelioma and asbestos related lung cancer as a result of past exposure to asbestos. Annual numbers of deaths are predicted to go on rising into the next decade."
• The TUC (UK) report cites a figure of 5000 deaths per year. TUC (UK)

The HSE does not assume that any minimum threshold exists for exposure to asbestos below which a person is at zero risk of developing mesothelioma, since they consider that it cannot currently be quantified for practical purposes; they cite evidence from epidemiological studies of asbestos exposed groups to argue that even if any such threshold for mesothelioma does exist, it must be at a very low level.(There is currently no scientific consensus as to whether there does indeed exist such a specific threshold ).

Previously it was possible to claim compensation for pleural plaques caused by negligent exposure to asbestos, on the grounds that although it is in itself asymptomatic, it is linked to development of diffuse pleural thickening, which causes lung impairment. It has been highly contentious, however, as to the probability of pleural plaques developing into pleural thickening or other asbestos related illnesses. On October 17, 2007 this point was clarified by the Law Lords′ ruling that workers who have pleural plaques as a result of asbestos exposure will no longer be able to seek compensation as it does not in itself constitute a disease.

The Control of Asbestos Regulations were introduced in the UK in November 2006 and are an amalgamation of three previous sets of legislation (Asbestos Prohibition, Asbestos Licensing and the Control of Asbestos at Work Regulations) aimed at minimising the use and disturbance of asbestos containing materials within British workplaces. Essentially this legislation bans the import and use of most asbestos products and sets out guidelines on how best to manage those currently in-situ.

Dutyholders of all non-domestic properties within the UK must establish an asbestos register and a management plan. The definition of "non-domestic" is "a property or structure (commercial, domestic or residential) where work is carried out" the obligation of the duty holder is that such operatives are not exposed to any asbestos based materials during the course of the work, the Asbestos Register states the presence or non presence of asbestos related to the inside and outside of the structure. The exception is where the property age (post-1999 when Chrysotile asbestos was banned) would indicate that such products will not have been used during the construction of the building.

The removal of high-risk asbestos products from non-domestic properties is tightly controlled by the HSE and high-risk products such as thermal insulation must be removed under controlled conditions by licensed contractors. Further guidance on which products this applies to can be found on the HSE website along with a list of licensees.

United States

According to the Environmental Working Group Action Fund, 10,000 people a year die from asbestos-caused diseases in the United States, including one out of every 125 American men who die over the age of 50.The Environmental Protection Agency (EPA) has no general ban on the use of asbestos. However, asbestos was one of the first hazardous air pollutants regulated under Section 112 of the Clean Air Act of 1970, and many applications have been forbidden by the Toxic Substances Control Act (TSCA).

According to a September 2004 of the American Journal of Respiratory and Critical Care Medicine, asbestos is still a hazard for 1.3 million US workers in the construction industry and for workers involved in the maintenance of buildings and equipment.

A Senate Subcommittee of the Health Education Labor and Pensions Committee heard testimony on July 31, 2001, regarding the health effects of asbestos. Members of the public, doctors, and scientists called for the United States to join other countries in a ban on the product.

Asbestos is not part of a ASTM (American Society for Testing and Materials) E 1527-05 Phase I Environmental Site Assessment (ESA). A Building Survey for Asbestos is considered an out-of-scope consideration under the industry standard ASTM 1527-05 Phase I ESA (see ASTM E 1527-05). ASTM Standard E 2356-04 should be consulted by the owner or owners' agent to determine which type of asbestos building survey is appropriate, typically either a baseline survey or a design survey of functional areas. Both types of surveys are explained in detail under ASTM Standard E 2356-04. Typically, a baseline survey is performed by an EPA (or State) licensed asbestos inspector. The baseline survey provides the buyer with sufficient information on presumed asbestos at the facility, often which leads to reduction in the assessed value of the building (due primarily to forthcoming abatement costs). Note: EPA NESHAP (National Emissions Standards for Hazardous Air Pollutants) and OSHA (Occupational Safety and Health Administration) Regulations must be consulted in addition to ASTM Standard E 2356-04 to ensure all statutory requirements are satisfied, ex. notification requirements for renovation/demolition. Asbestos is not a material covered under CERCLA (Comprehensive Environmental Response, Compensation, and Liability Act ) innocent purchaser defense. In some instances, the U.S. EPA includes asbestos contaminated facilities on the NPL (Superfund). Buyers should be careful not to purchase facilities, even with a ASTM E 1527-05 Phase I ESA completed, without a full understanding of all the hazards in a building or at a property, without evaluating non-scope ASTM E 1527-05 materials, such as asbestos, lead, PCBs, mercury, radon, et al. A standard ASTM E 1527-05 does not include asbestos surveys as standard practice.

