Mesothelioma of the Pleura*

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1 Current Approach to Malignant Mesothelioma of the Pleura* Joseph Aisner, MD Malignant mesothelioma of the pleura occurs primarily in individuals who were exposed to asbestos either in the workplace or home. The incidence of malignant mesothelioma is rising and, reflective of the malignancy's long latency period, is expected to continue to increase into the next century. Current treatment measures, including surgery, radiation therapy, chemotherapy, intrapleural therapy, and combined-modality therapies, have had varying impacts on survival. This paper explores current trends in the treatment of malignant pleural mesothelioma. (CHEST 1995; 107:332S-344S) Tumors of the pleura comprise a diverse and difficult group of diagnostic and management problems. The more commonly seen tumors metastatic to the pleura can originate from various different primary cancers. The rare primary tumors can present as either localized or diffuse tumors. The localized tumors tend to be benign whereas the diffuse tumors, primarily mesotheliomas, are usually highly malignant. The clinical approach to the management of malignant pleural mesothelioma has generated considerable interest. MALIGNANT PLEURAL MESOTHELIOMA Epidemiology Malignant mesothelioma has been closely associated with asbestos exposure ever since it was reported in 1960 by Wagner et all and subsequently confirmed by others throughout the world.2"4 There may be 3,000 or more cases of mesothelioma seen annually in the United States.5,6 The exact incidence and death rate, however, can be difficult to ascertain since in the past mesothelioma was often reported as lung cancer. Mesothelioma has probably increased in incidence7'8 due in part to the increased use of asbestos during and following World War IL. The incidence is expected to continue to rise into the next century, reflecting the large population of 8 million or more who were asbestos-exposed.568 On the East and West Coasts of the United States, where shipbuilding industries once flourished, malignant mesothelioma can be linked to asbestos exposure in nearly 80% of cases. Correlation with asbestos exposure has not been as high in the midwest.9 Reflecting workplace exposure, malignant mesothelioma is seen more frequently in men than *From the Departments of Medicine, Environmental, and Community Medicine, University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, Cancer Institute of New Jersey, New Brunswick. Reprint requests: Dr. Aisner, CINJ, 303 George St, New Brunswick, NJ S women, and the median age at presentation is greater than 60 years, reflecting a long period of latency. Mesothelioma has also been reported among family members of asbestos workers and in young adults as a consequence of household or neighborhood exposure.1'10"13 Thus, even relatively mild exposure to asbestos increases the risk of mesothelioma. The direct application of asbestos fibers onto the pleural surfaces of experimental animals is known to produce mesotheliomas, and some fiber types are more potent in this regard than others.14 The thin, rodlike amphiboles are believed to be more carcinogenic than the chrysotile asbestos fibers, although contamination of chrysotile fibers with amphibole fiber forms is common The carcinogenic effects of asbestos fibers are believed to be related to their size and shape rather than their chemical composition.18 Asbestos fibers separate into minute fragments. These small inhaled fibers are not easily cleared in the upper airways; they tend to migrate through the distal endothelium into the interstitial tissues, where they penetrate the visceral pleura.19 The fibers are then ingested by macrophages, which become damaged in the process, thereby leaking enzymes, cytokines, and superoxide radicals. The asbestos fibers thus produce an inflammatory and fibrotic reaction.20 The fibers can also carry absorbed carcinogens, which may further contribute to the carcinogenic process. Other possible causal factors include radiation therapy,21-25 extravasated thoratrast,26 and other fibers such as zeolite and erionite with physical properties similar to asbestos.14,27-29 Diagnosis and Staging Most often signs and symptoms associated with pleural effusion or nonpleuritic chest pain induce patients to seek medical attention. Fever, sweats, weight loss, and easy fatigability are also common presenting complaints.30 Thrombocytosis,31 32 disseminated intravascular coagulation, thrombophlebitis, pulmonary emboli, and Coombs positive he-

