MESOTHELIOMA OVERVIEW

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25.1 OVERVIEW

25.11 How Mesothelioma was Named

Most cancers are named after the part of the body where the cancer originates. Mesothelioma begins in the tissue that surrounds different organs inside the body. This tissue, called mesothelium, protects organs by making a special fluid that allows the organs to move. Mesothelium surrounds the lungs, stomach, and heart, and tumors can begin in any of these areas. Three quarters of mesothelial tumors begin in the pleura of the lungs, with the remainder in the peritoneum (stomach), and a small number in the heart.

25.12 Differences from Other Lung Cancers

For many patients with other forms of lung cancer, this chapter may be better ignored since many statements about mesothelioma will not apply to other forms of lung cancer. The presentation of mesothelioma as well as its treatment varies from non-small cell or small lung cancer.

25.13 Why a Rare Cancer Has Been So Intensively Studied

Mesothelioma is a rare cancer which has attracted much attention. First, it is perhaps the only cancer with a clear environmental component. Mesothelioma is directly related to exposure to asbestos with about 80% of mesotheliomas tied to asbestos exposure. The disease is studied to understand how a cancer develops in relation to a specific causative agent.

25.14 Why Surgery is Difficult

The ideal treatment for lung cancer is surgical resection of the tumor which can eliminate the prospect of metastasis (transfer of the cancerous cells to other organs) and removes the tumor from the lung. Five year survival rates of between 50% and 80% have been reported in early stage one patients with other forms of lung cancer. Surgery has been difficult to perform with mesothelioma because it is really a group of tumors.

25.15 Diffuse Malignant Mesothelioma

Unlike other cancers where a single tumor develops in the large or small breathing pathways, with mesothelioma, a group of tumors develops in the pleura. A more accurate term for mesothelioma is diffuse malignant mesothelioma. The disease is described in a textbook (17) at page 757 of the Comprehensive Textbook of Thoracic Oncology:

“Mesothelioma of the pleura is characterized by local growth and invasion of contiguous structures and by relatively late spread to distant organs. Recent studies provide evidence that pleural mesothelioma begins in the parietal layer and subsequently spreads to involve the visceral pleura. Pleural effusion (fluid in the pleura of the lung) usually is present.... Proliferation of mesothelioma cells and accompanying stromal elements form firm, gray nodules that subsequently coalesce [and] the pleura gradually thickens."

The nature of the disease unfortunately makes it difficult to treat. When tumors can be surgically removed, the patient enjoys a good prognosis. With mesothelioma, since there is usually a group of tumors spread throughout the pleura, surgery can be difficult to perform, though there is literature discussing it as an option.

25.16 Smoking Not A Cause

While most lung cancer is associated with smoking, that appears to play little or no role in mesothelioma. Studies do not indicate a clear increased risk with smoking and the tumors do not develop in the breathing areas of the lung.

25.17 Long Latency

When questioned, some patients may not recall recent exposure to asbestos. However, mesothelioma has a long latency period, (period to develop) and heavy asbestos exposure has been traced 20 and 30 years before the patient developed the disease. A heavy exposure, sometimes y of short duration, may create the conditions for the disease. It is a cancer which develops and spreads slowly. Here is a summary of the differences and similarities with non-small cell cancer and mesothelioma.



CONDITION OR NON-SMALL CELL
FEATURE MESOTHELIOMA LUNG CANCER
Typical Presentation A group of nodules in the pleura part of the lung Single nodule
Primary Danger Loss of breathing capacity and serious problems in the lungs themselves Metastasis to lymph nodes, and other organs
Role of Asbestos Primary Cause Limited role, may combine with smoking to play causative role
Chemotherapy By injection or sometimes applied to the area itself. Given by injection to disseminate throughout the body.
Smoking Apparently little if any role. Primary cause
Epidermal Growth Factor Inhibitors and Iressa
Clinical trials continuing with some studies discussing a role. Helpful in non-smokers, efficacy in others unclear.
P-53 Tumor Suppressor Gene Debatable impact, and P-53 genetic damages is not seen in many studies. Regulation of apoptosis is a problem. Significant role in cell repair and apoptosis. P-53 abnormalities significant in non-small lung cancer as well as other cancers.

Surgery

Complex procedure on the pleura, performed at only a few specialized facilities, with used other treatment modalities. Removal of the nodule. a common procedure.
Post-surgical chemotherapy or radiation for stage 1 patients remains experimental.


