Patterns of failure following surgical resection for malignant pleural mesothelioma.

The optimum therapeutic strategy for patients with localized malignant mesothelioma continues to evolve. For patients who are eligible candidates, surgical resection plays an important role. An encouraging 45% 5-year survival rate has been reported for patients with early-stage disease who undergo EPP and have the favorable features of epithelial histology and the absence of mediastinal lymph node involvement.

Most patients present with more advanced disease, however, and the optimum local and systemic treatment for these patients has not been defined. No randomized trials evaluating the various surgical or adjuvant therapeutic approaches have been performed. Evaluation of treatment efficacy based on observed patterns of failure may suffer from treatment selection biases. Most studies also do not separate out the failure patterns based on the initial stage (clinical or pathologic) of the disease.

Consequently, it is difficult to discern the potential impact of a given adjuvant therapy. Given these limitations, however, some consistent observations from the available data can be made. For patients who undergo P/D, local recurrence (within the surgically operated hemithorax) is the most common form of recurrence. Efforts to decrease the chance of local recurrence after P/D have included the use of intrapleural and intravenous chemotherapy, brachytherapy, and external beam radiation therapy. None of these adjuvant treatment trials was randomized, and when compared with historical controls, none of the treatments used suggested a consistent outcome benefit. After P/D, the use of radiation is limited by the potential toxicity of the underlying organs, most importantly, the intact lung. Doses required to treat mesothelioma effectively are above the doses that would lead to damage to the lung parenchyma. Cisplatin and mitomycin have been used as agents have modest activity against mesothelioma. The doses of cisplatin used may not have been optimal, although they were based on prior pharmacokinetic studies.

Alternative approaches for patients who undergo P/D, such as the use of escalating doses of heated intrapleural cisplatin (given with a renal protecting agent, sodium thiosulfate, which provides the opportunity to deliver higher doses of chemotherapy), are being pursued by Sugarbaker et al. The availability of more active systemic chemotherapy agents or other intrapleural agents also may offer better therapeutic options for patients who undergo P/D.

Recently, Vogelzang et al presented the findings of a large randomized study that compared cisplatin/premetrexed to cisplatin and demonstrated an improvement in response rate (41% for cisplatin/pemetrexed versus 19% for cisplatin) and median survival (12.1 versus 9.3 months, respectively; P = 0.020). Other chemotherapy regimens with encouraging activity in mesothelioma include the combination of cisplatin and gemcitabine, with response rates ranging from 16% to 48%.

From a review of available data, patients with mesothelioma who have undergone P/D (with or without intrapleural chemotherapy) who are evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital are offered therapy with systemic chemotherapy alone. After P/D, radiation is used only for palliative treatment. Patients who have undergone P/D are also appropriate candidates to receive chemotherapy or other novel therapeutic strategies being evaluated in clinical trials.

For patients who have undergone EPP, the pattern of recurrence is predominantly a combination of local and distant failure (Table 1). The local recurrence rates, however, seem to be lower than rates seen after P/D. This observation may represent a shift of the natural history of the disease. Metastatic mesothelioma is often seen late in the course of the disease, but it may become the dominant source of disease after aggressive local surgical management.

Many studies define abdominal recurrence as a site of distant recurrence, although this may represent transdiaphragmatic extension of the pleural mesothelioma. Advances in local therapy also may decrease the rate of abdominal recurrences. True distant recurrences (bone, central nervous system, contralateral hemithorax) remain less common. The lowest rate of local recurrence (13%), with a 4% local-only recurrence rate, was seen in the study by Rusch et al, who used 54 Gy hemithorax radiation as adjuvant therapy. This is the lowest rate of local recurrence after an EPP that has been reported. Baldini et al reported a 50% local recurrence rate, with a 13% local-only rate, after trimodality therapy.

One possibility for the differences between these two reports is the lower dose of radiation (30.6 Gy) used in the latter study. In the study by Rusch et al, distant failures predominate, and the patients are appropriate candidates for systemic chemotherapy, which could be administered either as neoadjuvant or adjuvant therapy. Kestenholz et al currently are performing a phase II clinical trial of neoadjuvant cisplatin and gemcitabine administered for three cycles followed by EPP and adjuvant radiation therapy.

A similar approach also is being pursued in an ongoing clinical trial using neoadjuvant cisplatin/pemetrexed for four cycles before EPP followed by 54 Gy of adjuvant hemithorax radiation. Alternatively, patients who have undergone EPP could be treated with adjuvant chemotherapy in addition to adjuvant radiation therapy.

Currently, patients evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital who have undergone EPP are offered adjuvant chemotherapy followed by hemithorax radiation to 54 Gy in an effort to maximize local and distant control rates. Further clinical studies are needed for all patients with mesothelioma to define the optimum surgery and duration and types of adjuvant therapy. The appropriate multimodality approaches most likely will differ based on disease stage, histology, and patient performance status. intrapleural chemotheraphy treatments.

Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA. sterman@mail.med.upenn.edu

Advances in the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a neoplasm that is commonly fatal and for which there are no widely accepted curative approaches. Mesothelioma is unresponsive to most chemotherapy and radiotherapy regimens, and it typically recurs even after the most aggressive attempts at surgical resection. Multimodality approaches have been of some benefit in prolonging survival of very highly selected subgroups of patients, but they have had a relatively small impact on the majority of the patients diagnosed with this disease. As the incidence of pleural mesothelioma peaks in the United States and Europe over the next 10 to 20 years, new therapeutic measures will be necessary. This review will discuss the roles of chemotherapy, radiotherapy, surgery, and combined modality approaches in the treatment of pleural mesothelioma, as well as scientific advances made in the past decade that have led to the development of experimental techniques, such as photodynamic therapy, immunotherapy, and gene therapy, that are currently undergoing human clinical trials. These promising new avenues may modify the therapeutic nihilism that is rampant among clinicians dealing with mesothelioma.

Treatment of malignant pleural mesothelioma

In Japan, it is predicted that mesothelioma will rapidly increase in the future. Malignant pleural mesothelioma that accounts for approximately 90% of mesothelioma as a whole has a median survival time of approximately nine months which is considered a poor prognosis. As for the treatment of this disease,extrapleural pneumonectomy or pleurectomy/decortication are available for those patients who can be surgically operated on. However, since a complete cure rate is low when only surgical treatment is performed, generally a multimodality treatment is performed wherein chemotherapy and/or radiotherapy are combined. For chemotherapy, a large-scale randomized phase III study demonstrated that a treatment using two agents: pemetrexed, which is a new multitargeted antifolate, and cisplatin is effective. Pemetrexed will be the drug of first choice for mesothelioma in the future. As other treatment methods, chemohyperthermia, treatments using various kinds of cytokines and angiogenesis inhibitors, genetic treatment and photodynamic therapy have been attempted. The current treatment results for this disease are very poor, and there has been a strong demand for establishing an effective treatment method.

Peritoneal mesothelioma: treatment approach based on natural history.

A more modern treatment strategy for diffuse malignant peritoneal mesothelioma may be suggested (figure 3). Clinical suspicion of diffuse malignant mesothelioma (peritoneal carcinomatosis) calls for laparoscopy with evaluation of parietal and visceral peritoneum and multiple biopsies sufficient for definitive histologic diagnosis. Cytologic examination of ascitic fluid is not likely to be of benefit. CT of chest, abdomen, and pelvis is needed for evaluation of visceral involvement and the presence of distant metastases. Contrast enhancement of the gastrointestinal and urinary tract is necessary with the CT. Additional radiologic techniques for detection of distant metastases should be used if there are clinical or laboratory signs of extraperitoneal spread. After histologic diagnosis and extent of tumor spread have been documented, and if no symptoms of intestinal obstruction are present, the patient may be subjected to two to three courses of induction intraperitoneal chemotherapy. This will provide the clinician with important information on tumor response to chemotherapy, minimize tumor accumulation on bowel surfaces, and provide time for surgical conditioning. The time devoted to induction chemotherapy will allow occult distant metastases to be detected. In patients with a response or stable disease, cytoreductive surgery is attempted approximately 2 months after completion of induction chemotherapy. Surgery must be aimed at achieving complete or near-complete cytoreduction through the use of peritonectomy procedures [46,47]. Additional intraperitoneal chemotherapy should be administered intraoperatively and in the early postoperative period (figure 3). This treatment strategy may be the most feasible one according to existing knowledge of the natural history of diffuse malignant peritoneal mesothelioma. Only further phase II clinical trials can reveal the extent to which it is beneficial. Because of the rare occurrence of this disease, the quickest answer would come as a result of cooperative study by several groups experienced in these treatment modalities.