2 molytic anemia have also been reported.30 The median durations of survival for patients with malignant mesothelioma have ranged from 4 to 18 months. Better survival is associated with younger age,33'34 good performance status,30 early stage,35 epithelial histology, 33'36 lack of chest pain,33'37 and a normal platelet count.3335 Roentgenograms can show evidence of asbestos exposure such as pleural plaques or calcifications in the diaphragm, although asbestosis is not a necessary precondition. Recently, asymptomatic individuals were identified with an incidental effusion on a routine chest x-ray film,38 leading to diagnosis at an earlier stage. A CT scan of the chest provides the best preoperative assessment of the extent of disease.39 Thickening of the pleura with involvement of theinterlobar fissures and atelectasis are the earliest evidence observed on CT scans. 24,40-43 In early disease, discreet nodules and coalescent plaques are seen on the visceral and parietal pleura at the time of thoracoscopy or surgery. Early pleural effusions tend to become progressive rinds of tumor that encase the lung as they grow.44 As the disease progresses, there is also loss of diaphragmatic and intercostal muscle movement, chest contraction, and scoliosis. Mesotheliomas tend to grow and invade locally until late in their natural history; dysphagia, chest pain, cord compression, plexopathy, Horner's syndrome, or superior vena cava syndrome can arise from their extension into the esophagus, ribs, vertebrae, nerves, and superior vena cava.30'38 The tumor also tends to grow along drainage and thoracotomy tracts Extension into the pulmonary parenchyma, chest wall, medastinum, and diaphragm are common as the disease progresses (Fig 1). Mediastinal and cervical lymph nodes may also become FIGURE 1. Surgically resected lung (pleuropneumonectomy) and mesothelioma. Note thick pleural rind on outside of lung and involvement of pleura within fissure. Close inspection shows extension of tumor into pulmonary parenchyma such that removal of pleura (stripping) would likely leave tumor behind. (Photograph courtesy of S.C. Aisner, MD, Department of Pathology, University of Maryland School of Medicine.) involved. Symptomatically, as the disease advances, the patient typically complains of fatigue and dyspnea that is out of proportion to the chest x-ray findings due to the arteriovenous shunting of blood in the poorly aerated, trapped lung. Most patients undergo repeated diagnostic and therapeutic thoracenteses with negative or indeterminant cytologic findings despite having active tumors. Diagnosis based on a needle biopsy is often very difficult because of the small specimens obtained. Immunocytochemistry and electron microscopy can be helpful in this situation,47'48 but larger tissue samples are usually required for these procedures Newer techniques such as thoracoscopy and pleuroscopy have been used with considerable success in obtaining adequate tissue samples.52 Boutin et al46'52 showed that thoracoscopy can be nearly 95% as accurate as an open thoracotomy performed for diagnostic purposes. Generous samples are usually taken for diagnosis, and samples of uninvolved lung are sometimes obtained for counting asbestos fibers.53 Three histologic subtypes of mesothelioma are usually defined: epithelial, sarcomatous, and mixed (epithelial/sarcomatous) Most mesotheliomas occur with the epithelial subtype, and these have variously been described to show papillary, solid, tubular, or vacuolated patterns. The sarcomatous form appears similar to a fibrosarcoma with predominantly spindle- or ovoid-shaped cells. The mixed or biphasic form demonstrates both epithelial and sarcomatous elements, and the finding of both elements is virtually diagnostic of malignant mesothelioma. Metastatic adenocarcinoma originating from lung, breast, ovarian, stomach, kidney, or prostate cancers can sometimes be difficult to distinguish grossly and histologically from the epithelial form of mesothelioma. In fact, malignant mesothelioma was not recognized as a unique entity until the late 1930s, due in part to these difficulties.56 Today, histochemistry, immunohistochemistry, and electron microscopy can usually provide this distinction. Since it is rare in mesothelioma, a positive mucicarmine stain is very suggestive of adenocarcinoma. Periodic acid-schiff stain (PAS) before and after diastase digestion, alcian blue stain, and colloidal-iron stains can also be helpful in distinguishing mesothelioma from metastatic disease.54'57 Electron microscopy is considered by most to be the reference method for defining the diagnosis of malignant mesothelioma The characteristic features on electron microscopy for the epithelial form include numerous long, slender, branching surface microvilli, desmosomes, abundant tonofilaments, and intracellular lumen formation on polygonal cells.49'50 Elongated nuclei and abundant rough endoplasmic reticulin are found in the sarcomatous subtype. CHEST / 107 / 6 / JUNE, 1995 / Supplement 333S

