Mesothelioma radical treatment

The incidence of malignant pleural mesothelioma is increasing. Untreated, patients with this disease experience a rapid and horrendous clinical decline. Surgery plays a role in the diagnosis, staging, and treatment of this malignancy. Surgery, chemotherapy, and radiotherapy alone have been unable to achieve major improve ments in survival for most patients. More recent phase II trials suggest that surgery, at one time a purely palliative approach, may have a potentially curat ive role when used in combination with chemotherapy and ra diotherapy.

(CHEST 1995; 107:345S-350S)

Malignant pleural mesothelioma is an uncommon yet devastating malignancy. The National Cancer Institute Cancer Statistics Branch reports the incidence of invasive mesothelioma has steadily increased from 0.5 cases per 100,000 population in 1975 to 0.9 cases per 100,000 population in 1990.[1a] This translates to a modest increase from the 1,500 cases diagnosed in 1986.1b Additionally, there is a geographic maldistribution of cases in the United States, with an incidence in some areas of New England four times greater than the national average.[2]

Asbestos exposure has been causally linked to diffuse malignant pleural mesothelioma. Owing to its unique combination of pliability and heat resistance, asbestos was commonly used as an insulating agent prior to 1970. An estimated 8 million workers in the United States have been exposed to asbestos in the workplace.[3] Additionally, the families of workers have been frequently exposed to fibers embedded in work clothes or to insulation in schools and playrooms. The peak incidence of mesothelioma occurs 35 to 45 years after exposure.[3] Because the danger of asbestos was not recognized until the 1960s,[4,5] a continued increase in the annual incidence of the disease is expected into the next century.

At our institution, the typical clinical presentation of malignant pleural mesothelioma occurs in male smokers in their 40s to 60s who have had a remote occupational exposure. In New England, many patients were exposed to asbestos in construction or the shipbuilding industry prior to government restrictions in the 1970s.[6]

The disease is characterized by an insidious onset of symptoms, with a rapid and progressive decline in health after diagnosis. Malignant pleural mesothe lioma is a relentless local disease. Patients ralely dieof complications of systemic spread, but instead die because of failure of local control. Median survival of untreated patients is 4 to 12 months.[6-11]

Three cell types of pleural mesothelioma have been identified. Epithelial cell type has been associated with a better prognosis both with and without treatment.[12-14] Sarcomatous cell type has been associated with a worse outcome. The mixed-cell tyype, or biphasic pattern, contains elements of both the epithelial and sarcomatous cell types and may behave like the sarcomatous variety.[13,15]

The first challenge in evaluating a patient suspected of having diffuse malignant pleural mesothelioma is to establish a clear histologic diagnosis. Reactive mesothelial cells seen with pleural needle biopsy specimens and pleural fluid cytologic studies can be difficult to distinguish from cancerous mesothelioma cells. In addition, the epithelial va-iant of mesothelioma can be difficult to distinguisl from subpleural adenocarcinoma or small cell carcinoma, tumors with very different treatment option.[3] Video-assisted thoracoscopy has been very usefu, in obtaining a sufficient pleural biopsy specimen to establish clearly the diagnosis.

SINGLE-MODALlTY TREATMENTS OF PLEURAL MESOTHELIOMA

Surgery

Surgery has been used to establish a pathologic diagnosis, palliate symptoms, and to resect gross tumor in an effort to cure the patient with malignant pleural mesothelioma.

Extrapleural pneumonectomy has been applied as a single-modality treatment for diffuse malignant pleural mesothelioma; reports of this treatment are summarized in Table 1 [12,14, 16-18] In general the operative mortality rate in these reports was high, ranging from 9 to 31%. A lesser surgical procedure, parietal pleurectomy without pneumonectomy, has been associated with an improved operative mortality rate of between 1.5 and 5 4%.19-21 Although both operations appear to offer a period of local control, neither provides a substantial improvement in overall survival when applied as a single-modality treatment to this disease.

[TABULAR DATA 1 OMITTED]

Radiation Therapy

Because the entire ipsilateral pleural surface is at risk for involvement by diffuse malignant pleural mesothelioma, the entire ipsilateral hemithorax is treated with radiation therapy (RT). The dose-limiting thoracic structures are the spinal cord (45 Gy), heart (45 Gy), and hlng (20 Gy).[22] Thus, safe thoracic radiation doses are below the 60- to 70-Gy doses thought to be necessary to control 3-cm masses of solid tumor.[6] The smaller doses, however, may be effective in controlling microscopic disease after surgical debulking. Small series[12,23] using RT as palliative single-modality therapy have reported symptomatic relief without a significant improvement in survival in patients receiving more than 40 Gy.

If RT is used as adjuvant therapy after debulking, 40 to 45 Gy should be delivered to the entire hemithorax, with a 5- to 5.5-Gy boost to areas at high risk for recurrence. When the lung is not included in the resection (as after pleurectomy), tangential fields need to be used to prevent severe radiation pneumonitis.6 When a pneumonectomy has been performed, a shift of the abdominal viscera into the inferior hemithorax may limit the safe dose to 30 Gy.

Chemotherapy

Single-agent doxorubicin has produced response rates of 0 to 40% in patients with malignant mesothelioma; similarly, response rates for chemotherapy combinations have only been 40% or less.24 In a randomized multi-institutional trial of cisplatin and doxorubicin vs cisplatin and mitomycin, the Cancer and Leukemia Group B reported response rates of 13% in both treatment arms.25

Supportive Care

The failure of individual modality treatme lts in controlling diffuse malignant pleural mesotheLioma has contributed to a nihilistic outlook on the part of many caregivers. The poor overall results and considerable toxic reactions associated with these treatments have led many authors to recommend supportive care alone for these patients. However, the natural progression of this disease is horrible to witness.

Patients treated with supportive care alone generally suffer from recurrent pleural effusions, dyspnea, and orthopnea. Fever combined with an enlarging tumor burden leads to profound cachexia, malaise, and weakness. Thoracentesis grants a reprieve of pulmonary symptoms for a few days, but further depletes the patient of protein. Pleurodesis ii frequently unsuccessful or only partially successful. As the affected lung becomes encased in tumor, a significant ventilation/perfusion mismatch dev lops, leading to unrelenting orthopnea. Patients c1nnot sleep due to the sensation of smothering and soon have no ability to care for themselves. Some develop chest wall pain that responds poorly to high-dose narcotics. The side effects of the narcotics frequently contribute to the misery of the patient and the frustration of the family.

MULTIMODALITY TREATMENT

The failure of single-modality therapy to treat successfully malignant pleural mesothelioma has led to pilot studies of multimodality treatments. Since 1985, we have used an aggressive trimodality protocol combining extrapleural pneumonectomy with sequential postoperative chemotherapy (doxorubicin, cyclophosphamide, and cisplatin for four to six cycles) and up to 55 Gy adjuvant RT to the postoperative hemithorax.[13] The treatment plan is summa rized in Figure 1. Although a toxic regimen, it offersthe best chance of a long-term disease-free interval for a subgroup of patients.

Extrapleural pneumonectomy within this context is not meant as a curative procedure, but as a cytoreductive procedure. Its use in combination with two other modalities will, it is hoped, produce symptomatic relief, a long disease-free period, and possible cure for the individual patient. It entails the removal of the entire lung with its pleural envelope, along with the ipsilateral pericardium and diaphragm.

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