At Risk Jobs and Locations

It is inhalation of asbestos fibers which can cause mesothelioma or asbestos lung cancer. Even low exposure levels of the tiny fibers or asbestos dust are very dangerous. After the 1980's workplace exposure to asbestos became more rare, but it can take up to 40 years for signs of mesothelioma asbestos lung cancer are noticed.

Most patients were exposed to asbestos fibers on the job or in the workplace in what is known as occupational exposure. Another form of exposure is called paraoccupational exposure. This form of asbestos exposure can be harder to determine the source, but it is usually contracted by a family member of someone who has been exposed in the workplace.

Typically the family member is exposed to asbestos dust or fibers from the worker's clothing, and when the clothing is handled the dust is released and inhaled. Family members that are exposed in this way, may be exposed to smaller amounts, but are still very much at risk.

In the same way, those that have homes or work work near facilities that have asbestos may also be at risk even though there is not obvious direct contact. The fine asbestos dust can easily be carried by the wind over long distances.

In the past, some of the industries that could have been a source of asbestos were factories, shipyards, power plants, oil refineries, steel manufacturing plants, and any company or job site involved with construction or the removal of old building materials. Often the demolition of buildings that contain asbestos can release the dust into the environment, and trucks hauling the materials can further spread the fine asbestos fibers.

Likewise, people who live near these types of sites likely to have asbestos around the facility are also at risk: refineries, power plants, factories, shipyards, steel mills and building demolition are types of work sites that can release asbestos fibers into the environment and contaminate nearby residential neighborhoods.

Trades:

* Manufacturing of asbestos products (insulation, roofing, building, materials)
* Vehicle repair (brakes & clutches)
* Construction workers and contractors
* Maritime workers
* Miners and drillmen
* Offshore rust removals
* Oil refinery workers
* Power plants
* Railway workers
* Sand or abrasive manufacturers
* Shipyards / ships / ship builders
* Steel mills
* Tile cutters

Occupations:

* Auto Mechanics
* Boiler makers
* Bricklayers
* Building Inspectors
* Carpenters
* Drywallers
* Electricians
* Floor Coverings
* Furnace Workers
* Glazers
* Grinders
* Hod carriers
* Insulators
* Iron workers
* Laborers
* Longshoremen
* Maintenance workers
* Merchant marines
* Millwrights
* Operating Engineers
* Painters
* Plasterers
* Plumbers
* Roofers
* Sand blasters
* Sheet metal workers
* Steam fitters
* Tile setters
* Welders
* United States Navy veterans
* Welders

Many occupations have an increased risk for developing lung cancer. For example, asbestos insulation workers have 92 times the risk of developing of lung cancer, and smelter workers have 3-8 times the risk of developing lung cancer. The risk of lung cancer is also increased in people who work in the manufacturing of certain industrial gases, pharmaceuticals, soaps and detergents, paints, inorganic pigments, plastics, and synthetic rubber. The risk of developing lung cancer is related to the amount of exposure to the cancer-causing agent.

For example, the risk of lung cancer in humans is proportional to the number of cigarettes smoked. The risk of developing lung cancer is 8-20 times greater in smokers compared to people who have never smoked. A smaller, but real risk exists for cigar and pipe smokers. Some lung cancer causing agents react together to significantly worsen the risk of developing cancer. The combined exposure to asbestos and tobacco smoke clearly multiplies the risk of developing lung cancer.

The risk of lung cancer is greater for those living in urban areas. This risk is approximately 1.2 to 2.3 times that of people living in rural areas. There is also an increased risk of lung cancer in smokers whose close relatives have had lung cancer. Scarring in the lungs from previous infections or injury can be associated with and increased risk of cancer.

Alimta for Mesothelioma

There are a number of mesothelioma treatments that can be used to help treat the symptoms of Mesothelioma and to deal with this illness. While there is no cure for mesothelioma, other methods can be used to help lengthen the expected lifespan of the person afflicted with the disease.

Alimta is a drug that has been used to help stop the rapid growth of mesothelioma cancerous cells within your body. This drug was brought about during 2004 and, since then, it has been helping patients that have Mesothelioma improve and stop the spread of this deadly disease. It has successfully helped patients live longer and happier lives just by taking Alimta. This particular medication has undergone careful and rigorous scrutiny successfully, which has allowed it to be approved by the FDA.

Alimta does more than simply work well for Mesothelioma - this drug has also been used to treat other various cancers. It has helped particularly well in lung cancers, among others and has starkly improved the quality of treatment that cancer treatments can receive since 2004. It can also be very helpful to anyone who is already taking other medications for their mesothelioma as Alimta can be combined with other treatment options.

While Alimta is not going to completely make your Mesothelioma go away, it will halt the progress of any cancerous cells within your body. This is why Alimta is a perfect to use as a medication because people that have mesothelioma may not have long to live. Once they have been diagnosed with Mesothelioma, most patients with the cancer are not likely to survive very long once the symptoms start to show. Hence, Alimta has been extremely helpful to people who are suffering from Mesothelioma - Alimta helps by halting the progress of the cancer, allowing the patient to live a longer and more fulfilled life than they normally could have.

Commonly, another drug that often goes well with Alimta is Cispltain, which is another form of cancer fighting medication. Often, Cisplatin is used in combination with Alimta because these two cancer-fighting agents complement themselves well when working to fight off mesothelioma. This is one element where two medications can be used in combination with each other to improve the health of a patient with Mesothelioma.

If you are wondering how the new drug Alimta will help you, then you should know that this cancer fighting medication could work for you in helping to destroy cancerous cells. Alimta actually works on the cancer cells themselves, decreasing their ability to grow at their natural rate. This actually provides you with less cancer cells in your body, which will give you a longer life but without this medical assistance you could be left with the 6-12 months that people who are diagnosed with mesothelioma have. Alimta has been tested and proven to help patients who are suffering with mesothelioma and this medication is currently being tested on other cancers to try to stop the growth of other cancerous diseases.

Your doctor should know several things before treating you with Alimta. It is important that you tell your doctor if you have any previous medical problems. In most cases, they will run you through a rigorous pre-screening process. Your doctor will want to know everything possible about both your full medical history and the medical history of your family before you start treatment for Alimta.
Make sure that you tell the doctor if you are allergic to any medications, even though a doctor should have your full medical chart. There are may be instances when not all allergies that you have are written down and getting this sorted out is important prior to starting the treatment. If the doctor gave a patient a medication that he or she was allergic to, that patient could get sick or even die from this allergic reaction. It is also a good idea that, prior to taking Alimta, the doctor be well informed of a complete and exhaustive list of each of the medications that you take, how frequently, and how much at a time, including both prescribed and over the counter medications. This will help the doctor make sure that Alimta will not have a bad side effect with another one of your medications that you are currently taking.

Alimta is not a simple medication to take. It is far more than just taking a pill with some water. In this particular treatment, specific guidelines must be followed in order to have a successful treatment. Before taking Alimta, it is important to also take two other supplements with this medication, Vitamin B-12 and folic acid. The combination of these two supplements with the medication can create the best possible beneficial situation for the patient. These supplements are taken primarily because there is also a chance of a small skin inflammation after you first start taking the Alimta. Make sure to ask your doctor in which way you could lower the chance of having this outbreak, it is recommended that your doctor should put you on a steroid to lessen the chance of a bad skin reaction when taking Alimta.

The side effects of any medication are important to be aware. Hence, you should know all of the side effects of any medication prior to deciding to use it as a treatment for your cancer. Most cancer medications have a wide list of side effects, but that is because all of these cancer-destroying medications work on killing the cancerous cells within your body. It is quite frequent that these medications will also damage healthy cells, which is why there is such a chance for side effects. A few of the side effects that Alimta has are loss of hunger, sores inside the mouth, rashes throughout the body, exhaustion, depression, general weakness, and other similar side effects. These may sound bad, however it is much preferred that a patient deal with such minor side effects in order to extend his or her life. The benefits outweigh the risks.