History

The first lawsuit against asbestos manufacturers was brought in 1929. The parties settled that lawsuit, and as part of the agreement, the attorneys agreed not to pursue further cases. In 1960, an article published by Wagner et al. was seminal in establishing mesothelioma as a disease arising from exposure to asbestos. The article referred to over 30 case studies of people who had suffered from mesothelioma in South Africa. Some exposures were transient and some were mine workers. Prior to the use of advanced microscopy techniques, malignant mesothelioma was often diagnosed as a variant form of lung cancer. In 1962 McNulty reported the first diagnosed case of malignant mesothelioma in an Australian asbestos worker. The worker had worked in the mill at the asbestos mine in Wittenoom from 1948 to 1950.

In the town of Wittenoom, asbestos-containing mine waste was used to cover schoolyards and playgrounds. In 1965 an article in the British Journal of Industrial Medicine established that people who lived in the neighbourhoods of asbestos factories and mines, but did not work in them, had contracted mesothelioma.

Despite proof that the dust associated with asbestos mining and milling causes asbestos-related disease, mining began at Wittenoom in 1943 and continued until 1966. In 1974 the first public warnings of the dangers of blue asbestos were published in a cover story called "Is this Killer in Your Home?" in Australia's Bulletin magazine. In 1978 the Western Australian Government decided to phase out the town of Wittenoom, following the publication of a Health Dept. booklet, "The Health Hazard at Wittenoom", containing the results of air sampling and an appraisal of worldwide medical information.

By 1979 the first writs for negligence related to Wittenoom were issued against CSR and its subsidiary ABA, and the Asbestos Diseases Society was formed to represent the Wittenoom victims.

In Leeds, England the Armley asbestos disaster involved several court cases against Turner & Newall where local residents who contracted mesothelioma claimed compensation because of the asbestos pollution from the company's factory. One notable case was that of June Hancock, who contracted the disease in 1993 and died in 1997.

Legal issues

The first lawsuits against asbestos manufacturers were in 1929. Since then, many lawsuits have been filed against asbestos manufacturers and employers, for neglecting to implement safety measures after the links between asbestos, asbestosis, and mesothelioma became known (some reports seem to place this as early as 1898). The liability resulting from the sheer number of lawsuits and people affected has reached billions of dollars. The amounts and method of allocating compensation have been the source of many court cases, reaching up to the United States Supreme Court, and government attempts at resolution of existing and future cases. However, to date, the US Congress has not stepped in and there are no federal laws governing asbestos compensation .

Notable people who have lived for some time with mesothelioma

Although life expectancy with this disease is typically limited, there are notable survivors. In July 1982, Stephen Jay Gould was diagnosed with peritoneal mesothelioma. After his diagnosis, Gould wrote "The Median Isn't the Message" for Discover magazine, in which he argued that statistics such as median survival are just useful abstractions, not destiny. Gould lived for another 20 years, eventually succumbing to metastatic adenocarcinoma of the lung, not mesothelioma. Author Paul Kraus was diagnosed with peritoneal mesothelioma in July 1997. He was given a prognosis of less than a year to live and used a variety of complementary modalities. He continues to outlive his prognosis and wrote a book about his experience "Surviving Mesothelioma and Other Cancers: A Patient's Guide" in which he presented his philosophy about healing and the decision making that led him to use integrative medicine.

Society and culture

Notable cases

Mesothelioma, though rare, has had a number of notable patients.

* Malcolm McLaren, former manager of New York Dolls and Sex Pistols, died on 8 April 2010.

* Billy Vaughn, American bandleader, died in 1991.

* Hamilton Jordan, Chief of Staff for U.S. President Jimmy Carter and lifelong cancer activist, died in 2008.

* Richard J. Herrnstein, psychologist and co-author of The Bell Curve, died in 1994.

* Australian anti-racism activist Bob Bellear died in 2005.

* British science fiction writer Michael G. Coney, responsible for nearly 100 works, also died in 2005.

* American film and television actor Paul Gleason, perhaps best known for his portrayal of Principal Richard Vernon in the 1985 film The Breakfast Club, died in 2006.