3 Stage I II III IV Table 1-Butchart Staging Classification Tumor confined within the capsule of the parietal pleural, involving only ipsilateral pleura, lung, pericardium, and diaphragm Tumor invading chest wall or involving mediastinal structures, such as esophagus, heart, opposite pleura Tumor penetrating diaphragm to involve peritoneum; involvement of opposite pleura and lymph nodes outside the chest Distant bloodborne metastases I II III IV T-Primary Tx TO TI T2 T3 T4 Table 2-UICC Staging of Mesothelioma* TINOMO T2NOMO TINIMO T2N1MO T3NOMO T3NlMO TlN2MO T2N2MO T3N2MO Any TN3MO T4, any N, MO Any T and N, MI Tumor and Extent Primary tumor cannot be assessed Evidence of primary tumor Primary tumor limited to ipsilateral, parietal, and/or visceral pleura Tumor invades any of the following: ipsilateral lung, endothoracic fascia, Although the Butchart staging system is the one most widely used in pleural mesothelioma (Table 1), it does not uniformly predict survival outcomes or offer adequate description of the degree of chest wall invasion or lymph node involvement, the latter of which has been shown to have prognostic significance.59 Chahinian60 and subsequently the International Union Against Cancer (UICC)61 developed a TNM-based staging system that considers the extent of local invasion and the involvement of regional lymph nodes (Table 2). In the UICC system, the translation of TNM categories into stages I-IV disease is organized in a manner similar to that used for non-small cell lung cancer. However, the data to associate the degree of local tumor, the impact of regional nodal involvement, organ invasion, etc, with long-term survival have not, as yet, been well established. For this reason, a new revision of the TNM system is under development. TREATMENT MEASURES Surgery While surgical procedures to obtain diagnostic material are of critical importance, the role of surgery as a therapeutic manipulation remains controversial. Although pleurectomy can reduce the recurrence of effusions,62,63 surgery has little role in the palliative management of mesothelioma. In the past, most patients presented with locally advanced disease for which aggressive surgery was not a realistic option. Today, however, with the risk of disease in asbestos-exposed individuals well recognized, many patients are diagnosed with earlier stages of mesothelioma, and such patients may have a longer survival. Thus, surgical excision may be a reasonable approach in patients with disease confined to the pleural space. Two surgical procedures have been described as potentially therapeutic: decortication (pleurectomy) and extrapleural pneumonectomy. With pleurectomy, the pleura and pericardium are stripped from the apex of the lung to the diaphragm. diaphragm, pericardium Tumor invades any of the following: ipsilateral chest wall muscle, ribs, mediastinal organs or tissues Tumor extends to any of the following: contralateral pleura or lung by direct extension, peritoneum or intraabdominal organs by direct extension, cervical tissues N-Lymph Nodes Nx Regional lymph nodes cannot be assessed NO No regional lymph node metastases NI Metastases in ipsilateral bronchopulmonary of hilar lymph nodes N2 Metastases in ipsilateral mediastinal lymph nodes N3 Metastases in contralateral mediastinal, internal mammary, supraclavicular, or scalene lymph nodes M-Metastases Mx Presence of distant metastases cannot be assessed MO No (known) distant metastases Ml Distant metastases present *Staging based solely on clinical measures is designated ctnm. Staging based on pathologic information is designated ptnm. 334S

4 Table 3-Pleurectomy for Diffuse Pleural Mesothelioma* No. Author Patients Year 2-Year Survival, % Median Survival, mo Lewis et a McCormack et a165 and Hilaris et a168 95f Law et a DaValle et a Wanebo et a (F) (E) - 21 Achatzy et a Ruffie et a Brancatisano et al Rusch *Reprinted from Aisner et al.73 fforty-one patients received pleurectomy followed by external-beam radiation; 54 patients received pleurectomy followed by implant and external-beam radiation. F=fibrosacomatous form; E=epithelial form. Since the tumor grows from the pleura into adjacent tissues and lung (Fig 1), a clean separation of lung and visceral pleura is often difficult. Operative mortality from pleurectomy is usually low (1 to 2%), and complications include bronchopleural fistulae, hemorrhage, and subcutaneous emphysema. Various studies using this approach have reported median survivals ranging from 6.7 to 21 