Mesotheliona Clinical Trials

In order to one day find a mesothelioma cure, doctors engage in clinical trials where they test new mesothelioma drugs to determine the if they are effective.

Mesothelioma clinical trials follow a plan of very strict scientific guidelines, which is called a protocol. The protocol explains everything that will happen in the study. It must be approved by review boards made up of health care professionals and other qualified people before the study can enroll patients.

When a potential mesothelioma drug is first identified, preclinical studies, which are conducted in a laboratory setting, help to find out whether the drug is safe to test in humans. During this stage, the drug is usually studied in animals to answer questions about how a drug works and how the body changes and disposes of it. Humans do not participate in preclinical studies. There are four possible phases of cancer clinical trials in humans, each designed to answer different questions about the treatment being studies.

In Phase I mesothelioma clinical trials, doctors are primarily studying the safety of giving mesothelioma drugs to humans, while also looking for the best way to give a medication (for example, as a pill, an injection, or an infusion). They will usually study how the mesothelioma drug is eliminated from the body in humans. Also, doctors are trying to find the right doses for further testing. They carefully watch for any side effects. Phase I study drugs are usually given to small groups of humans. During this phase, for drugs used to treat mesothelioma cancer, investigators may be able to find out which tumors a treatment works best in.

In Phase II mesothelioma clinical trials, the mesothelioma drug is studies in a larger group. The primary purpose of these studies is to see how well the drug or treatment shrinks tumors in patients with specific types of cancer. The investigator will watch closely for side effects and will also watch how the disease responds to the treatment.

In Phase III mesothelioma clinical trials, the new cancer treatment is generally compared to a standard existing treatment. Patients are usually randomly assigned (that is, a process similar to flipping a coin is used to determine which treatment the patient receives) to receive either a standard treatment or the new treatment. During the trial, patients may or may not be told which treatment they are getting but are told what to expect and what to watch for. Occasionally, even the doctor will not know which treatment each patient is getting so that he or she can remain unbiased about how the disease is responding to the treatment. (This is uncommon in cancer clinical trials). Phase III studies are designed to ensure that any side effects that patients experience are identified treated according to local standards of care.

Phase IV mesothelioma clinical trials study a drug that has already been approved by the Food and Drug Administration. Drug companies often sponsor these trials to study even more uses of drugs already available

Clinical Trials: Mesothelioma

California

Duarte; City of Hope National Medical Center
A Double-Blind Placebo Controlled Randomized Phase II of Gemcitabine & Cisplatin With Or Without the VEGF Inhibitor Bevacizumab in Patients with Malignant Mesothelioma

San Diego; Sharp Clinical Oncology Research
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Colorado

Aurora; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

Aurora; University of Colorado Cancer Center
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Florida

Miami; Oncology / Hematology Group of South Florida
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Tampa; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

Illinois

Chicago; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

Chicago; University of Chicago Medical Center, Section of Hematology / Oncology
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Indiana

South Bend; Northern Indiana Cancer Research Consortium
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Maryland

Baltimore; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

Massachusetts

Boston; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

Michigan

Grand Rapids; Spectrum Health, Cook Research Department
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

New Jersey

Somerville; Somerset Medical Center
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

New Mexico

Albuquerque; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

New York

New York; Columbia-Presbyterian Medical Center
ALIMTA Plus Gemcitabine as Front-Line Chemotherapy for Patients with Malignant Pleural or Peritoneal Mesothelioma. A phase II Clinical Trial.

New York; Columbia-Presbyterian Medical Center
Open - Label Study of Alimta (pemetrexed) Combination with Cisplatin for Chemonaive Patients with Malignant Pleural Mesothelioma.

New York; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

New York; Columbia Presbyterian Medical Center
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

New York; Columbia University Medical Center
A phase II, open-label, non-randomized, multicenter, single agent study of intravenous sdx-102 for the treatment of patients with MTAP - deficient cancers.

New York; Columbia-Presbyterian Medical Center
Phase II trial of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma.

New York; Columbia-Presbyterian Medical Center
Phase II trial of perioperative gemcitabine and cisplatin chemotherapy in resected pleural mesothelioma

New York; Biomedical Research Alliance of New York
Cancer in the Lungs- Caused by exposure to asbestos

Oklahoma

Tulsa; Southwestern Regional Medical Center
Open-Label Study of ALIMTA (pemetrexed) and Cisplatin in chemonaive patients with malignant Pleural Mesothelioma.

Texas

Austin; Lone Star Oncology Consultants, PA
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Houston; S. R. Burzynski Clinic
Phase II Study Of Antineoplastons A10 And AS2-1 In Patients With Mesothelioma

Wisconsin

Madison; Research Center
ALIMTA Plus Gemcitabine (Gemzar) for Patients with Malignant Pleural or Peritoneal Mesothelioma who have not had previous chemotherapy

International

D-14109 Berlin, Germany; Pneumologie II, Zentralklinik Emil von Bering
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

D-21075 Hamburg, Germany; Allgemeines Krankenhaus Harburg
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

D-22927 Grosshansdorf, Germany; Krankenhaus Grosshansdorf, Zentrum fur Pneumologie und Thoraxchirurgie, Pneumo.- Onkolog. Abteilung
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

D-81675 Munchen, Germany; TU Munchen, Klinikum Rechts der Isar, Med. Klinik Hamatologie und Onkologie
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

D-82131 Gauting, Germany; Asklepios Fachkliniken, Zentrum fur Pneumologie und Thoraxchirurgie
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Alessandria, Italy; Azienda Osped. Nazion Antonio e Biagio e Cesare Arrigo, Divisione di Pneumologia
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Genova, Italy; Struttura Semplice di Pneumotisiologia, Ospedale San Marino
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Pavia, Italy; IRCCS - Policlinico San Matteo, Clinica Malattie dell Apparato Respiratorio
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Pavia, Italy; IRCCS - Policlinico San Matteo, Divisione di Pneumologia
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen.

Venezia, Italy; Ospedale Civile di Venezia, Unita Operativa Oncologia Medica
ONCONASE ® plus doxorubicin vs. doxorubicin for patients with Malignant Pleural or Peritoneal Mesothelioma who have had no more than one prior chemotherapy regimen

General Information / Anatomy / Function / Statistics

• Mesothelioma are tumours originating from the lining of the body cavities; this includes the chest and abdomen. Although the most common type of mesothelioma begins within the chest, this cancer should not be confused with lung cancer. Mesotheliomas arise from the serosal lining outside of the lungs within the chest or outside the bowel within the abdomen.
• About 100 new cases of malignant mesothelioma appear in Canada each year
• 30-40 cases are seen at the BC Cancer Agency each year
• Malignant mesothelioma is usually not curable

Symptoms / Signs

• Symptoms and signs from mesotheliomas depend upon location of the mesothelioma, its size and whether it is benign or malignant
• Benign forms of the disease are generally asymptomatic
• The symptomatology of malignant mesotheliomas is due to tumour growth resulting in invasion of surrounding structures and/or the production of fluid (pleural effusion, ascites, or pericardial effusion). Chest pain may be caused by invasion of the chest wall. Pleural effusion causes collapse of adjacent lung and shortness of breath.
• Symptoms of distant spread are possible, but uncommon since the tumour is usually a local problem and blood borne spread is uncommon
• Patients with more advanced disease may be ill generally with fever, night sweats and weight loss
• Involvement of the membrane around the heart (pericardium) may cause heart rhythm disturbances

Etiology / Carcinogens / Risks

• There is a definite association between asbestos and mesothelioma. The risk associated with asbestos exposure has been shown by many investigators and inhalation of asbestos poses the most serious hazard.
• In approximately 30% of mesotheliomas, no asbestos exposure can be traced
• Crocidolite (Cape blue asbestos), the main cancer causing form of asbestos, is associated with over 90% of pleural and peritoneal mesotheliomas. Other types of asbestos fibre have been associated in a less significant way.
• Individuals at highest risk are those employed in the asbestos industry; dockyard workers, especially if they dismantle asbestos-insulated steam piping; those who handle and manufacture asbestos compounds; insulators and steam fitters; and those in demolition and construction industries
• Spouses and children of asbestos workers are also at risk
• The latent interval between exposure to asbestos and development of tumour is long (15-25 years)
• Mesothelioma is not caused by cigarette smoking but asbestos exposure and cigarette smoking both increase the risk of lung cancer

Prevention

• The only method of prevention is avoidance of asbestos exposure
• Cigarette smoking should be avoided by all persons and asbestos exposed individuals should avoid cigarette smoke in particular because asbestos plus cigarette smoking can cause lung cancer

Diagnosis / Screening / Staging / Grading / Types

• The chest X-ray is a very helpful test, usually showing thickening of the pleura or pleural effusion in patients with pleural mesothelioma. Sometimes a CT scan of the chest may be required for further information.
• A pleural biopsy is essential for pathological confirmation of the disease. Although pleural fluid cytology may be abnormal, this is often difficult to interpret.
• Patients having peritoneal mesothelioma may require an abdominal surgery for exploration of the peritonial surfaces and biopsy of any lesions observed

Types

• Mesotheliomas may be of epithelial or sarcomatous. Sarcomatous types are more malignant and tend to be resistant to treatment.