* Mickie Most, an English record producer, died of mesothelioma in 2003.

* Paul Rudolph, American architect, died in 1997.

* Bernie Banton, an Australian workers' rights activist, fought a long battle for compensation from James Hardie after he contracted mesothelioma after working for that company. He claimed James Hardie knew of the dangers of asbestos before he began work with the substance making insulation for power stations. Mesothelioma eventually took his life along with his brothers and hundreds of James Hardie workers. James Hardie made an undisclosed settlement with Banton only when his mesothelioma had reached its final stages and he was expected to have no more than 48 hours to live. Australian Prime Minister Kevin Rudd mentioned Banton's extended struggle in his acceptance speech after winning the 2007 Australian federal election.

* Actor Steve McQueen was diagnosed with peritoneal mesothelioma on December 22, 1979. He was not offered surgery or chemotherapy because doctors felt the cancer was too advanced. McQueen subsequently sought alternative treatments at clinics in Mexico. He died of a heart attack on November 7, 1980, in Juárez, Mexico, following cancer surgery. He may have been exposed to asbestos while serving with the U.S. Marines as a young adult—asbestos was then commonly used to insulate ships' piping—or from its use as an insulating material in automobile racing suits (McQueen was an avid racing driver and fan).

* United States Congressman Bruce Vento died of mesothelioma in 2000. The Bruce Vento Hopebuilder award is given yearly by his wife at the MARF Symposium to persons or organizations who have done the most to support mesothelioma research and advocacy.

* Rock and roll musician and songwriter Warren Zevon, after a long period of untreated illness and pain, was diagnosed with inoperable mesothelioma in the fall of 2002. Refusing treatments that he believed might incapacitate him, Zevon focused his energies on recording his final album The Wind, including the song "Keep Me in Your Heart," which speaks of his failing breath. Zevon died at his home in Los Angeles, California, on September 7, 2003.

* Christie Hennessy, the influential Irish singer-songwriter, died of mesothelioma in 2007, and had stridently refused to accept the prognosis in the weeks before his death.[41] Hennessy's mesothelioma has been attributed to his younger years spent working on building sites in London.

* Bob Miner, one of the founders of Software Development Labs, the forerunner of Oracle Corporation, died of mesothelioma in 1994.

* Scottish Labour MP John William MacDougall died of mesothelioma on August 13, 2008, after fighting the disease for two years.

* Australian journalist and news presenter Peter Leonard of Canberra succumbed to the condition on September 23, 2008.

* Terrence McCann, Olympic gold medalist and longtime Executive Director of Toastmasters, died of mesothelioma on June 7, 2006, at his home in Dana Point, California.

* Merlin Olsen, Pro Football Hall of Famer and television actor, died on March 10, 2010, from mesothelioma that had been diagnosed in 2009.

Epidemiology

Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. The incidence rate varies from one country to another, from a low rate of less than 1 per 1,000,000 in Tunisia and Morocco, to the highest rate in Britain, Australia and Belgium: 30 per 1,000,000 per year. For comparison, populations with high levels of smoking can have a lung cancer incidence of over 1,000 per 1,000,000. Incidence of malignant mesothelioma currently ranges from about 7 to 40 per 1,000,000 in industrialized Western nations, depending on the amount of asbestos exposure of the populations during the past several decades. It has been estimated that incidence may have peaked at 15 per 1,000,000 in the United States in 2004. Incidence is expected to continue increasing in other parts of the world. Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age. Approximately one fifth to one third of all mesotheliomas are peritoneal.

Between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States. Between 1973 and 1984, the incidence of pleural mesothelioma among Caucasian males increased 300%. From 1980 to the late 1990s, the death rate from mesothelioma in the USA increased from 2,000 per year to 3,000, with men four times more likely to acquire it than women. These rates may not be accurate, since it is possible that many cases of mesothelioma are misdiagnosed as adenocarcinoma of the lung, which is difficult to differentiate from mesothelioma.