SIMILARITIES

Chemotherapy Platinum-based chemotherapy such as Cisplatin or Carboplatin is the main form. Extends life but does not provide an overall cure. Same
Radiation Effective at local control of tumor and relieving symptoms. Long-term survival benefit is uncertain Same
Surgery Used only for early stage disease Same


25.2 DIAGNOSTIC TOOLS AND STAGING

A physician will look inside the chest cavity with an instrument called a thorocoscope. This test, called thororcopy, is usually performed at a hospital. Before the test, a local anesthetic is given. The physician may also look inside the abdomen (peritoneoscopy) with a special tool called a peritoneoscope. Biopsies (taking and analysis of tissue) are usually done during the thorocoscope or peritoneoscopy.

25.21 Staging

Mesothelioma uses a different staging system called the Butchert system using stages one through four to designate the extent of spread of mesothelioma:

Localized Mesothelioma
Stage I: The cancer is found in the lining of the chest cavity near the lung and heart or in the diaphragm or the lung.

Advanced mesothelioma
Stage II: The cancer has spread beyond the lining of the chest to lymph nodes in the chest.
Stage III: Cancer has spread into the chest wall, center of the chest, heart, through the diaphragm, or abdominal lining, and in some cases into nearby lymph nodes.
Stage IV: Cancer has spread to distant organs or tissues.

25.23 Types of Mesothelioma and Distinguishing Mesothelioma from Adenocarcinoma

There are three tissue types of mesothelioma. 50-70% of mesothelioma are of the epithelioid type. Less common are mixed byphasic and sarcomatoid.

In some cases, mesothelioma is not easily distinguished from adenocarcinoma, a type of non-small cell lung cancer discussed in chapter 2. This has both medical and legal implications; substantial sums can be awarded for mesothelioma while the association between adenocarcinoma and asbestos is disputed. Medically, adenocarcinoma would be placed in the non-small cell category while mesothelioma is treated as a separate disease. Some mesothelioma tumors have a tubulopappilary growth pattern that presents like adenocarcinoma, and a Canadian panel disagreed on the diagnosis of mesothelioma in 30% of the cases. Immunohistochemistry and other tests can help distinguish the two diseases and provide better information for treatment or compensation. .

25.24 Treatment Overview

If the mesothelioma is confined to a limited area, surgery may be tried. Unlike non-small cell lung cancer, a single tumor cannot be removed, and the surgery for mesothelioma is more complex. A three part program of surgery, radiation, and chemotherapy has been studied. For advanced mesothelioma, various forms of chemotherapy are used, though with limited success. Interestingly, with mesothelioma, chemotherapy may be applied directly into the tumor area, as opposed to injection into the bloodstream as with most forms of cancer.

25.3 CONTRIBUTING GROWTH FACTORS AND GENES

25.31 Apoptosis and Mesothelioma

Apoptosis, or cell death, is the body’s way of getting rid of diseased or damaged cells. “Apoptosis is the carefully regulated process of programmed cell death that is critical for maintaining normal cell and tissue homeostasis. Dysregulation of cell death pathways often results in tumor initiation, progression, and drug resistance in many human cancers.” Xia (15).
In many forms of cancer, the process goes awry, with genetically damaged cells permitted to multiply. Some suggest failure of the apoptotic system o plays a critical role in mesothelioma. One study “found that three mesothelioma cell lines (1 with wild-type p53) were highly resistant to apoptosis induced by oxidant stimuli (asbestos, H2O2) or nonoxidant stimuli (calcium ionophore) compared with primary cultured mesothelial cells.”

25.32 Survivin

The body is a complex system. Just as there are apoptosis proteins to signal cell death, there are anti-apoptosis proteins which impact the normal process of cell death. Such proteins can be elevated in various forms of cancer. Survivin is an apoptosis inhibitor that has been detected in many cancers. “Survivin a member of the IAP gene family, is ... up-regulated in cancer cells and completely down-regulated and undetectable in normal adult tissues.” Xia (15).
A recent study indicates its particular importance in mesothelioma, “Survivin was overexpressed in 7 of 8 (87.5%) mesothelioma cell lines assayed and in all (12 of 12; 100%) freshly resected mesothelioma tissues analyzed.” Xia (15). Survivin is a reasonable target for gene therapy. “Survivin, an inhibitor of apoptosis protein, deserves attention as a selective target for cancer therapy because it lacks expression in differentiated adult tissues but is expressed in a variety of human tumors.” Olie (16).

25.33 Platelet Derived Growth Factor

PDGF has also been associated with response to asbestos and developement of mesothelioma:

“One early response to asbestos observed in rat inhalation models is the rapid induction both platelet-derived growth factor (PDGF) A and B chains in the bronchiolar-alveolar epithelium and underlying mesenchymal cells, which is sustained for at least 2 wk after exposure. Interestingly, the (PDGFR) receptor but not (PDGFR) is also elevated in asbestos-exposed rat lung suggesting a possible role for autocrine stimulation in the early stages of asbestos-associated lung damage.” Metheny (6).