Treatment

• Treatment unsatisfactory with no recent advances
• Malignant mesotheliomas are serious illnesses and cure of the disease is rare
• Survival with this type of cancer obviously varies with the extent of the disease, but overall it is in the region of one year

Surgery

• Because of the large area of pleural surfaces, complete surgical removal is rarely technically feasible. The advisability of resection is always considered at diagnosis, but only a small minority of cases are eligible for an attempted resection. Spread of disease to the chest wall, heart, or esophagus often rules out the possibility of an operation.

Radiation

• Radiation may be given for control of symptoms in a localized area. Radiation therapy does not have the power to cure this disease. Radiation cannot be given to the entire tumour because this would involve the treatment of large volumes of normal tissue and the dose of radiation required for tumour control is too high for this to be tolerated. Radiation can, however, be of value in controlling pain in a localized area.

Chemotherapy

• Benefits from chemotherapy treatments for mesothelioma are uncertain as the tumour is often resistant. The best available treatment programs do not have the power to cure any patients with mesothelioma. 20% of patients may have a temporary shrinkage of the disease with currently available drugs.

General Support and Symptom Control

• If pain is associated with mesothelioma, good drug prescriptions are available that can control this. Pleural effusions (fluid build up) can be treated by a small surgical procedure that removes the fluid, permitting re-expansion of the lung and improvement in shortness of breath. Some patients with mesothelioma may have very slow growing tumours and if symptoms are not present, it is often advisable to follow the patient with regular chest X-rays without specific therapy. When symptoms do occur, they should be assessed on an individual basis.
• Chemotherapy may be considered for treatment of recurrent thymoma

Treating Malignant Pleural Mesotheliomas: An Uphill Climb

Introduction

Malignant pleural mesothelioma (MPM) seems to be on the increase worldwide and especially in the United States, with 2000 to 3000 new cases reported annually. Individuals who have been exposed to asbestos carry a 20% lifetime risk for acquiring MPM; smoking exacerbates the disease.

As MPM is a universally fatal cancer at present, with patients dying from pulmonary complications and infections, more effective treatment strategies are desperately needed. A somber series of presentations at the 9th World Conference on Lung Cancer in Tokyo suggested, however, that no potential breakthrough treatments seem to be on the horizon. Indeed, as the presentations suggested, there still is no standard treatment regimen for MPM.

Theories of Negativity

Triple Combination: Methotrexate (MTX) Plus Interferon Alpha and Gamma

Dr. Ola Brodin, from South Hospital, Stockholm, Sweden, reviewed results from a phase 2 multicenter Northern European trial in which patients received triple combination therapy, consisting of high-dose MTX, alpha interferon, and gamma interferon.^[1] Previously, single institutional trials reported response rates of 37%, 12%, and 24% for single-agent high-dose MTX, interferon alpha, and interferon gamma, respectively. The investigators designed this study to ascertain whether the 3 agents together would behave synergistically, or at least prove to be additive, as a previous in vitro Finnish study had suggested that MTX and interferon alpha behaved in a synergistic fashion.

MTX 3000 mg, followed by leucovorin rescue every 2 weeks, with interferon alpha 3 million units subcutaneously on days 3 to 8, and interferon gamma 40 mcg on days 3, 7, and 11 were given for 3 cycles every 2 weeks. Patients who showed responses were then given 3 more courses of therapy every 3 weeks at lower doses. Most patients (27) received all 6 planned cycles, whereas 4 patients received 5 cycles, 2 patients received 4 cycles, 7 patients received 3 cycles, and 3 patients received only 1 cycle.

A total of 49 patients were enrolled, but 6 were not included in the final analysis, because 4 patients were not treated, 1 was found to have peritoneal disease, and an additional patient had been previously treated. Among the 43 treated patients, 39 were evaluable. The overall response rate of 19% consisted of 8 partial remissions (PRs). There were 22 patients (51%) with stable disease and 9 patients (21%) with progressive disease. Median survival time was 15 months, with longer survival seen among those patients achieving a PR. Toxicity was primarily hematologic, with 4 grade 3 neutropenias noted. Rather than enhance the effect of the other drugs, it seems that this triple combination led to competition among the various compounds, resulting in a worse response rate than with each agent used separately. The investigators concluded that interferon would not be included in the development of future chemotherapy combination strategies for treatment of MPM.

Vinorelbine plus Oxaliplatin

A second combination approach, combining vinorelbine and oxaliplatin, was reviewed by Dr. Jeremy Steele of the London Lung Cancer Group.^[2] Building on previous data in which a 20% to 25% response rate was achieved with single-agent vinorelbine in the treatment of poor-prognosis MPM,^[3] Dr. Steele and colleagues from St. Bartholomew's Hospital in London paired oxaliplatin with vinorelbine. A total of 21 patients were given vinorelbine 30 mg/m² on days 1 and 8 with oxaliplatin 130 mg/m² on day 1 every 3 weeks for a total of 6 cycles. Seventeen patients have completed treatment while 4 continue on therapy. To date, only 2 partial responses (11.8%) were seen, with stable disease in 13 (76%) and progressive disease in 2 patients. Toxicity was significant, with 61% grade 3 and 4 neutropenia. Phlebitis (9%) was the most common nonhematologic complication.

While this low level of activity was disappointing, Dr. Steele suggested that the low response rate might be due to the large number of stage 4 patients included in the study (62%), the higher proportion of less favorable histologic subtypes (sarcomatoid 33%, mixed 24%), as well as a higher proportion of performance status (PS)-2 patients (24%). Additionally, he suggested, it might be necessary to increase the dose of vinorelbine. For the present, oxaliplatin does not seem to contribute significantly to the treatment of MPM and should probably not be included in further clinical trials.

Weekly Vinorelbine Therapy

In a separate presentation, Dr. Steele updated last year's American Society of Clinical Oncology (ASCO) results on the weekly vinorelbine therapy mentioned before.^[4] A total of 64 patients, 64% with epithelioid tumors, 9% with sarcomatous tumors, and 27% with biphasic disease were given vinorelbine 30 mg/m² weekly for 6 weeks (constituting 1 cycle). A median of 2 cycles were administered (range 1-10), with 4 patients receiving ongoing treatments between cycles 4 and 6. Distribution by stage included 3% of patients in stage 1, 28% in stage 2, 28% in stage 3, and 39% in stage 4.

There were 12 PRs (21%), 36 patients (63%) with stable disease, and 9 patients (16%) with progressive disease. Quality of life, as measured by the Rotterdam Symptom Checklist, was enhanced significantly, with 49% of patients reporting improvements in lung-related symptoms, whereas 56% reported general physical improvements. Toxicity was primarily hematologic, with 63% asymptomatic grade 3 and 4 neutropenia, and an 18% incidence of neutropenic fevers. Other toxicities included phlebitis, malaise, anorexia, nausea, and vomiting, all reported in 12% of cases.

Dr. Steele concluded that use of vinorelbine correlated with significant improvements in quality of life, with acceptable toxicity and a respectable (20%+) response rate. He also suggested that this agent warrants further study with a best supportive care control arm. Postpresentation questioners were skeptical about the degree of improvement in patient quality of life and suggested that perhaps the mere fact that patients were seen on a weekly basis could account in large part for their enhanced well being. It was also suggested that the addition of pulmonary function studies would more accurately reflect the degree of response to treatment beyond chest x-rays and CT scans.

