Malignant mesothelioma rate survival

Malignant mesothelioma is an uncommon and usually fatal cancer, for which there is no standard treatment. However, surgical resection remains the mainstay of treatment because of the inability to treat the entire hemithorax effectively with radiation and the lack of effective chemotherapy drugs. Extrapleural pneumonectomy is the only technically feasible operation for patients who have bulky local tumor and chronic entrapment of the lung, but pleurectomy/decortication is associated with a lower operative morbidity and mortality, and seems to lead to an equally good survival in patients who have early-stage disease. Because of the high risk of local recurrence after surgical resection by either extrapleural pneumonectomy or pleurectomy/decortication, efforts have been directed at developing effective adjuvant treatment. Radiation given postoperatively after pleurectomy/decortication has led to a minimal improvement in survival and to significant side effects. Adjuvant chemotherapy is considered investigational but is currently being evaluated in a clinical trial using high-dose intrapleural and systemic chemotherapy after pleurectomy/decortication. Additional well-designed prospective trials are needed to alter the dismal outcome of this disease.

Combined-modality therapy with extrapleural pneumonectomy, adjuvant chemotherapy and radiation is discussed by Dr. Sugarbaker in this issue, and this paper addresses the use of pleurectomy/decortication and adjuvant therapy for malignant mesothelioma. It is still unclear whether the type of operation performed influences overall survival. Both extrapleural pneumonectomy and pleurectomy/decortication allow the removal of all gross tumor in carefully selected patients. Neither procedure should be considered a curative cancer operation, because the margins of resection are vital structures (eg, esophagus, spine, aorta) that cannot be removed en bloc with the tumor.

NATURAL HISTORY OF MALIGNANT MESOTHELIOMA

Several issues are worth emphasizing before proceeding to a discussion of pleurectomy/decortication and adjuvant therapy. The value of any cancer treatment must be viewed within the context of the natural history of the disease. In malignant mesothelioma, there is some variation in the reported length of survival with supportive care alone. For example, Law et al[1] reported a median survival of 18 months from the onset of symptoms in 64 patients treated with supportive care. In contrast, Hulks et al[2] reported median survivals of less than a year from the time of diagnosis in 68 patients, depending on whether the presenting symptoms were shortness of breath (median survival, 44 weeks) or chest pain (median survival, 22 weeks). The discrepancy between these 2 series may be explained by the fact that the symptoms of malignant mesothelioma are insidious and nonspecific. It is difficult for patients to pinpoint their onset, and diagnosis is often delayed for 3 to 6 months. In most reported series, survival from the time of diagnosis is less than a year for patients treated with supportive care alone.

Our ability to evaluate treatment regimens in malignant mesothelioma is limited by our poor understanding of its natural history and prognostic factors and by the lack of an accurate, universally accepted staging system.[3] The several proposed staging systems are based on imprecise descriptors of the local extent of the tumor ("T status") and nodal involvement ("N status"). None has been verified by clinicopathologic correlation. Without an accurate staging system, it is almost impossible to compare the results of various treatment regimens. Our knowledge of malignant mesothelioma is also limited by the fact that most of the reported series are retrospective because it is an uncommon neoplasm. There have been few large, prospective clinical trials.

The major initial problem in malignant mesothelioma is local control of intrathoracic tumor. However, several autopsy series have shown that at least half of all mesothelioma patients ultimately develop metastases in sites as diverse as the thyroid, prostate, spine, and brain.[4,5] Therefore, patients face the dual threat of local and distant disease, and any treatment regimen should try to address both of these problems.

FACTORS INFLUENCING TREATMENT OF MALIGNANT MESOTHELIOMA

The treatment of mesothelioma is also influenced by several other factors. These patients are usually older (over age 50) and often have concomitant medical problems. Their cancer is not caused by smoking, but many of them have been smokers and have coronary or peripheral vascular disease. Because of smoking and asbestos exposure, patients often have impaired pulmonary function with a combination of obstructive and restrictive lung disease. Hearing loss is common because many patients have worked in industries (eg, shipbuilding or construction) where noise levels are high. This restricts the use of some chemotherapeutic agents such as cisplatin. Mesothelioma patients are often unable to tolerate extensive operations or aggressive combined-modality therapy.[4,6]

Currently available treatment for malignant mesothelioma has several shortcomings. As discussed earlier, surgical resection allows the complete removal of all gross tumor but cannot provide microscopically negative margins. The use of radiation is limited by the huge volume of the tumor and the intolerance to radiation of adjacent intrathoracic organs.[7] As Dr. Antman et al[8] pointed out, there are few active chemotherapeutic agents. The best reported response rates have been seen with the combination of either cisplatin and mitomycin, or cisplatin and doxorubicin and are only in the 20% to 30% range. By default, surgical resection remains the mainstay of treatment.

SURGICAL MANAGEMENT

Pleurectomy/decortication entails removing all gross pleural tumor while leaving the lung in place. Along with this, it is often necessary to resect the pericardium and diaphragm, and to reconstruct them, just as is done in an extrapleural pneumonectomy. This can be an extremely tedious operation, but if performed carefully in appropriately selected patients, it allows as complete a removal of tumor as does an extrapleural pneumonectomy. However, in patients who have a thick, confluent tumor peel, obliteration of the pleural space and chronic encasement of the underlying lung, tumor may not be completely resectable by pleurectomy/decortication. In these cases, extrapleural pneumonectomy is the only technically feasible operation.

There have been few large-scale prospective clinical trials in malignant mesothelioma, especially with respect to the relative value of extrapleural pneumonectomy and pleurectomy/decortication. In 1985, the Lung Cancer Study Group initiated a prospective trial to evaluate extrapleural pneumonectomy.[6] The objectives of this study were to determine the proportion of patients with malignant mesothelioma who might be candidates for an extrapleural pneumonectomy; to determine the mortality and the morbidity of this procedure in a multi-institutional setting; to assess the impact of extrapleural pneumonectomy in the absence of adjuvant therapy on survival; and to examine the patterns of relapse after this procedure. Patients were eligible if they had biopsy-proven malignant mesothelioma, as confirmed by immunohistochemistry and/or electron microscopy. Patients were considered for an extrapleural pneumonectomy if they did not have significant underlying cardiovascular disease and had a predicted postresection [FEV.sub.1] of at least 800 ml/s. Patients who did not qualify for an extrapleural pneumonectomy received treatment at the discretion of their physician. All patients were followed postoperatively by serial computed tomography scans every 3 months.

Over a 2 1/2 year period, 83 patients were entered into this trial. Only 20 of the 83 patients underwent an extrapleural pneumonectomy. Thus, this treatment appears to be an option for a select subset of mesothelioma patients. In the registry arm of the study, there were 26 patients who had a limited operation (usually a pleurectomy/decortication), and 37 patients who were not deemed candidates for any operation whatsoever.

Three of the extrapleural pneumonectomy patients died postoperatively, for an operative mortality rate of 15%. Causes of death included pulmonary embolus in 1 patient and respiratory failure in the other 2 patients. As Dr. Sugarbaker has noted in his paper, operative mortality rates as low as 5% have been reported in single-institution studies, where patients are probably more carefully selected for this operation and fewer surgeons are involved in doing the operations.[9,10] Extrapleural pneumonectomy is more complex than a standard pneumonectomy, and individual technical experience will greatly influence the operative mortality rate.