Learn more about the Center for Mesothelioma and Asbestos-Related Diseases
Petr F. Hausner, M.D., Ph.D.
Chief, Hematology/Oncology, Baltimore Veterans Affairs Medical Center
Assistant Professor of Medicine, University of Maryland School of Medicine
Malignant pleural mesothelioma (MPM) is an uncommon, mostly incurable cancer originating in the parietal pleura. Its etiologic agent is known, pathogenesis is complex, diagnosis in most cases delayed and prognosis unreliable. Modern therapy of mesothelioma is multimodal, with surgery and chemotherapy occupying central stage. There is hope, that with better understanding of its cellular and molecular pathogenesis novel treatment approaches could be introduced.
Asbestos exposure is documented in only 50-80% of patients with MPM, though crystals of the amphibole (straight, rod-like) crocidolite were found on the pleura of most patients with mesothelioma (Suzuki and Yuen 2002). Inhaled asbestos fibers brake through alveoli and eventually concentrate in “milky spots” of the parietal pleura (Boutin, Dumortier et al. 1996) which are most prevalent in intercostals spaces of costovertebral gutters. Milky spots or anthracotic “black spots” are subserosal collections of macrophages and lymphocytes located on lymphatic capillaries. These cell collections are traversed by specialized post-capillary venules, suggesting resemblance to lymph nodes. Mesothelial cells covering milky spots have stem cell properties, they are cuboid, their connections to surrounding cells incomplete, leaving open access routes to the subserosal connective tissue. It is likely that macrophages activated by indigestible asbestos fibers produce cytokines which induce the proliferation of mesothelial cells covering milky spots while reactive oxygen produced by the same macrophages contributes to DNA damage. Moreover, effusion fluid originates in milky spots and is absorbed through milky spots. Mesothelioma cells metastasize to milky spots where they gain access to subserosal connective tissue through the gaps between mesothelial cells.
Malignant transformation of mesothelial cells might be assisted by the Simian Virus 40 (SV40), a small, 5,243 bp circular ds DNA virus, which drives cells into replication by its small t-antigens’ ability to bind Rb and large T-antigens’ ability to blocks their death through its binding to p53. SV40 was found in most mesotheliomas in the USA (Carbone, Pass et al. 2003) and is likely contributing to the malignant transformation leading to mesothelioma by driving mesothelial proliferation and possibly by upregulating the expression of VEGF receptor (Catalano, Romano et al. 2002).
Once transformed, mesothelioma cells metastasize into other milky spots of the parietal pleura (explaining why mesothelioma appears to develop initially in a multifocal fashion), and to sites where the subserosal connective tissue matrix of the parietal or visceral pleura was made accessible by inflammation or mechanical erosion. Once adhering to the connective tissue matrix, mesothelioma induces brisk angiogenesis and desmoplasia. The growth of mesothelioma is further driven by growth factors emanating from irritated pleural cells and macrophages (PDGF, IL-6, IL-8, TGF-?,VEGF, VEGF-C etc). Mesothelioma is locally invasive (MMP, tenascin C), metastasizes to regional lymph nodes and in the late stages of the disease distantly.
The unilateral pleural effusion, which is the hallmark of mesothelioma remains often undiagnosed unless a cell block is prepared from at least 500 ml of fluid and examined immunohistochemically. Staining for calretinin (+), WT1 (+), cytokeratin (5/6+ and 7,8,18 and 19-), EMA (+),TTF-1 (-), CEA (-), Ber-EP4 (mostly-), MOC-31(-) will help to distinguish mesothelioma (+) from adenocarcinoma (-) (Ordonez 2003). Staining for desmin helps to distinguish reactive mesothelial proliferations (+) from mesothelioma, an important distinction (Attanoos, Griffin et al. 2003). A videoassisted thoracoscopy helps to identify pleural disease, yields generous amounts of malignant tissue for ultimate diagnosis, and identifies the presence of early T stage.
The differentiation pathway of the cancer cell, which can be established by histology as epithelial, mixed (biphasic), or sarcomatoid is the most important prognostic characteristic of the tumor, ability to induce angiogenesis another one. Patients with mesotheliomas whose SUV is less than 4 in a FDG PET scan have a survival of 24 month, whereas those with SUV > 4 have a survival of 14 month, independently on histology. Clinical stage, location and other patient characteristics such as performance status and sex (female beneficial) follow. The extent of pleural inflammatory reaction can be judged from the white blood cell count and platelet count (high counts portent poor prognosis). About 10% of mesotheliomas have a good prognosis, which can be best predicted from a slow growth rate.