Gemcitabine Plus Cisplatin

J.W. van Haarst,^[5] from University Hospital Rotterdam in The Netherlands, reviewed data from a multicenter phase 2 trial that sought to validate a previous single institutional study that had reported a response rate of 48% in MPM with a combination of gemcitabine and cisplatin.^[6] Given as single agents, gemcitabine and cisplatin have shown response rates ranging from 7% to 14% in MPM, and in vitro studies have suggested a synergistic interaction between these 2 compounds.

Van Haarst and colleagues enrolled 32 patients with stage 2 through 4 MPM, 28 of which were stage 3 and 4. Histologically, 25 patients had epithelial tumors, 2 sarcomatous tumors, and 4 mixed tumors. Treatment consisted of gemcitabine 1250 mg/m² on days 1 and 8 with cisplatin 80 mg/m² on day 1. Cycles were repeated at 3-week intervals for a maximum of 6 cycles. A cohort of 25 patients was needed to render the study statistically significant, and a response rate of 20% or greater was needed to establish validity. Ten patients were not evaluable, 5 because they received less than 2 cycles of therapy and 3 because of toxicity. One patient refused treatment and another was lost to follow-up.

Of the 22 patients who were evaluable, only 4 (15%) had a PR. Median survival time was 10 months with a 1-year survival of 30%. There were 2 cases of leukopenias, whereas nonhematologic toxicities were insignificant. Because the observed response rate was less than 20%, the study did not meet its own standard for validity.

Dr. van Haarst speculated that the discrepancy between the single institutional trial results and this multicenter trial was likely due to differences in patient selection, treatment schedules, and methodology in evaluating treatment. Following the presentation, Dr. Byrne, the author of the single institutional study, noted that when a larger number of patients was eventually accrued (55), the response rate dropped from 48% to 32%.^[6]

Docetaxel

Two other studies failed to show any significant improvement over current therapies. The first, presented by Dr. Vorobiof from the Standton Oncology Centre in Johannesburg, South Africa, employed single-agent docetaxel among 31 patients with MPMs.^[7] Docetaxel 100 mg/m² was administered every 3 weeks with standard steroid pre- and posttreatment medication. Patients were evaluated with chest x-rays and CTs after every 3 cycles. Five patients were not evaluable, 3 having died within the first 2 weeks following the first cycle of chemotherapy, 1 from unknown causes, a second from toxicity while receiving alternative medications, and a third from progressive disease. A fourth patient refused treatment and a fifth was diagnosed incorrectly. Four more were not evaluable because treatment was ongoing.

Of the 22 patients who were evaluable, there were 3 PRs. Stable disease was observed in 11 and there were 6 minor responses (25% or less reduction in tumor burden). Median duration of response was longer for those who responded partially compared with those with stable disease (20 weeks vs 11 weeks). Median survival was a little over 12 months. Grade 3 and 4 toxicities included 4 patients with neutropenia, 4 with diarrhea, and 4 with mucositis. A majority of patients (13) experienced no toxic side effects. One individual from the audience pointed out that the results from this trial were less than encouraging, given that the response rate (10%) and the death rate (10%) were the same.

Cisplatin, Ifosfamide, and Mitomycin

Dr. Metinas, from Osmangazi University in Eskisehir, Turkey, reported on a single institutional trial on only 12 patients, that incorporated a control arm of 12 individuals.^[8] Among 16 patients treated with combination chemotherapy, consisting of cisplatin 90 mg/m² over 3 days, ifosfamide 2 g/m² over 3 days, and mitomycin 8 mg/m² on day 1, 4 were not evaluable due to inadequate follow-up. A partial response was seen in 3 patients, while 1 patient experienced tumor "regression," but deemed a minor response. The median survival time was 6 months for the patients who received chemotherapy vs 4 months for the 10 patients who received best supportive care alone. This difference was not statistically significant. Those patients with responsive or stable disease did have a longer and statistically significant median survival time (8.5 months) compared with those with progressive disease (3.5 months). The unusual feature about this trial was the fact that a control arm was established, a difficult proposition in most clinical settings.

Accentuating the Positive

Intrapleural Liposomal NDDP

Two additional presentations were interesting because they discussed new approaches to treat this MPM. Dr. Dong Shin and colleagues,^[9] from the M.D. Anderson Cancer Center in Houston, Texas, studied the intrapleural administration of a liposomal cisplatin analogue (L-NDDP) in 34 patients who were diagnosed with MPM and free-flowing pleural effusions. Various dose levels of L-NDDP were given intrapleurally, ranging from 250 mg/m² to 550 mg/m² every 3-4 weeks. The first 8 patients were treated at the time of thoracoscopy; 2 of them died after 1 and 3 courses of chemotherapy. Subsequently, the remaining patients were treated 1 week after catheter placement with no ensuing complications. Eleven patients were deemed not evaluable, 4 because of nontreatment and 7 due to loss of follow-up, leaving 23 evaluable patients.

Twenty-three patients had both and pre- and posttreatment biopsy samples available for analysis. No evidence of tumor could be found posttreatment in 13 patients (56%). Cytology samples were available in 18 pre- and posttreatment patient specimens, of which 15 (83%) had no evidence for residual tumor following treatment. Dose-limiting toxicity was pleuritic pain, as well as nausea and vomiting. Only 1 grade 4 neutropenia was observed, with 2 grade 3 thrombocytopenias, 1 grade 3 neutropenia, and 1 grade 3 anemia.

The author concluded that this approach was highly effective with an overall response rate of 33%. But he also acknowledged a colleague's assertion that this approach does not address the systemic nature of malignant mesotheliomas, making it unlikely to impact on overall survival. Moreover, so few patients would be able to benefit from this therapeutic modality, given the often widespread nature of disease at time of presentation. Currently, an ongoing phase 2 trial is looking at whether L-NDDP can be given preoperatively, followed by surgery, then radiation therapy.

Carboplatin Plus Pemetrexed Disodium

Dr. A. Calvert, from the Department of Medical Oncology at Newcastle-upon-Tyne, England, discussed the use of pemetrexed disodium (LY231514, MTA), a novel multi-targeted anti-folate that inhibits several folate-dependent enzymes, especially thymidylate synthase (TS).^[10] This phase 1 study enrolled from 3-6 patients at various dosing levels of pemetrexed disodium with carboplatin ranging from 400 mg/m² and area under the curve (AUC) 5, respectively. Pemetrexed disodium was given over 10 minutes intravenously on day 1, followed by infusion of carboplatin. Cycles were repeated every 21 days.

Among 29 enrolled patients with MPM, 27 were treated. Maximum tolerated dose of pemetrexed disodium was established at 500 mg/m². Of 25 patients evaluable for response, 10 achieved PRs (40%) and 15 demonstrated stable disease, all at various dose levels. No patient had progressive disease. Toxic effects were primarily myelosuppression with 60% leukopenia, neutropenia, and thrombocytopenia at the highest dose level. Most patients with grade 3 and 4 hematologic toxicities remained asymptomatic. Mild nonhematologic toxic effects included nausea, vomiting, asthenia, rash, and transitory elevations of liver transaminases. Furthermore, symptomatic improvement was documented in 14 cases, whereas CT scanning detected radiologic improvement in 10 patients. Patients received a median number of 6 courses of treatment. Median time to progression was almost 1 year, whereas median survival time was 410 days, a significant improvement over the 9-12 month survival of historic controls. Phase 2 trials with single agent pemetrexed disodium, as well as a randomized trial with pemetrexed disodium in combination with cisplatin, are currently ongoing.

