Treatment of Mesothelioma by Stage

Stage I: Many patients with stage I pleural mesothelioma have their cancer removed by pleurectomy/decortication or extrapleural pneumonectomy, as described in the section How Is Mesothelioma Treated. Patients with peritoneal mesotheliomas in an early stage might also benefit from surgery. The value of adjuvant chemotherapy or radiation therapy (treatments given after surgery) for stage I mesothelioma is being studied. Radiation therapy may be used if your general health is too poor to tolerate a major operation. Some doctors have had success with putting cisplatin into the thoracic space after the surgery. This can also be used in the abdomen for peritoneal mesothelioma.

Stages II, III: Treatment options include palliative and supportive care providing relief of symptoms, such as thoracentesis (to remove fluid accumulation in the chest cavity) along with pleurodesis, paracentesis (removing fluid from the abdomen), operations to remove as much of the tumor as possible in some cases, and radiation therapy or chemotherapy aimed at easing symptoms. Cure is usually not possible for patients in these stages. Enrollment in clinical trials evaluating the newest treatment possibilities in large medical centers should be considered. Some patients can have long remissions after extensive surgery by experts.

Other approaches include putting chemotherapy or radioactive drugs directly into the pleural space or abdominal cavity. This can be done simply with the doctor placing a needle into the pleural space or abdomen after numbing the skin with local anesthetic. Although this only kills some of the cancer cells, it often helps slow down fluid collection.

Stage IV: Because stage IV mesothelioma has spread to distant organs, a cure is not possible. The goals of using any aggressive therapy such as chemotherapy and radiation therapy should be clear to you and your family. You might want to consider enrolling in a clinical trial in a large medical center. These studies evaluate the newest treatment possibilities.

Supportive care may be the best choice, perhaps in the setting of a good hospice program. Pain management is an important aspect of your care. It is important for you to know that drugs are available to effectively treat pain due to mesothelioma. You should not hesitate to request pain medicines or discuss pain control problems with your cancer care team.

Malignant Mesothelioma Surgery

Surgery

Surgery for pleural mesothelioma may be done for 1 of 2 reasons: to relieve pain and discomfort caused by the tumor (called palliation) or to cure.

Palliative surgery is typically done in cases where the tumor has already spread beyond the mesothelium and is difficult to remove completely, or if you are too ill to tolerate a more extensive operation.

Curative surgery is offered if you are in otherwise good health and the tumor is thought to be localized and can be removed completely. Unfortunately, the cancer cells tend to spread into the chest wall, around the heart, over nerves, and the diaphragm. It is often difficult to detect this spread. Because of this, doctors are not clear on the exact role of surgery. It is not likely to cure you but may extend your life. Curative surgery is being done in some cancer centers and a few of the patients who have had the surgery are experiencing long remissions of their disease.

Depending on the stage of a mesothelioma, surgery may be used to remove the cancer and some of the surrounding tissue. Often, however, an operation is not appropriate and you may have only smaller procedures to relieve symptoms.

A thoracentesis, where fluid in the chest is removed by placing a needle into the chest cavity, may be done to make a patient more comfortable. Sometimes talc or drugs that cause scarring may be injected into the chest cavity to try to prevent the fluid from returning. This is called pleurodesis. These techniques are successful in controlling the fluid, at least temporarily, in as many as 90% of patients. Because pleural fluid can compress the lung and cause shortness of breath, these procedures can help you breathe more easily, however, they do not cure the cancer.

In the case of peritoneal mesothelioma, a needle may be inserted into the abdomen to drain the fluid. Similarly, a needle inserted into the pericardium (sac around the heart) can drain pericardial fluid and help relieve circulatory problems. Sometimes the cancer cells spread along the needle path, and a tumor nodule may form under the skin of that area. This concern should not prevent fluid removal, though.

Two surgical procedures may be offered if you have pleural mesothelioma: pleurectomy/decortication and extrapleural pneumonectomy.

Pleurectomy/decortication: Pleurectomy/decortication is usually a palliative procedure (relieves symptoms without curing the cancer) in cases where the entire tumor cannot be removed. This procedure removes the pleura, where the majority of the tumor is located. It can control the build up of fluid improve breathing and decrease pain caused by the cancer.