“Overexpression of PDGF-A is sufficient to cause tumorigenic conversion of T antigen- immortalized human mesothelial cells.” That is, where the cells have already been altered, the addition of Platelet-derived growth factor can transform them in mesothelioma cancer cells. Thus, one reasonable hypothesis is that PDGF plays a role in many mesotheliomas as a partial cause. Identifying persons with elevated levels of PDGF through tissue sample could help early diagnosis. Developing a drug which inhibited the development of PDGF is also a possibility.

25.34 Vascular Endothelial Growth Factor and Mesothelioma

Vascular Endothelial Growth Factor (VEGF) is associated with the spread of tumors or angiogenesis. Scientists are investigating its role in mesothelioma and whether the new anti-VEGF agents being tested on NSCLC would work on mesothelioma.

25.35 Apoptosis and Mesothlioma

The failure of the body’s normal system of programmed cell death or apoptosis appears to play an important role in mesothelioma.

“The unresponsiveness of this tumor to most conventional agents may in part be explained by a resistance to the induction of programmed cell death or apoptosis. Although the discrete mechanism of action varies, many conventional treatments depend on an ability to engender apoptosis as a final common pathway. Histone (20).

As with other cancers, the targets are two-fold, restore apoptosis and the work done by tumor-suppresor genes, and attack the growth factors which stimulate reproduction of cells. Histone found BCL-XL protein played a vital role and could be limited in a laboratory setting. “ We also show that a reduction in BCL-XL protein expression is associated with cell death and apoptosis induced by NaB.” Histone (20).

25.4 RELATIONSHIP TO ASBESTOS EXPOSURE

25.41 Asbestos is the Primary Cause of Mesothelioma

There is extensive and overwhelming evidence that mesothelioma primarily comes from exposure to asbestos. (Note, the author of this book is an attorney who represents mesothelioma plaintiffs in claims against asbestos companies.) Although the risks of asbestos exposure were known throughout the last 40 years, many forms of asbestos came with little or no warnings.
The notorious Sumner-Simpson documents explained how two major asbestos manufacturers concealed the dangers of asbestos.
Asbestos manufacturers failed to utilize basic precautions to make their product safe, such as encapsulating the asbestos so it would not become airborne, recommending precautions to minimize dust exposure which was extensive in earlier years, recommending pulmonary examinations, and utilizing safer substitutes. Today in the United States, asbestos is essentially banned, though it continues to be used in some other countries.

25.42 Compensation for Mesothelioma Patients

Because the products were dangerous, not properly labeled and caused serious injuries, many victims of asbestos diseases, particularly mesothelioma have obtained substantial compensation. The largest producer/manufacturer of asbestos, Johns Manville developed a claims facility which has provided over billions of dollars in compensation to the victims of their asbestos products. While direct claims against manufacturers were filed in the 1980's and 90's, today’s claims include distributors and others involved in the process. In addition to compensatory damages, some courts have awarded punitive damages, because of the disregard of known risks by the manufacturers.

25.43 Worker-Compensation Claims

In addition to claims against manufacturers, victims of mesothelioma may have claims for medical bills, temporary and permanent disability against their employers. In such cases, the worker would not only need to show his workplace exposure causes his illness, he would not need to identify the specific products used.

25.44 Jobs Where Asbestos Was Used

Unfortunately even brief exposure to asbestos may cause mesothelioma. These jobs have customarily involved the use of asbestos:

1. Insulators and pipefitters,
2. Brake mechanics, and
3. Janitors and roofers.

This is only a brief list since asbestos was universally used for insulation, heat prevention and other purposes.

25.44 Statute of Limitations Issues

Mesothelioma typically develops from 20-30 years after the date of first exposure. Obviously if the statute of limitations were two years from the date of exposure, virtually every claim would be time-barred. Instead most states use a discovery rule, finding that the statute of limitations begins two years or some other period after the date the patient knew or had reason to know of a claim. In some cases, the court will conclude that period when the patient is first diagnosed with the disease. Most patients with mesothelioma will be entitled to some form of compensation, frequently a significant amount. Anyone interested in filing a claim should consult an attorney.

25.45 Claims for Those Outside the United States

The Johns Manville Claims Facility allows claimants from other countries to submit claims for asbestos-related mesothelioma. If an American company made an asbestos product which caused a disease overseas, frequently a claim can be presented in the United States.

25.46 Causation

The plaintiff would have the burden of identifying the products which caused his exposure. Frequently this is done circumstantially, by showing that co-workers were exposed to a particular product, or by demonstrating that a product was shipped to a particular site.