Implications for Clinical Practice

Clearly, much work needs to be done before a standard treatment for MPM is defined. Until then, clinicians are urged to enroll such patients in randomized clinical trials whenever possible in order to further our understanding and refine our treatment approaches. Expanding our knowledge of the biology and molecular makeup of malignant mesothelioma will likely lead to more selective and specific therapies, even if more promising modalities remain elusive for the time being

Mesothelioma Statistics by Country

Country/Region	Extrapolated Incidence	Population Estimated Used
Mesothelioma in North America (Extrapolated Statistics)
USA	2,755	293,655,4051
Canada	305	32,507,8742
Mexico	984	104,959,5942
Mesothelioma in Central America (Extrapolated Statistics)
Belize	2	272,9452
Guatemala	133	14,280,5962
Nicaragua	50	5,359,7592
Mesothelioma in Caribbean (Extrapolated Statistics)
Puerto Rico	36	3,897,9602
Mesothelioma in South America (Extrapolated Statistics)
Brazil	1,727	184,101,1092
Chile	148	15,823,9572
Colombia	397	42,310,7752
Paraguay	58	6,191,3682
Peru	258	27,544,3052
Venezuela	234	25,017,3872
Mesothelioma in Northern Europe (Extrapolated Statistics)
Denmark	50	5,413,3922
Finland	48	5,214,5122
Iceland	2	293,9662
Sweden	84	8,986,4002
Mesothelioma in Western Europe (Extrapolated Statistics)
Britain (United Kingdom)	565	60,270,708 for UK2
Belgium	97	10,348,2762
France	566	60,424,2132
Ireland	37	3,969,5582
Luxembourg	4	462,6902
Monaco	0	32,2702
Netherlands (Holland)	153	16,318,1992
United Kingdom	565	60,270,7082
Wales	27	2,918,0002
Mesothelioma in Central Europe (Extrapolated Statistics)
Austria	76	8,174,7622
Czech Republic	11	1,0246,1782
Germany	773	82,424,6092
Hungary	94	10,032,3752
Liechtenstein	0	33,4362
Poland	362	38,626,3492
Slovakia	50	5,423,5672
Slovenia	18	2,011,473 2
Switzerland	69	7,450,8672
Mesothelioma in Eastern Europe (Extrapolated Statistics)
Belarus	96	10,310,5202
Estonia	12	1,341,6642
Latvia	21	2,306,3062
Lithuania	33	3,607,8992
Russia	1,350	143,974,0592
Ukraine	447	47,732,0792
Mesothelioma in the Southwestern Europe (Extrapolated Statistics)
Azerbaijan	73	7,868,3852
Portugal	98	10,524,1452
Spain	377	40,280,7802
Georgia	44	4,693,8922
Mesothelioma in the Southern Europe (Extrapolated Statistics)
Italy	544	58,057,4772
Greece	99	10,647,5292
Mesothelioma in the Southeastern Europe (Extrapolated Statistics)
Albania	33	3,544,8082
Bosnia and Herzegovina	3	407,6082
Bulgaria	70	7,517,9732
Croatia	42	4,496,8692
Macedonia	19	2,040,0852
Romania	209	22,355,5512
Serbia and Montenegro	101	10,825,9002
Mesothelioma in Northern Asia (Extrapolated Statistics)
Mongolia	25	2,751,3142
Mesothelioma in Central Asia (Extrapolated Statistics)
Kazakhstan	142	15,143,7042
Tajikistan	65	7,011,556 2
Uzbekistan	247	26,410,4162
Mesothelioma in Eastern Asia (Extrapolated Statistics)
China	12,187	1,298,847,6242
Hong Kong s.a.r.	64	6,855,1252
Japan	1,194	127,333,0022
Macau s.a.r.	4	445,2862
North Korea	212	22,697,5532
South Korea	452	48,233,7602
Taiwan	213	22,749,8382
Mesothelioma in Southwestern Asia (Extrapolated Statistics)
Turkey	646	68,893,9182
Mesothelioma in Southern Asia (Extrapolated Statistics)
Afghanistan	267	28,513,6772
Bangladesh	1,326	141,340,4762
Bhutan	20	2,185,5692
India	9,993	1,065,070,6072
Pakistan	1,493	159,196,3362
Sri Lanka	186	19,905,1652
Mesothelioma in Southeastern Asia (Extrapolated Statistics)
East Timor	9	1,019,2522
Indonesia	2,237	238,452,9522
Laos	56	6,068,1172
Malaysia	220	23,522,4822
Philippines	809	86,241,6972
Singapore	40	4,353,8932
Thailand	608	64,865,5232
Vietnam	775	82,662,8002
Mesothelioma in the Middle East (Extrapolated Statistics)
Gaza strip	12	1,324,9912
Iran	633	67,503,2052
Iraq	238	25,374,6912
Israel	58	6,199,0082
Jordan	52	5,611,2022
Kuwait	21	2,257,5492
Lebanon	35	3,777,2182
Saudi Arabia	242	25,795,9382
Syria	169	18,016,8742
United Arab Emirates	23	2,523,9152
West Bank	21	2,311,2042
Yemen	187	20,024,8672
Mesothelioma in Northern Africa (Extrapolated Statistics)
Egypt	714	76,117,4212
Libya	52	5,631,5852
Sudan	367	39,148,1622
Mesothelioma in Western Africa (Extrapolated Statistics)
Congo Brazzaville	28	2,998,0402
Ghana	194	20,757,0322
Liberia	31	3,390,6352
Niger	106	11,360,5382
Nigeria	166	12,5750,3562
Senegal	101	10,852,1472
Sierra leone	55	5,883,8892
Mesothelioma in Central Africa (Extrapolated Statistics)
Central African Republic	35	3,742,4822
Chad	89	9,538,5442
Congo kinshasa	547	58,317,0302
Rwanda	77	8,238,6732
Mesothelioma in Eastern Africa (Extrapolated Statistics)
Ethiopia	669	71,336,5712
Kenya	309	32,982,1092
Somalia	77	8,304,6012
Tanzania	338	36,070,7992
Uganda	247	26,390,2582
Mesothelioma in Southern Africa (Extrapolated Statistics)
Angola	103	10,978,5522
Botswana	15	1,639,2312
South Africa	417	44,448,4702
Swaziland	10	1,169,2412
Zambia	103	11,025,6902
Zimbabwe	34	1,2671,8602
Mesothelioma in Oceania (Extrapolated Statistics)
Australia	186	19,913,1442
New Zealand	37	3,993,8172
Papua New Guinea	50	5,420,2802

About extrapolations of prevalence and incidence statistics for Mesothelioma:

These statistics are calculated extrapolations of various prevalence or incidence rates against the populations of a particular country or region. The statistics used for prevalence/incidence of Mesothelioma are typically based on US, UK, Canadian or Australian statistics. This extrapolation calculation is automated and does not take into account any genetic, cultural, environmental, social, racial or other differences across the various countries and regions for which the extrapolated Mesothelioma statistics below refer to. As such, these extrapolations may be highly inaccurate (especially for developing or third-world countries) and only give a general indication (or even a meaningless indication) as to the actual prevalence or incidence of Mesothelioma in that region.

About prevalence and incidence statistics in general for Mesothelioma:

The word 'prevalence' of Mesothelioma usually means the estimated population of people who are managing Mesothelioma at any given time (i.e. people with Mesothelioma). The term 'incidence' of Mesothelioma means the annual diagnosis rate, or the number of new cases of Mesothelioma diagnosed each year (i.e. getting Mesothelioma). Hence, these two statistics types can differ: a short disease like flu can have high annual incidence but low prevalence, but a life-long disease like diabetes has a low annual incidence but high prevalence.

Mesothelioma in the United States

	ABSTRACT

Using 1973–2000 mesothelioma incidence data released by the Surveillance, Epidemiology, and End Results Program in April 2003, the authors estimated the parameters of a birth-cohort and age model to determine whether previously reported patterns of mesothelioma in the United States have changed. Compared with analyses based on data through 1992, a slower decline was found in male cases immediately after a peak in 2000–2004, but no other notable changes in the time pattern were detected. Analysis confirmed that the annual number of male mesothelioma cases, which increased steeply from the 1970s through the mid-1990s, has leveled off in terms of both the age-adjusted rate and the absolute numbers of cases. After a peak of approximately 2,000 cases, a return to background levels is expected by 2055. The total projected number of male mesothelioma cases in 2003–2054 is approximately 71,000. The maximum lifetime risk for males, which occurs for the 1925–1929 birth cohort, is 1.8 x 10–3. The age-adjusted rate for females is constant, as are the female lifetime mesothelioma risk across birth cohorts (3.6 x 10–4) and the annual risk (3.9 x 10–6). The time pattern of cases for females supports the existence of a threshold exposure for mesothelioma and a quantifiable background rate.

asbestos; incidence; mesothelioma

Abbreviations: Abbreviation: SEER, Surveillance, Epidemiology, and End Results.