Extrapleural pneumonectomy: Extrapleural pneumonectomy is a far more extensive operation and is most often used in patients with localized mesothelioma of the epithelioid type, when the surgeon thinks a cure is possible. It is a difficult operation and is done only by surgeons in large specialized medical centers. You should talk with your doctor about an appropriate treatment center nearest to your home. The operation removes the pleura lining the chest wall, diaphragm, pericardium, and the whole lung on the side of the tumor. The diaphragm and the pericardium are then reconstructed with prosthetic material. You must be in overall good health with no other serious illnesses to tolerate the surgery. This operation attempts to remove all or most of the cancer and some surrounding tissues as well.

Surgical treatment of peritoneal mesothelioma is often done either to help relieve symptoms or to remove the tumor from the wall of the abdomen and other digestive organs. As with pleural mesothelioma, these tumors are often too extensive to remove completely. Similar operations can be done to remove a mesothelioma from the pericardium (the sac around the heart).

Surgery for mesothelioma of the tunica vaginalis testis, which occurs in the groin, is also not usually curative. Most of the time surgery is done because the tumor resembles a hernia. The surgeon attempts to treat a suspected hernia and only realizes the diagnosis after the surgery is begun. This kind of mesothelioma can’t be entirely removed.

Researches

basic research

The following projects emerged from years of interdisciplinary discussion and collaboration among researchers at the Brigham and Harvard Medical Area interested in mesothelioma. The strategic approach has been to build an integrated research effort among multiple disciplines each contributing to a different aspect of the program. All projects share access to patients, clinical samples, and a central database of patient and research data. Only patients who consent will be studied. Each project is ultimately designed to improve patient therapy and outcome.

The Epidemiology Project will collect patient history and exposure data to assess genetic susceptibility factors for development of malignant pleural mesothelioma (MPM). The basic science and preclinical projects (Growth Regulatory Lesions in Mesothelial Oncogenesis, Kinase Targets and Genomic-based Projects) will contribute to the biology of MPM development, discover and validate molecular markers or targets, and develop targeted therapies. The Clinical Management Project will attract patients, track outcome data, supply patient blood and tissue samples to the other projects, and assess new options for diagnostic tools, chemotherapy, surgery and post-treatment care. Synergistic progress is expected from the coordinated efforts of the proposed studies.

Abstracts of the Individual Projects

Epidemiology of Malignant Mesothelioma – Karl T. Kelsey, M.D.
e goal of this project is to conduct a comprehensive epidemiologic study of MPM to investigate the underlying disease etiology using both a case control and a case-series design. The case control study includes all incident cases of MPM identified through the Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. This project will recruit the base population for the entire program. We will administer a detailed risk factor, demographic and clinical questionnaire to both cases and controls that will be used to identify exposures and traints that increase the risk of MPM.

Tumor profiling, including assessment of epigenetic silencing, will be used to further our understanding of the mechanism of action of asbestos, asbestiforma materials and other exposures that may contribute to this disease.

Thus, the objectives of the proposed study are to further the understanding of the extent and etiology of malignant mesothelioma.

Growth Regulatory Lesions in Mesothelial Oncogenesis – James G. Rheinwald, Ph.D.
Our long-term objective is to characterize the mechanisms responsible for malignant behavior of mesothelioma, with a focus on identifying genes responsible for specific stages of neoplastic progression and critical oncogenes that confer aggressive tumorigenic behavior. We know little about the mechanisms by which the mesothelial cell, the normal progenitor of mesothelioma, acquires the ability to spread laterally, dedifferentiate, invade, and colonize distant sites within the body cavities.

The aims of this project are based on two lines of our previous research. One has used cell culture to discover mechanisms of growth regulation, replicative lifespan limits, the differentiation/ dedifferentiation process of normal human mesothelial cells, and autocrine mitogen-independence of mesotheliomas. The other line of research has used microarray hybridization and molecular biologic methods to identify a set of abnormally expressed genes in mesothelioma, which have proved to be of prognostic value, and also represent a set of candidate oncogenes that may be critical to the malignant behavior of this cancer.

Kinase Targets in Mesothelioma - Jonathan A. Fletcher, M.D.
The aims of the proposed studies are to make therapeutic advances in mesothelioma by characterizing kinase activation mechanisms in mesothelioma patients and by evaluating clinical regimens designed to circumvent these mechanisms.