Multimodality Therapy

All of the standard approaches to treating solid tumors—radiation, chemotherapy, and surgery—have been investigated in patients with malignant pleural mesothelioma. Although surgery, by itself, is not very effective, surgery combined with adjuvant chemotherapy and radiation (trimodality therapy) has produced significant survival extension (3–14 years) among patients with favorable prognostic factors. However, other large series of examining multimodality treatment have only demonstrated modest improvement in survival (median survival 14.5 months and only 29.6% surviving 2 years). Reducing the bulk of the tumor with cytoreductive surgery is key to extending survival. Two surgeries have been developed: extrapleural pneumonectomy and pleurectomy/decortication. The indications for performing these operations are unique. The choice of operation depends on the size of the patient's tumor. This is an important consideration because tumor volume has been identified as a prognostic factor in mesothelioma. Pleurectomy/decortication spares the underlying lung and is performed in patients with early stage disease when the intention is to remove all gross visible tumor (macroscopic complete resection), not simply palliation. Extrapleural pneumonectomy is a more extensive operation that involves resection of the parietal and visceral pleurae, underlying lung, ipsilateral diaphragm, and ipsilateral pericardium. This operation is indicated for a subset of patients with more advanced tumors, who can tolerate a pneumonectomy.

Heated Intraoperative Intraperitoneal Chemotherapy

A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute. The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.

This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.

This technique is also used in patients with malignant pleural mesothelioma.

Immunotherapy

Treatment regimens involving immunotherapy have yielded variable results. For example, intrapleural inoculation of Bacillus Calmette-Guérin (BCG) in an attempt to boost the immune response, was found to be of no benefit to the patient (while it may benefit patients with bladder cancer). Mesothelioma cells proved susceptible to in vitro lysis by LAK cells following activation by interleukin-2 (IL-2), but patients undergoing this particular therapy experienced major side effects. Indeed, this trial was suspended in view of the unacceptably high levels of IL-2 toxicity and the severity of side effects such as fever and cachexia. Nonetheless, other trials involving interferon alpha have proved more encouraging with 20% of patients experiencing a greater than 50% reduction in tumor mass combined with minimal side effects.

Chemotherapy

Chemotherapy is the only treatment for mesothelioma that has been proven to improve survival in randomised and controlled trials. The landmark study published in 2003 by Vogelzang and colleagues compared cisplatin chemotherapy alone with a combination of cisplatin and pemetrexed (brand name Alimta) chemotherapy in patients who had not received chemotherapy for malignant pleural mesothelioma previously and were not candidates for more aggressive "curative" surgery. This trial was the first to report a survival advantage from chemotherapy in malignant pleural mesothelioma, showing a statistically significant improvement in median survival from 10 months in the patients treated with cisplatin alone to 13.3 months in the group of patients treated with cisplatin in the combination with pemetrexed and who also received supplementation with folate and vitamin B₁₂. Vitamin supplementation was given to most patients in the trial and pemetrexed related side effects were significantly less in patients receiving pemetrexed when they also received daily oral folate 500mcg and intramuscular vitamin B₁₂ 1000mcg every 9 weeks compared with patients receiving pemetrexed without vitamin supplementation. The objective response rate increased from 20% in the cisplatin group to 46% in the combination pemetrexed group. Some side effects such as nausea and vomiting, stomatitis, and diarrhoea were more common in the combination pemetrexed group but only affected a minority of patients and overall the combination of pemetrexed and cisplatin was well tolerated when patients received vitamin supplementation; both quality of life and lung function tests improved in the combination pemetrexed group. In February 2004, the United States Food and Drug Administration approved pemetrexed for treatment of malignant pleural mesothelioma. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give.

Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported for pemetrexed in combination with cisplatin, but raltitrexed is no longer commercially available for this indication. For patients unable to tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, or vinorelbine on its own, although a survival benefit has not been shown for these drugs. For patients in whom cisplatin cannot be used, carboplatin can be substituted but non-randomised data have shown lower response rates and high rates of haematological toxicity for carboplatin-based combinations, albeit with similar survival figures to patients receiving cisplatin.^[31]

In January 2009, the United States FDA approved using conventional therapies such as surgery in combination with radiation and or chemotherapy on stage I or II Mesothelioma after research conducted by a nationwide study by Duke University concluded an almost 50 point increase in remission rates.

Radiation

For patients with localized disease, and who can tolerate a radical surgery, radiation is often given post-operatively as a consolidative treatment. The entire hemi-thorax is treated with radiation therapy, often given simultaneously with chemotherapy. This approach of using surgery followed by radiation with chemotherapy has been pioneered by the thoracic oncology team at Brigham & Women's Hospital in Boston. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.

Although mesothelioma is generally resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms arising from tumor growth, such as obstruction of a major blood vessel. Radiation therapy when given alone with curative intent has never been shown to improve survival from mesothelioma. The necessary radiation dose to treat mesothelioma that has not been surgically removed would be very toxic.