	INTRODUCTION

Mesothelioma incidence often is interpreted as an indicator of exposure to asbestos. Projections of the number of mesothelioma cases over time may be used to evaluate various asbestos health management interventions including exposure limits and products bans. Mesothelioma projections also provide a foundation for estimating the number of potential lawsuits from persons claiming occupational exposure to asbestos or exposure resulting from use of previously manufactured asbestos-containing products. Noting recent publications discussing mesothelioma incidence in North America and that projected numbers of future mesothelioma cases in the Netherlands, Sweden, and the United Kingdom have been adjusted based on new data (1–4), we analyzed current Surveillance, Epidemiology, and End Results (SEER) Program data (5) to update mesothelioma trends in the United States.

	MATERIALS AND METHODS

We applied maximum likelihood estimation (6) to SEER data (5) to estimate the parameters of a birth-cohort and age model (7). The SEER database contains information on cancer incidence in the United States by year of diagnosis and age from nine cancer registries for 1973 through 1991 and 11 registries for 1992 through 2000. The SEER registries represent 14 percent of the US population, are similar to the United States regarding measures of poverty and education, and tend to be more urban than the general US population (8–10). For males and females, we extracted counts of mesothelioma cases and corresponding population counts for each year and each 5-year age interval from 0–4 through 85 years or older. These data were realigned into 5-year birth-cohort categories (1885–1889 through 1970–1974).

Incidence estimates calculated from the model were combined with mortality rates for all causes in a survival analysis to calculate, for each birth cohort, the probability of mesothelioma occurring in each 5-year age interval, conditioned on cancer-free survival to that age interval (11). These probabilities were used to calculate the lifetime risk of mesothelioma for each birth cohort.

For all-cause mortality, we created a table of cohort mortality rates by 5-year age interval for each birth cohort. The cohort mortality rates were developed from two sources: 1) cross-sectional mortality rates for 5-year age intervals from the SEER system, years 1969–2000 (12); and 2) cross-sectional mortality rates by 10-year age intervals for individual years 1900 through 1968 (13). We factored the 10-year age intervals into two 5-year intervals and then realigned the results to form a table of cohort mortality rates for birth cohorts 1900–1904 through 1995–1999.

To project the annual number of future mesothelioma cases, we required natality data (14), mesothelioma probabilities for each age interval, and all-cause mortality rates for future birth cohorts. The number of births for all future birth cohorts was set equal to the number of births reported for the most recent birth cohort, 1995–1999.

Future birth-cohort mesothelioma probabilities for females, starting with the 1965–1969 cohort, were set to the average of past probabilities for females, which have been relatively constant since the 1900–1904 birth cohort. Mesothelioma probabilities for males have been declining toward those for females. Therefore, probabilities for males in future birth cohorts starting with 1965–1969 were set equal to the averages for females, which we interpreted as background rates for mesothelioma. All-cause mortality rates for the year 2000 were used for all future birth cohorts.

	RESULTS

Trend in age-adjusted rates
The age-adjusted incidence (figure 1) indicates a consistently higher rate for males versus females across all years, an increasing trend over the years for males, and a virtually constant rate for females. Accounting for a latency period of 20–40 years for mesothelioma, the increased incidence for males reflects the increased use of asbestos (15) in the United States (figure 2) and the high levels of occupational exposure prior to the late 1960s, when formal workplace exposure limits were established. The age-adjusted rate for males was flat from 1990 through 2000. Projections of future male mesothelioma cases, discussed later, indicate that the number of male cases per year has peaked and is declining.

FIGURE 1. Age-adjusted incidence rates of mesothelioma (pleural + peritoneal) in the United States based on Surveillance, Epidemiology, and End Results Program data released in April 2003.

FIGURE 2. Asbestos use (consumption) in the United States and projected numbers of male and female mesothelioma cases based on a birth-cohort and age model estimated from Surveillance, Epidemiology, and End Results (SEER) Program data for two periods, 1973–1992 and 1973–2000..

Comparison of trends: data for 1973–1992 versus 1973–2000
A direct comparison of mesothelioma trends based on current data with trends published by Price (7) would not be meaningful because the SEER data have changed since 1992. Two registries were added starting with 1992 data, and mesothelioma counts for the years 1973 through 1991 have been corrected. Therefore, our modeling is based on the current SEER database, first using cases diagnosed from 1973 through 1992 and then using all cases, 1973 through 2000.

Model fits
For each data set (males, females; two time intervals), the predicted values tracked the observed values reasonably well, although there were a few data points with large deviances. The 1973–1992 data sets had 80 data points; the 1973–2000 data sets had 101 data points. When the large deviances were excluded, the statistical fits were acceptable (p > 0.05 based on total deviance) for each model. The numbers of data points remaining were, for 1973–1992, 79 for males and 80 for females and, for 1973–2000, 92 for males and 99 for females.

Lifetime risk of mesothelioma
For females, the lifetime risk of mesothelioma is approximately constant at 3.6 x 10–4 (figure 3). The lifetime risk for males (1973–1992 data, not shown) is a maximum of 2.1 x 10–3 for the 1925–1929 birth cohort and then declines sharply for subsequent cohorts, except for an isolated increase for the 1940–1944 cohort. Regarding the 1973–2000 data, the maximum risk is 1.8 x 10–3 (figure 3). The trend is relatively flat before starting downward after the 1940–1944 cohort.

FIGURE 3. Lifetime probability (risk) of mesothelioma (pleural + peritoneal) and 95% confidence intervals (vertical bars) based on a birth-cohort and age model estimated from 2003 Surveillance, Epidemiology, and End Results Program data covering 1973–2000

Projected number of mesothelioma cases
For the two data sets, mesothelioma projections for females (figure 2) are virtually identical. Although the age-adjusted rate for females is constant, the number of mesothelioma cases increases slightly over time as a function of population size and shifting age distribution. Currently (2003), the annual estimate of female mesothelioma cases is approximately 560.

The trend for males in both data sets peaks in the 2000–2004 time frame at slightly more than 2,000 mesothelioma cases (figure 2). The 1973–2000 model shows fewer mesothelioma cases than the 1973–1992 model during the peak years, but not overall. The total numbers of male mesothelioma cases projected for 2003 through 2054 are 70,990 for the 1973–2000 data and 73,892 for the 1973–1992 data.

	DISCUSSION

Overall, there have been no substantive changes in the time pattern of mesothelioma incidence in the United States since 1992. This conclusion would not be apparent if the current results using SEER data for 1973–2000 were compared with the results published by Price (7) that were based on SEER data for 1973 through 1992. That estimated model (7) showed a sharper decline in the number of annual male mesothelioma cases, projecting approximately 7,000 fewer cases between 2003 and 2054, than the model based on the most current data. However, a comparison to the Price results (7) would not be meaningful because of changes in SEER data and application of the cohort mortality rates used here. Therefore, it was necessary to reestimate the model using revised data through 1992 for comparison to the model based on current data through 2000. This comparison indicated no substantive change in the time pattern or number of future cases.

In addition to describing the time pattern of mesothelioma incidence, our results contain information about the potential effects of environmental exposures to asbestos and two related issues: 1) the existence of an exposure threshold and 2) the existence and magnitude of a background rate (i.e., mesotheliomas not associated with asbestos exposure). (In this discussion, threshold does not mean an exposure below which the risk of mesothelioma is zero; the threshold is an asbestos exposure level associated with a negligible incremental risk of mesothelioma.)

The constancy alone of the mesothelioma risk for females over time supports the existence of a threshold exposure. The effects, if any, of environmental exposures for the US population as a whole cannot be observed for males; as a group, males experienced high occupational exposures that masked low-exposure effects. In contrast, female exposures to asbestos have been primarily environmental. In the 1930s through the 1960s, women generally did not work in industries in which men experienced high levels of exposure to asbestos. For some women, exposures have been domestic (i.e., they live in households with men who were exposed occupationally), but the number of women with high levels of domestic exposure, although not zero, would have been relatively small. However, all women were exposed to asbestos in the environment, an exposure that would have increased since the 1930s, especially the dramatic increase during the 40-year period from 1930 to 1970 in the amount of asbestos used in US products (figure 2). As use increased, higher environmental exposures would have resulted from asbestos mining, manufacturing, and product use (e.g., vehicle brake systems, construction materials, and other asbestos-containing products) during this period and beyond for as long as the asbestos-containing products were in use.

