CHAPTER TWENTY FIVE: MESOTHELIOMA

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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 first starts. This type of cancer 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 Mesothelioma is Different 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 vary from non-small cell and 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. From a scientific perspective, 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 at page 757 of the Comprehensive Textbook of Thoracic Oncology:

 

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 The Role of Latency

When initially questioned, some patients may indicate that they do not recall recent exposure to asbestos. However, mesothelioma appears to have a long latency period, or period to develop, and heavy asbestos exposure has been traced 20 and 30 years before the patient developed the disease. It appears a heavy exposure, but possibly of short duration, may create the conditions for the disease, and that it is a cancer which develops and spreads slowly.

25.18 Differences and Similarities to Non-Small Cell Lung Cancer

DIFFERENCES BETWEEN MESOTHELIOMA AND NON-SMALL CELL LUNG CANCER

CONDITION OR FEATURE

MESOTHELIOMA

NON-SMALL CELL LUNG CANCER

Initial 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

Epidermal Growth Factor Inhibitors and Iressa

Clinical trials beginning

Shown to be effective in stabilizing disease. Combination with chemotherapy being investigated

Chemotherapy

Frequently applied to the area itself.

Given by injection to disseminate throughout the body.

Smoking

Small, if any role

Primary cause

Asbestos

Primary Cause

Limited role

Surgery

Complex procedure on the pleura, performed only a few specialized facilities.

Removal of the nodule. a common procedure.

SIMILARITIES BETWEEN MESOTHELIOMA AND NON-SMALL CELL LUNG CANCER

CONDITION OR FEATURE

MESOTHELIOMA

NON-SMALL CELL LUNG CANCER

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 thorocoscope, is usually done in the 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. The peritoneoscope is put into an opening made in the abdomen to ascertain the existence of peritoneal mesothelioma. This test is also usually done in the hospital with a local anesthetic. Biopsies are usually done during the thorcoscope 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:

! 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 malignant 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.

22.22 Types of Mesothelioma

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

25.23 Distinguishing Mesothelioma from Adenocarcinoma

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 mesothelioma is hotly disputed. Medically, adenocarcinoma would be placed in the non-small cell category while mesothelioma is individually evaluated.

"Well_differentiated tumors have a tubulopappilary growth pattern that may be indistinguishable from an adenocarcino

ma. A Canadian panel disagreed on the diagnosis of mesothelioma in 30% of the cases. Some suggest that immunohistochemistry can help distinguish the two diseases and provide better information for treatment and prognosis Here are some figures based on chapter nine, (Antman 1).

25.23 Pathological Differences Between Adenocarcinoma and Mesothelioma

Antman in her book on asbestos diseases including mesothelioma comments:

"the microvilli are the most dramatic aspect of a mesotheliomas ultrastructure. The microvilli not only appear very long, but they are extensively branched with secondary and tertiary branching points. Using the length to diameter ratio (LDR) one is able to compare mesotheliomas with adenocarcinomas with respect to the character of their microvilli ... [and] mesotheliomas have significantly longer [ones] than adenocarcinomas." Antman 1 at 209.

22.24 Treatment Overview

The following is excerpted from the National Cancer Institute webpage on mesothelioma. (2)

"LOCALIZED MALIGNANT MESOTHELIOMA (STAGE I)

If the cancer is only in one place in the chest or abdomen, your treatment will probably be surgery to remove part of the pleura and some of the tissue around it. If the cancer is found in a larger part of the pleura, your treatment may be one of the following:

1. Surgery to remove the pleura and the tissue near it to relieve symptoms, with or without radiation therapy after surgery.

2. Surgery to remove sections of the pleura, the lung, part of the diaphragm, and part of the lining around the heart.

3. External beam radiation therapy to relieve symptoms.

4. A clinical trial of surgery followed by chemotherapy given inside your chest.

5. A clinical trial of surgery, radiation therapy, and/or chemotherapy.

ADVANCED MALIGNANT MESOTHELIOMA (STAGES II, III, AND IV)

Your treatment may be one of the following:

1. Draining of fluid in the chest or abdomen (thoracentesis or paracentesis) to reduce discomfort. Drugs also may be put into the chest or abdomen to prevent further collection of fluid.

2. Surgery to relieve symptoms.

3. Radiation therapy to relieve symptoms.

4. Chemotherapy.

5. A clinical trial of surgery, radiation therapy, and chemotherapy.

6. Chemotherapy given in the chest or abdomen.

25.3 GROWTH FACTORS AND MESOTHELIOMA

25.31 Transforming Growth Factor

"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 developement of PDGF is also a possibility.

25.32 Vascular Endothelial Growth Factor and Mesothelioma

Vascular Endothelial Growth Factor (VEGF) is associated with the spread of tumors or angiogenesis.

25.6 GENE THERAPY FOR MESOTHELIOMA

25.61 Epidermal Growth Factor Receptors and Mesothelioma

Given the limited success of surgery and chemotherapy, scientists are evaluating other forms of treatment for mesothelioma. The epidermal growth factor (EGF) is associated with the creation and spread of lung cancer as well as other types of cancer. Drugs which inhibit this growth factor are beginning to play an important role in treatment of patients with advanced non-small cell cancer, and may play an equal role in treating mesothelioma. Our chapter on EGF and Iressa discusses these drugs and recent studies, and here we look at such drugs specifically in relation to treatment for mesothelioma.