Surgery

Surgery, by itself, has proved disappointing. In one large series, the median survival with surgery (including extrapleural pneumonectomy) was only 11.7 months. However, research indicates varied success when used in combination with radiation and chemotherapy (Duke, 2008). (For more information on multimodality therapy with surgery, see below). A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. Less common is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.

Treatment

The prognosis for malignant mesothelioma remains disappointing, although there have been some modest improvements in prognosis from newer chemotherapies and multimodality treatments. Treatment of malignant mesothelioma at earlier stages has a better prognosis, but cures are exceedingly rare. Clinical behavior of the malignancy is affected by several factors including the continuous mesothelial surface of the pleural cavity which favors local metastasis via exfoliated cells, invasion to underlying tissue and other organs within the pleural cavity, and the extremely long latency period between asbestos exposure and development of the disease. The histological subtype and the patient's age and health status also help predict prognosis.

Pathophysiology

The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.

Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers). However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System. Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.

Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localized lesions of accumulated asbestos fibers in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumor.

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibers remain unclear despite the demonstration of its oncogenic capabilities (see next-but-one paragraph). However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibers has not yet been achieved. In general, asbestos fibers are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

Analysis of the interactions between asbestos fibers and DNA has shown that phagocytosed fibers are able to make contact with chromosomes, often adhering to the chromatin fibers or becoming entangled within the chromosome. This contact between the asbestos fiber and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.

Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:

• Neurofibromatosis type 2 at 22q12
• P16^INK4A
• P14^ARF

Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:

• Inactivation of tumor suppressor genes
• Activation of oncogenes
• Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
• Activation of DNA repair enzymes, which may be prone to error
• Activation of telomerase
• Prevention of apoptosis

Asbestos fibers have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.

Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

Diagnosis

Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytopathology if this fluid is aspirated with a syringe. For pleural fluid, this is done by thoracentesis or tube thoracostomy (chest tube); for ascites, with paracentesis or ascitic drain; and for pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure). Unfortunately, the diagnosis of malignant mesothelioma by cytology alone is difficult, even with expert pathologists.

Generally, a biopsy is needed to confirm a diagnosis of malignant mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. Alternatively, the chest surgeon might directly open the chest (thoracotomy). If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small incision in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.

Immunohistochemical studies play an important role for the pathologist in differentiating malignant mesothelioma from neoplastic mimics. There are numerous tests and panels available. No single test is perfect for distinguishing mesothelioma from carcinoma or even benign versus malignant.

Typical immunohistochemistry results

Positive	Negative
EMA (epithelial membrane antigen) in a membranous distribution	CEA (carcinoembryonic antigen)
WT1 (Wilms' tumour 1)	B72.3
Calretinin	MOC-3 1
Mesothelin-1	CD15
Cytokeratin 5/6	Ber-EP4
HBME-1 (human mesothelial cell 1)	TTF-1 (thyroid transcription factor-1)

There are three histological types of malignant mesothelioma: (1) Epithelioid; (2) Sarcomatoid; and (3) Biphasic (Mixed). Epithelioid comprises about 50-60% of malignant mesothelioma cases and generally holds a better prognosis than the Sarcomatoid or Biphasic subtypes.

[edit] Staging

Staging of mesothelioma is based on the recommendation by the International Mesothelioma Interest Group. TNM classification of the primary tumor, lymph node involvement, and distant metastasis is performed. Mesothelioma is staged Ia–IV (one-A to four) based on the TNM status.

Screening

There is no universally agreed protocol for screening people who have been exposed to asbestos. Screening tests might diagnose mesothelioma earlier than conventional methods thus improving the survival prospects for patients. The serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening. Doctors have begun testing the Mesomark assay which measures levels of soluble mesothelin-related proteins (SMRPs) released by diseased mesothelioma cells.