The major purpose of staging in MPM is to identify patients who might benefit from surgery. The emphasis of the International Mesothelioma Interest Group (IMIG) staging system is therefore on early disease. The survivals of patients with stages higher than stage I is equally dismal. Parietal plaques only (T1a) or if accompanied by minimal local involvement of the visceral pleura (T1b) constitute T1 and stage I (SI). Confluent involvement of the parietal pleura including fissures, with or without lung involvement or diaphragmatic muscle involvement constitutes T2 and SII. Invasion into the endothoracic fascia or mediastinal fat, resectable chest wall involvement and nontransmural involvement of the pericardium defines T3 and Stage III (alternatively triggered by hilar lymph nodes positive for cancer - N1 or ipsilateral mediastinal lymphadenopathy - N2). More advanced disease that is all patients with T4 or N3 or M1 have stage IV disease.
Staging is best done by computerized axial tomography (CT). Positron emission tomography (PET) though positive in nearly all patients with mesothelioma, does not help in defining the extent of pleural disease (Flores, Akhurst et al. 2003). The major contribution of PET might be its ability to rule out distant metastases (Flores, Akhurst et al. 2003). PET may be falsely positive at sites of talk accumulations from pleurodesis. MRI assists the evaluation of both endothoracic fascia and diaphragmatic invasion. With gadolinium enhancement staging accuracy can be improved. Endoscopic ultrasound could identify mediastinal lymphadenopathy, but a mediastinoscopy would sample lymph nodes best and thus define the nature of mediastinal lymphadenopathy if critical. Patient characteristics are reflected in the performance status and in a recently developed prognostic index.
Very early disease T1a could be treated by pleurectomy/decortification. There is a high rate of local recurrence and no 5 year survivors. It is unclear, whether survival could be improved by adjuvant radiotherapy or chemotherapy, neoadjuvant therapy, radiation, intrapleural chemotherapy or brachytherapy etc. Thus, pleurectomy/decortification is often performed for symptom palliation and where extrapleural pneumonectomy appears not to be feasible during a planned extrapleural pneumonectomy. Hyperthermic perfusion utilizing intrapleural cisplatin at a dose up to 225 mg/m2 and i.v. thiosulfate rescue was shown in a recent phase I study to be safe and effective in extending survival.
Extrapleural pneumonectomy for stage I and II induces long term survival in about 20% of patients. Careful selection of patients utilizes premorbid exercise capacity, absence of bronchitis or astma (Butchart 1999). It is a surgery riddled with mortality, particularly if done in the right hemithorax and out of skilled centers. Extrapleural pneumonectomy is often done as part of multimodality therapy, including chemotherapy – intrapleural hyperthermic and cisplatin based, radiation to the operated hemithorax, and systemic adjuvant chemotherapy. Under optimal conditions in patients with epithelial histology, stage I, absence of mediastinal lymphadenopathy, negative surgical margins a 46% survival can be achieved according to Dr. Sugarbakers’ series (Sugarbaker, Flores et al. 1999).
Until recently, chemotherapy could only show a roughly 20% response rate, with doxorubicin (14% RR as single agent), vinorelbin (24%) (Steele, Shamash et al. 2000), cisplatin 14% when given at regular once every 3 weeks doses but 36% when given at 80 mg/m2 once a week (Planting, Schellens et al. 1994) and high dose methotrexate (41%) being the best approved drugs. Pemetrexate (ALIMTA), an inhibitor of multiple enzymes of the folate pathway (TS, DHFR, GARFT), showed a 14% single agent response rate (Scagliotti, Shin et al. 2003), but in combination with cisplatin, which achieved a 17% single agent response rate in the control arm, pemetrexate accomplished in a large phase III study a 40% response rate and a 3 month survival advantage compared to cisplatin alone (12.1 versus 9.3 months) (Vogelzang, Rusthoven et al. 2003). Pemetrexates’ toxicity was found to be high in the absence of folate and can be substantially diminished by oral folate and intramuscular vitamin B12 administration. The combination of cisplatin and pemetrexate is available on a compassionate basis in the community. ALIMTA based chemotherapy improves quality of life, in particular pain dyspnea and cough well before other symptoms are aleviated or response documented. Though single agent gemcitabine had response rate varying in different studies from 0% to 38%, it had a negative CALGB trial, but was found to be active against mesothelioma in combination with cisplatin, and possibly carboplatin. A phase II trial utilizing gemcitabine and pemetrexate is underway and open in our institution. The same chemotherapy combination is available on study in a neoadjuvant setting, given before a planned extrapleural pneumonectomy. This study is also open in our institution. Other novel chemotherapy combinations are promising e.g. raltitrexed (Tomudex) with oxaliplatin (Fizazi, Doubre et al. 2003).