This project will identify and evaluate activated receptor tyrosine kinase proteins as novel therapeutic targets in mesothelioma. Oncogenic receptor tyrosine kinases play key roles in the pathogenesis of many types of cancer, and they have emerged recently as compelling therapeutic targets, particularly when activated by genomic mutations resulting in kinase sequence alterations or overexpression. These therapeutic developments have prompted the large-scale validation of small molecule, peptide, and immunological inhibitors of various receptor tyrosine kinase proteins with suspected roles in tumorigenesis. EGRF and MET have been implicated as potential receptor tyrosine kinase targets in mesothelioma, and our own preliminary proteomic and in vitro studies suggest that AXL can also be activated strongly in mesothelioma.

The overall aim of this project is to discover oncogenic kinase targets (both receptor and non-receptor tyrosine kinases), and to determine whether such kinases serve as appropriate therapeutic targets for patients with mesothelioma. This project is highly translational in that the objective is to identify drug targets that are evaluable in the near-term in clinical trials.

Genomic-based Prognosis, diagnosis, and Development of Novel Therapeutic Strategies in Mesotheleioma - Raphael Bueno, M.D.
Malignant Pleural Mesothelioma (MPM) is a highly malignant neoplasm for which therapy is inadequate. We have studied gene expression in MPM with microarrays and developed diagnostic and predictive tests for patients undergoing surgery for this disease using the gene ration methods. We also discovered that the anti apoptotic gene IAP-1 mediates chemotherapy resistance in mesothelioma cell lines. In this project we plan to test our diagnostic and prognostic tests in tissue biopsies obtained from patients enrolled in the clinical projects of this program project. We hope to identify the best predictive and diagnostic test for each of the therapies and at the same time discover new targets for research.

We will also work on elucidating the mechanism by which IAP-1 mediates cisplatin resistance in MPM cell lines. We will determine if any additional anti apoptotic genes mediate such resistance and then construct cell line models to test inhibitors of involved pathways with the hope of identifying new targets for therapy. This approach will also be used for other potential targets discovered during our microarray analysis.

Lung Cancer Diagnosis

Diagnosis

Chest x-rays may not show a tumor but may show other clues that indicate a problem related to lung cancer. An x-ray may show spots or images suggestive of fluid accumulation, masses, enlarged lymph nodes or pneumonia.

A chest CT (Computerized Axial Tomography) is a more precise way of studying chest anatomy. Both chest CT and MRI (magnetic resonance imaging) scans use computers to produce highly detailed cross-sectional (slices) images of the body. They can show 3-dimensional images that help determine the size, shape, and location of a tumor. A CT scanner uses fine streams of X-rays taken from many angles to produce picture of anatomical details within a "slice" through the person. Magnetic Resonance Imaging (MRI) does much the same thing, but using magnetic and radiowave fields.

PET (Positron Emission Tomography) scanning is different from CT and MRI scanning. A CT or MRI scan shows only structural details of the tissue, whereas the PET scan provides a color-coded image of the tissue’s function.

Simple sugars, labeled with radioactive tracers, are injected into the body intravenously (or inhaled as a gas). All cells pick up the sugar, but since tumor cells are metabolically more active than normal cells, a larger concentration of the radioactive sugar will accumulate in them. The PET scanner picks up the radiation given off by the sugar as it journeys through the body and collects in the targeted tissue (the tissue ‘lights up’ called a ‘hot spot’). A computer reassembles the signals into actual images and shows in fine detail the metabolism of the sugar in the tumor cells. PET can tell you whether a tumor is benign or malignant, the extent of the disease, and if the tumor has spread or has recurred.

PET/CT is a new technique that fuses PET and CT technologies into a single device. The PET scan picks up the metabolic activity in the body, and the CT scan provides a detailed picture of the body’s structure. By taking the pictures simultaneously, the two images are overlaid so that the tumor "hot spot" on the PET scan corresponds directly to the physical mass on the CT scan, thus eliminating the visual side-by-side comparison. This new technology has the potential to substantially impact treatment plans for many patients.

A sputum (mucus coughed up from the lungs) sample can be used to look for the presence of cancerous cells. If there are cancer cells in the bronchi, some of these cells are likely to be shed and carried up the throat in the sputum.