Causes of Mesothelioma

Working with asbestos is the major risk factor for mesothelioma. In the United States, asbestos is the major cause of malignant mesothelioma and has been considered "indisputably" associated with the development of mesothelioma. Indeed, the relationship between asbestos and mesothelioma is so strong that many consider mesothelioma a “signal” or “sentinel” tumor.
A history of asbestos exposure exists in most cases. However, mesothelioma has been reported in some individuals without any known exposure to asbestos. In rare cases, mesothelioma has also been associated with irradiation, intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates, such as erionite. Some studies suggest that simian virus 40 (SV40) may act as a cofactor in the development of mesothelioma.
Asbestos was known in antiquity, but it was not mined and widely used commercially until the late 19th century. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not publicly known. However, an increased risk of developing mesothelioma was later found among shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the official position of the U.S. Occupational Safety and Health Administration (OSHA) and the U.S. EPA is that protections and "permissible exposure limits" required by U.S. regulations, while adequate to prevent most asbestos-related non-malignant disease, they are not adequate to prevent or protect against asbestos-related cancers such as mesothelioma.
Likewise, the British Government's Health and Safety Executive (HSE) states formally that any threshold for mesothelioma must be at a very low level and it is widely agreed that if any such threshold does exist at all, then it cannot currently be quantified. For practical purposes, therefore, HSE assumes that no such "safe" threshold exists. Others have noted as well that there is no evidence of a threshold level below which there is no risk of mesothelioma. There appears to be a linear, dose-response relationship, with increasing dose producing increasing disease. Nevertheless, mesothelioma may be related to brief, low level or indirect exposures to asbestos. The dose necessary for effect appears to be lower for asbestos-induced mesothelioma than for pulmonary asbestosis or lung cancer. Again, there is no known safe level of exposure to asbestos as it relates to increased risk of mesothelioma.
The duration of exposure to asbestos causing mesothelioma can be short. For example, cases of mesothelioma have been documented with only 1–3 months of exposure.
People who work with asbestos wear personal protective equipment to lower their risk of exposure. Latency, the time from first exposure to manifestation of disease, is prolonged in the case of mesothelioma. It is virtually never less than fifteen years and peaks at 30–40 years. In a review of occupationally related mesothelioma cases, the median latency was 32 years. Based upon the data from Peto et al, the risk of mesothelioma appears to increase to the third or fourth power from first exposure.

Mesothelioma Signs and symptoms

Symptoms or signs of mesothelioma may not appear until 20 to 50 years (or more) after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma.
Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of Peritoneal Mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.
These symptoms may be caused by mesothelioma or by other, less serious conditions.
Mesothelioma that affects the pleura can cause these signs and symptoms:

Chest wall pain
Pleural effusion, or fluid surrounding the lung
Shortness of breath
Fatigue or anemia
Wheezing, hoarseness, or cough
Blood in the sputum (fluid) coughed up (hemoptysis)

In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.
Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage.

Symptoms include:

Abdominal pain
Ascites, or an abnormal buildup of fluid in the abdomen
A mass in the abdomen
Problems with bowel function
Weight loss

In severe cases of the disease, the following signs and symptoms may be present:
Blood clots in the veins, which may cause thrombophlebitis
Disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
Jaundice, or yellowing of the eyes and skin
Low blood sugar level
Pleural effusion
Pulmonary emboli, or blood clots in the arteries of the lungs Severe ascites

A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.

What is Mesothelioma

Mesothelioma, more precisely malignant mesothelioma, is a rare form of cancer that develops from the protective lining that covers many of the body's internal organs, the mesothelium. It is usually caused by exposure to asbestos.[1]

Its most common site is the pleura (outer lining of the lungs and internal chest wall), but it may also occur in the peritoneum (the lining of the abdominal cavity), the heart,[2] the pericardium (a sac that surrounds the heart) or tunica vaginalis.

Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or they have been exposed to asbestos dust and fiber in other ways. It has also been suggested that washing the clothes of a family member who worked with asbestos can put a person at risk for developing mesothelioma.[3] Unlike lung cancer, there is no association between mesothelioma and smoking, but smoking greatly increases the risk of other asbestos-induced cancers.[4] Compensation via asbestos funds or lawsuits is an important issue in mesothelioma (see asbestos and the law).

The symptoms of mesothelioma include shortness of breath due to pleural effusion (fluid between the lung and the chest wall) or chest wall pain, and general symptoms such as weight loss. The diagnosis may be suspected with chest X-ray and CT scan, and is confirmed with a biopsy (tissue sample) and microscopic examination. A thoracoscopy (inserting a tube with a camera into the chest) can be used to take biopsies. It allows the introduction of substances such as talc to obliterate the pleural space (called pleurodesis), which prevents more fluid from accumulating and pressing on the lung. Despite treatment with chemotherapy, radiation therapy or sometimes surgery, the disease carries a poor prognosis. Research about screening tests for the early detection of mesothelioma is ongoing.