Nevertheless, the mesothelioma risk for women has not increased. The age-adjusted mesothelioma rate for females was constant at an average of approximately 0.30 per 100,000 between 1973 and 1982, when it showed a one-time increase to 0.40 per 100,000 (figure 1). One might be tempted to interpret this change as a response to increasing environmental exposure. However, the female rate, which should have continued to increase after 1982 if the environmental exposure explanation is correct, remained constant after 1982. Therefore, the one-time mesothelioma increase for females does not indicate increasing exposure to asbestos in the environment but more likely a diagnostic effect. Environmental exposure levels, although increasing, have not triggered a risk response in women. Therefore, those exposure levels must have been below a threshold for mesothelioma.

A threshold higher than typical environmental asbestos exposures, as argued above, implies the existence of background mesotheliomas caused by agents other than asbestos that could account for most, if not all, female cases of mesothelioma. A number of studies provide evidence of background mesotheliomas (16–28). Simian virus 40 (SV40) is one of the nonasbestos agents that has been identified as a possible cause of mesothelioma (29, 30). Simian virus 40 was a contaminant in polio vaccines administered to 10–30 million people in the United States, mostly children, between 1955 and 1963 (30). It has not been determined whether simian virus 40 acting alone can cause mesothelioma (30). Our analysis does not indicate an increased risk in the 1955–1959 or 1960–1964 birth cohorts, those most likely to have received the contaminated vaccine (refer also to Strickler et al. (31)).

If all female cases of mesothelioma were unrelated to asbestos exposure, our analysis indicates that the lifetime background risk would be 3.6 x 10–4 (figure 3) and the current annual risk would be approximately 4 per million (over 5 per million if the population at risk is aged 20 years). These background risk levels would be upper bounds if a portion of female cases of mesothelioma were due to occupational, domestic, or unique high environmental exposures.

The background rates for females may not apply directly to males because the percentages of pleural and peritoneal mesotheliomas are different for men and women. In the SEER database, peritoneal mesotheliomas account for 7 percent of all mesotheliomas in males but 17 percent of all mesotheliomas in females. It is possible that peritoneal mesotheliomas in women are of two types but cannot be distinguished histologically: 1) those that are similar to mesotheliomas in males and 2) those that are unique, as evidenced in part by longer survival times of the cases (32; Andrew Churg, University of British Columbia, personal communication, 2002). On the basis of the differences between cases of mesothelioma in males and females, an adjustment to the background rates suggested above for females would be required if they were to be applied for males. For example, if all peritoneal mesotheliomas in females were excluded, the annual background rate for males would be 83 percent of the background rate for females.

The mesothelioma epidemic in the United States, which is beginning to recede, has been a consequence of ongoing high-level occupational exposure to asbestos from the 1930s through the 1960s in workplaces populated almost exclusively by males. Asbestos regulations promulgated by the US Occupational Safety and Health Administration (OSHA) in the early 1970s have led to dramatic reductions in exposure. These reductions are reflected in the pattern of mesothelioma incidence in the SEER data and were magnified through our modeling and analysis. It is unlikely that low environmental exposure to asbestos, or any other type of low-level asbestos exposure, is associated with more than a negligible risk of mesotheliom

Seeking Medical help

Mesothelioma can develop between 15 and 40 years or more after an exposure to asbestos. If you have been exposed to asbestos in the past and you start to suffer from any of the following symptoms you should visit your GP and mention your concerns:

* Pains in the lower back, abdomen or chest
* A persistent cough
* Breathing difficulties, shortness of breath or a feeling of tightness in the chest
* Rapid weight loss
* Problems with appetite or difficulty swallowing
* Sweating, fevers, diarrhoea or constipation
* Nausea or vomiting
* Swelling of the abdomen

Some people with mesothelioma have no symptoms at all in the early stages; therefore, if you know that you have been exposed to asbestos in the past and believe it may be the cause of your symptoms, it is always a good idea to visit a doctor for medical advice. Any damage caused by asbestos may be possible to detect with a scan or x-ray

Professions where asbestos was commonplace

At Thompsons Solicitors, we have helped many victims of asbestos to make mesothelioma claims. Due to the fact that we have dealt with so many of these mesothelioma claims we have seen a pattern develop showing the workers most at risk from developing mesothelioma and some of these are listed below.

Boilermakers and Laggers - It was commonplace for boilers to be insulated with asbestos lagging. Boilermakers also work alongside the contractors (laggers) who install and renew asbestos boiler insulation. This type of work has put boilermakers and laggers at a particularly high risk of developing mesothelioma.

Electricians - are at risk of developing mesothelioma because they also worked alongside laggers. Electricians also often have to cut or drill through asbestos insulation to install cable trays, instruments, switches and wiring systems.

Joiners and Carpenters and Builders - are also at risk of developing mesothelioma as a result of sawing, drilling and fixing or replacing asbestos cement board often used in partition walls, suspended ceilings, flooring, roof tiles and thermal insulation.

Motor Mechanics - may have been exposed to asbestos as it was frequently used in brake pads and clutches. This has put some Motor Mechanics at risk of developing mesothelioma.

Pipe Fitters and Plumbers - install, maintain and repair pipes, boilers and heating systems. The nature of their work means that they have to cut or drill through walls as well as cutting and assembling sections of pipe, removing and replacing damaged sections of pipe, valve and flanges etc. All of these tasks put them at risk of developing mesothelioma as pipes frequently used to be covered with asbestos lagging. As the pipes were cut, fibres from the asbestos lagging were released into the air and inhaled by the pipefitter or plumber.

Victims of mesothelioma are certainly not limited to the professions mentioned above. Our specialist mesothelioma solicitors have helped victims of this asbestos related disease with their mesothelioma claims who have worked in many other professions including fire fighters, teachers, police officers, managers and a professor.

Mesothelioma - Innovations in Treatment
Doctors and researchers are always on the lookout for new ways to treat malignant mesothelioma. The following innovations in treatment, while not a cure for malignant mesothelioma, show some promise in helping to treat the disease.

Mesothelioma - Alimta

Alimta, when given with another chemotherapy drug called cisplatin, is a chemotherapy drug recently approved by the FDA for the treatment of patients with malignant pleural mesothelioma.

Mesothelioma - Photodynamic Therapy

Photodynamic therapy uses special drugs and a special type of light to kill cancer cells during surgery. A drug that makes cancer cells more sensitive to light is injected into the patient’s vein several days before surgery. During surgery, a special light is used to locate the cancer. This treatment is being studied for early stages of malignant mesothelioma.

Mesothelioma - Immunotherapy

This type of treatment harnesses the power of the body’s own immune system. Immunotherapy is currently being researched as a treatment for malignant mesothelioma.

Mesothelioma - Gene Therapy

In studies of gene therapy for cancer, the goal is to improve the body’s natural ability to fight malignant mesothelioma directly or to make the cancer cells more sensitive to other kinds of therapy.

Mesothelioma - Brachytherapy

Brachytherapy is radiation therapy applied from within the body as opposed to from a machine outside the body. Radioactive sources are placed in or near the tumor, giving a high radiation dose to the tumor while reducing the radiation exposure in surrounding healthy tissues. This precision can help to minimize side effects.

Mesothelioma - Clinical Trials

A clinical trial (also clinical research) is a research study using human volunteers to answer specific health questions. Carefully conducted clinical trials help discover treatments that work in people and ways to improve health. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large groups of people or populations in natural settings. If you are interested in participating in a clinical trial, talk to your doctor about whether a clinical trial may be an appropriate option in your case.

Mesothelioma - Phase I

Phase I trials are considered the first step in testing the safety and efficacy of a new drug. Doctors and researchers are trying to determine many things about the drug’s effect on the disease and on the patient. Among the things that researchers are trying to determine are correct dosage, safety profile, and any side effects.

Mesothelioma - Phase II

At this stage, researchers select a relatively small group of patients to study the specific effects of the pre-determined dosage. Phase II studies also typically focus on a specific type of disease.

Mesothelioma - Phase III

During Phase III testing, researchers compare the effectiveness of the new, experimental drug against already existing therapies. Usually, patients are randomly assigned to therapeutic groups to cut down on the possibility of human bias. Phase III trials can be large, recruiting patients from across the country.