"Govindan and colleagues have investigated EGFR receptor expression in mesothelioma tissue, using ZymedTM antibodies. They found that nearly 60% of samples overexpressed EGFR, while none overexpressed HER-2, suggesting that it is worth considering anti-EGFR therapy in patients with mesothelioma.") www.EGFR-info.com (13) A recent presentation found that asbestos prompted production of the

epidermal growth factor and this could be duplicated in the laboratory:

"Over-expression of the epidermal growth factor receptor (EGFR) is a common finding in many solid tumors, including lung, breast and mesothelioma, and has been shown to correlate with both a poor prognosis and resistance to radiation and chemotherapy.... Recent evidence suggests that up-regulation and activation of EGFR may play a critical role in early carcinogenic events.... carcinogenic asbestos fibers upregulate the expression of the EGFR. Exposure of MET 5A cells to asbestos leads to the activation of nuclear factor-kB (NF-kB), a transcription factor important in the regulation of a number of genes intrinsic to inflammation, proliferation and lung defences. This study set out to examine the relationship between EGFR and NF-kB in MET 5A cells exposed to asbestos fibers... The selective EGFR tyrosine kinase inhibitor, PKI166 (Novartis), inhibited the DNA binding of NF-kB mediated by crocidolite asbestos fibers.... Modulation of the asbestos-mediated EGFR/NF-kB signalling pathway may be important in the development of novel therapeutic strategies for both the chemoprevention and treatment of malignant mesothelioma." Faux (4)

There are ongoing clinical trials testing EGF inhibitors like Iressa with mesothelioma

22.62 SV 40 and Iressa.

The incidence of malignant mesothelioma (MM) shows a strong epidemiological association with exposure to asbestos fibers. Recently, simian virus 40 (SV40) DNA sequences have been reported in MM tumor specimens from the United States and several European countries, and the SV40 tumor virus has been implicated as a potential co-factor in the etiology of this disease. However, several large studies from the US, Finland, and Turkey did not detect SV40 sequences in MM samples. To address this discrepancy, MM specimens from Turkey and the US were analyzed in the same laboratory under identical conditions to detect the presence of SV40 DNA. We detected SV40 sequences in 4 of 11 specimens from the United States, but in none of the 9 Turkish samples examined. These findings suggest that geographical differences exist with regard to the involvement of SV40 in human tumors.

25.63 Interferon Treatments

Interferon has had some significant beneficial effect in treating mesothelioma though significant side effects have been associated generally with Interferon. Interferons are proteins secreted by immune cells that "interfere" with a virus’s ability to reproduce and proliferate. In the laboratory, low concentrations of interferon help boost the power of natural killer T cells. With some tumors, interferons can help inhibit the development of the blood vessels that tumors need to metastasize and grow, a process called angiogenesis. There are three main types and 17 subtypes of interferon. In a French phase II study, over 50% of the participants showed some tumor reduction from Interferon. Astroul (7) . A Turkish study found moderately favorable results, a response rate of 24% combining Interferon with Cisplatin. Metintas (14)

25.64 Why Interferon Works

A recent study explains how Interleukin works on laboratory animals.

"Malignant mesothelioma appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12." Not all studies have been favorable. A study at New York’s renowned Sloan Kettering Cancer Center reported, "The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. We discuss various treatments in more detail in later chapters.

25.7 RELATIONSHIP TO ASBESTOS EXPOSURE

25.71 Mesothelioma Generally Comes from Exposure to Asbestos.

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. Asbestos manufacturers failed to utilize basic precautions to make their product safety such as encapsulating the asbestos so it would not become airborne, recommending uses that not expose workers to dust, suggesting bi_annual pulmonary examinations, and utilizing substitute products which did not cause cancer. Workers especially those in the United States have received substantial compensation for asbestos_related mesothelioma. The largest producer/manufacturer of asbestos, Johns Manville developed a claims facility which has provided over one billion dollars in compensation to victims of mesothelioma and other asbestos diseases. Individuals with mesothelioma are welcome to contact the author about compensation to which they may be entitled.

25.72 Asbestos Legal Claims

The asbestos products that most companies manufactured or distributed failed to carry appropriate warnings. Documents have been uncovered showing that corporations knew of the dangers of asbestos but failed to disclose or concealed them. The Sumner-Simpson correspondence was a series of letters in the 1930's and 40's where Johns Manville and Raybestos-Manhattan corporate executives discussed and concealed the dangers of asbestos. Because the products were dangerous, not properly labeled and caused serious injuries, many victims of asbestos diseases, particularly mesothelioma have obtained substantial compensation.

25.73 Jobs Where Asbestos Was Used

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

! Insulators and pipefitters

! Brake mechanics,

! Janitors and roofers,

! And many others since asbestos was universally used for insulation, heat prevention and other purposes).

25.74 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, any anyone interested in filing a claim should consult an attorney.

25.75 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.

25.76 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.

25.77 Bankruptcies of Asbestos Manufacturers

A number of manufacturers have declared bankruptcy but established 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.

25.78 Worker-Compensation Claims

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

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