25.47 Bankruptcies of Asbestos Manufacturers

A number of manufacturers have declared bankruptcy but established a claims facility to provide compensation to mesothelioma victims and their families. Indeed, because of the dangers their products presented, there are probably more asbestos companies in bankruptcy than not. Many have argued that limited funds that should have been devoted to mesothelioma have instead been used to compensate those with less serious disease.
25.48 Asbestos Legislation

Legislation has been introduced to limit claims. In some ways, that would benefit mesothelioma patients by assuring that limited funds would be devoted to those whose illness was clearly causes by asbestos. While manufacturers have been assertive in limiting liability, less attention has been paid to funding research to develop cures. Since mesothelioma is a relatively rare disease, drugs companies have not devoted significant attention to it.


REFERENCES

1. Antman, Asbestos-Related Malignancy(Grune & Stratton 1989).
2. National Cancer Institute website, Malignant Mesothelioma.
3. Sugarbaker, et. al., (3) Resection Margins, extra pleural nodal status, and cell type determine postoperative long term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 cases. J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.
4. Faux, EGFR Induced Activation of NF-kB in Mesothelial Cells by Asbestos Is Important in Cell Survival,”Proceedings of the American Association for Cancer Res earch, AACR, Vol. 42, March 2001.
5. Caminschi, Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12. Am J Respir Cell Mol Biol, 1999 Sep, 21:3, 347-56.
6. OReilly, A phase II trial of Interferon Alpha-2a and Carboplatin in patients with Advanced Malignant Mesothelioma. Cancer Invest, 1999, 17:3, 195-200.
7. Astoul, Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a Phase II study Cancer 1098 Nov, 83:10, 2099-104.
8. Amodio, Gemcitabine in peritoneal mesothelioma: a case report] Clin Ter, 1998 Nov, 149:6, 447-51.
9. Nakano, Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile. Cancer, 1999, Jun, 85:11, 2375-84.
10. Porohit, Weekly systemic Combination of Cisplatin and Interferon Alpha 2a in Diffuse Malignant Pleural Mesothelioma, Lung Cancer, 1998, Nov. 22.:2, 119-25.
11. Ryan & Vogelzang, A Review of Chemotherapy trials for Malignant Mesothelioma, Chest, 1998, Jan. 113:1, Supp. 66s-73s.”
12. Ardizzoni, Systemic Drug Therapy of Malignant Pleural Mesothelioma, Monaldi Arch Chest Dis, 1998 Apr, 53:2, 236-40.
13. Astra-Zeneca, www.egfr-info.com, publishers of Signal, a medical journal devoted to epidermal growth factor research.
14. Metitinas, , Cisplatin, Mitomycin, and Interferon-alpha2a combination chemoimmunotherapy in the treatment of diffuse malignant pleural mesothelioma. Chest, 1999 Aug, 116:2, 391-8.
15. Xia, Induction of Apoptosis in Mesothelioma Cells by Antisurvivin Oligonucleotides, Vol. 1, 687-694, July 2002 Molecular Cancer Therapeutics.
16. Olie, A Novel Antisense Oligonucleotide Targeting Survivin Expression Induces Apoptosis and Sensitizes Lung Cancer Cells to Chemotherapy, Cancer Research 60, 2805-2809, June 1, 2000.
17. Apoptosis, A Target for Cancer Therapy, Cancer Research Vol. 8, 2024-2034, July 2002.
The author explains the term’s history and the mechanism of apoptosis.
“In 1972, Kerr described a distinct morphology of dying cells and called it apoptosis. The term was coined based on the fact that the release of apoptotic bodies by dying cells resembled the picture of falling leaves from deciduous trees, called in Greek "apoptosis.” This type of cell death has also been called programmed or physiological cell death, and is characterized by a genetic controlled autodigestion of the cell through the activation of endogenous proteases. This process results in cytoskeletal disruption, cell shrinkage, membrane blebbing, nuclear condensation, and internucleosomal DNA fragmentation.”
18. Narasimhan, Resistance of pleural mesothelioma cell lines to apoptosis: relation to expression of Bcl-2 and Bax, Am J Physiol Lung Cell Mol Physiol 275: L165-L171, 1998.
19. Zanella, Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis, Am J Physiol Lung Cell Mol Physiol 277: L684-L693, 1999.
20. Histone, Deacetylase Inhibitor Downregulation of bcl-xl Gene Expression Leads to Apoptotic Cell Death in Mesothelioma, Am. J.Respir. Cell Mol. Biol., Volume 25, Number 5, November 2001 562-568.

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