Multiple attempts of active and passive immunization are underway. In an attempt to stimulate the immune system, an adenoviral construct containing the gene for interferon-??is given through a single chest tube instillation to eligible patients with a patent pleural cavity (Daniel Sterman’s trial open in Pennsylvania Medical Center). A trial of an anti-mesothelin antibody conjugated to pseudomonas aeruginosa immunotoxin is underway at the National Cancer Institute in Bethesda. Patients who have failed different other regimens are eligible.
Thalidomide, an antiangiogenic agent active in multiple myeloma is being evaluated in a phase II clinical trial available to patients with a performance status of 0 or 1, who are not eligible for surgery. Though beneficial in our preliminary experience and two already reported studies in terms of disease stabilization, no clear benefit could have been documented so far in our study, which is approaching its accrual goal.
It is difficult to administer radiation therapy to patients with mesothelioma because the involved pleura constitutes a very large volume for radiation if treated together with the whole lung and mediastinum. But, there is a role for radiation in preventing malignant seeding after invasive diagnostic procedures or thoracocentesis. Seven Gy administered daily in three consecutive sessions was shown to reduce track seeding from 40 % to 0% in a small randomized trial (Boutin, Rey et al. 1995). There might be a role of brachytherapy for positive margins after decortication/pleurectomy. Radiation to the involved hemithorax after pleuropneumonectomy is tolerable and therefore utilized as part of multimodality therapy e.g. 30 Gy in 1.5 daily fractions. Positive lymph nodes are treated in 2 Gy fractions to 54 Gy.
About 10 to 20% of patients treated with extrapleural pneumonectomy are alive and without evidence of disease 5 years after surgery. To improve further these statistics, chemotherapy and radiation have been added. Unfortunately many different chemotherapeutical regimens were utilized, currently paclitaxel 200 mg/m2 given together with carboplatin at an AUC of 2 every three weeks twice, followed by paclitaxel and carboplatin reduced to 1/3 of the original dose given weekly concurrently with radiation, followed by two cycles of full dose chemotherapy given every three weeks (Sugarbaker, Acherman et al. 2002). Unfortunately, paclitaxel has zero single agent activity and carboplatin might be less active than cisplatin. The radiation used as part of trimodality therapy is described above. There is little doubt that taxanes will be in the future replaced by pemetrexate in this indication.
Many attempts were made in the past at treating mesothelioma with intrapleural applications of chemotherapy ranging from single agent cisplatin administration to protracted perfusions with hyperthermic hypotonic fluids containing one or more cytotoxic agents (cisplatin, doxorubicin, liposomal doxorubicin, mitomycin C etc.). Some of these techniques might turn out to be useful for palliation.
Palliation of symptoms is an important part of mesothelioma therapy. Intractable pain will replace the initial dull pressure after the cancer has penetrated into intercostal nerves. NSAIDs often relieve pain well in the beginning, opiates and adjuvant medications (e.g. amitriptylin) have to be added later. Shortness of breath due to fluid accumulation can alleviated by drainage, chest tube placement with talk pleurodesis or if the lung does not appose to the chest wall, which is common, by inserting a tunneled “Pleurex” catheter. Such a catheter will be left in place for weeks during which it drains the chest slowly, allowing gradual lung expansion. The catheter will eventually cause autopleurodesis, after which it can be removed.
Though slow, there is progress in the understanding of the biology of mesothelioma. Modern imaging techniques contribute to staging, while immunohistology and molecular biology will sharpen the diagnosis and assist in prognosis. Treatments based on previous trials and developed through understanding of the pathogenesis of MPM together with all the experience oncology has acquired in more common diseases will help to formulate the most burning questions for next clinical trials.