A Bronchoscopy involves the use of a bronchoscope to directly view the airways into the lungs. A bronchoscope is a small tube that is inserted through the nose or mouth, down the throat, and into the bronchi (the small tubes that go into each lung). During the procedure, the surgeon may remove some tissue for analysis. Local anesthesia and mild sedation are generally used to make the patient comfortable during the procedure

A biopsy involves obtaining a small piece of tissue and examining it under a microscope. A biopsy is necessary to confirm a cancer diagnosis and to identify the specific type of cancer and its stage. To examine areas of the lungs that are not accessible during a bronchoscopy, physicians may perform a needle biopsy (called "fine needle aspiration" or FNA) to remove a small sample of tissue for analysis. Sometimes, surgical biopsies of the lung may be performed. If a surgical biopsy is needed, the surgeon will perform the surgery through an incision in the chest so that all or part of a tumor and/or lymph nodes can be removed.

Palliative therapies

Palliative care addresses physical, psychological, social and spiritual sources of distress for patients with advanced or life-threatening disease and their families. The goal of palliative care is to provide comfort and to maintain the highest possible quality of life for as long as life remains.

Those diagnosed with mesothelioma experience a variety of different symptoms. Often, the level of pain experienced with mesothelioma is very high. Pain control is usually one of the first symptoms addressed with mesothelioma palliative care. Palliation can include the traditional pain management programs, such as prescribing several different pain medications, but it also can focus on behaviour modification, stress management, meditation, or even massage therapy. Palliative surgery can be done to reduce pain caused by the tumor or to prevent fluid from accumulating. Studies have shown that radiation therapy is useful in relieving pain due to mesothelioma. Palliative care can be a sound choice to increase the remaining quality of life for patients who suffer from mesothelioma.

At the Brigham and Women’s Hospital, patients will have the opportunity to enrol in a quality of life protocol in which patients will undergo bi-weekly palliative care assessment and symptom management. Patients will be assessed and treated by skilled palliative care practitioners, teaming with the oncology team, anesthesia pain specialists and psychologists. The techniques and methods are available to make sure that every patient with mesothelioma can have adequate pain control at any stage of the disease.

Mesothelioma surgery

Treatment of mesothelioma depends on a number of factors, which include the stage of the cancer, the cancer’s location, how far it has spread, and the patient’s age and general health. Some surgical procedures treat the symptoms while others attempt to remove the diseased tumor.

Radiation therapy

Radiation therapy uses high-energy rays to damage or kill cells by preventing them from growing and dividing. It is delivered to the site of the tumor by machines called linear accelerators, which produce high-energy external radiation beams that penetrate the tissues deep into the areas where the cancer is located. This technique is called external beam radiation therapy (EBRT). Radiation therapy also can palliate the symptoms of mesothelioma by reducing pain, improving breathing, or relieving other side effects caused by the cancer.

Factors that can limit the application of this treatment include the volume of the tumor and how near it is to vital organs. Radiotherapy following surgical resection (adjuvant therapy) has been shown to reduce local cancer recurrence and improve the survival of patients with early-stage disease and is an essential part of the management of patients undergoing extrapleural pneumonectomy.

EBRT is delivered precisely by using computed tomography (CT) scan as well as PET scans to localize the areas at risk for tumor recurrence. Careful radiation planning allows for a higher dose of radiation to be directed at the tumor tissue and at the same time, decreasing the volume of normal tissue exposed to this high dose. Our faculty in radiation oncology has over 15 years of experience in treating mesothelioma patients with radiotherapy.

Intensity-modulated radiation therapy (IMRT) is a novel breakthrough in radiation oncology. It allows treatment of areas that were previously out of the reach of conventional radiation. IMRT for mesothelioma is available @ BWH one of the few sites in the country where this technique has been perfected. It requires a treatment team composed of radiation oncologist, physicists and radiation therapists to deliver. The state of the art machinery available here @ BWH represents the top-of the line in radiation delivery equipment. Preliminary data indicates significant improvements in local recurrences for mesothelioma patients undergoing this treatment.

New clinical trials investigating the optimum method for combining chemotherapy and radiation are underway at BWH/DFCI.