months (Table 3) Investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) have used pleurectomy combined with either external beam with or without interstitial irradiation or with postoperative intrapleural therapies and irradiation Among the 95 patients evaluated in these reports,65,68 a select group of 27 with the epithelial subtype had a median survival of 22.5 months and a 2-year survival rate of 41%. Epithelial subtype was also an important prognostic factor in the report by Wanebo et al,70 whose patients with the epithelial form survived longer than those whose tumor showed the fibrosarcomatous form. DaValle et a169 suggested that extrapleural pneumonectomy may be more useful for patients with minimal invasion of the visceral pleura, since in their experience the 11.2-month median survival with pleurectomy in patients with diffuse, malignant mesothelioma was not striking. Extrapleural pneumonectomy is a more extensive extirpative procedure in which the parietal and visceral pleura, the contained lung, pericardium, and diaphragm are resected en bloc. The diaphragmatic defect is replaced by a graft to prevent herniation of the abdominal contents, and the right pericardium is also reconstructed. This procedure has evolved over the years with subsequent changes in the surgical approach and perioperative complications. The various reports on extrapleural pneumonectomy are summarized in Table 4;58,59,69,75-83 median durations of survival have ranged from 4 to 21 months. Early studies using this procedure reported a postoperative mortality rate as high as 31%. With increasing experience, the more recent studies have seen operative and postoperative mortality rates reduced to below 5%. Serious complications occurring in up to 25% of patients in some series included bronchial leaks, empyema, vocal cord paralysis, chylothorax, arrhythmias, and respiratory insufficiency.76 Recent studies Table 4-Extrapleural Pneumonectomy for Diffuse Pleural Mesothelioma* No. Author Year Patients Mortality, % Median Survival, mo Woern Unspecified 19 Bamler and Maassen Butchart et a DeLaria et a DaValle et a Vogt-Moykopf et a Faber Probst et a lilt Geroulanos et a18' Rusch et a Sugarbaker et a Netaji et al t *From Aisner et al.73 tlncludes patients with pleurectomy and extrapleural pneumonectomy. CHEST / 107 / 6 / JUNE, 1995 / Supplement 335S

5 with careful preoperative screening have also reduced the rate of postoperative complications.59 Table 4 shows both an improving median survival rate and a reduced complication rate over time. In recent series, Rusch et a182 reported a 2-year survival of 33% with a 10-month median survival in 20 patients in a cooperative group study, whereas Sugarbaker et a159 reported a 40% 2-year survival rate and 21-month median survival for patients undergoing extrapleural pneumonectomy at a single institution. Surgical mortality rates for the two studies were 15% and 5%, respectively. Both studies also offered the details of treatment failure sites. In contrast to the pleurectomy series, some of the reports on extrapleural pneumonectomy showed a small percentage of 5-year survivors. Although the degree of surgery, selection criteria, and possible stage-shift biases preclude definitive statements, extrapleural pneumonectomy, in contrast to pleurectomy, may alter the natural history of pleural mesothelioma. A direct comparison of the surgical techniques of pleurectomy or extrapleural pneumonectomy and the natural history of mesothelioma is not possible because of the heterogeneity of the disease and the different patient selection criteria and degrees of surgical resection reported in the literature. Therefore, these surgical procedures cannot be recommended as standard therapy. Furthermore, since extrapleural pneumonectomy is associated with high morbidity and mortality rates when performed with inadequate training, it should likely be reserved for those institutions with experience in this surgical approach. Given the dismal natural history of mesothelioma, however, it is of considerable importance that patients with early stage disease be referred to treatment centers specializing in this malignancy before attempts are made to obliterate the pleural space with pleurodesis. By evaluating the surgical techniques among patients with early stage disease, we are most likely to define an optimal approach for treatment. Radiation Therapy The role of radiation therapy (RT) in the definitive treatment of pleural mesothelioma remains uncertain. Several small studies of definitive RT45'66'67'84-86 noted symptomatic improvement in some patients45,66,67'84'86 and control of effusions in a fraction.66'67'85 There are also some anecdotal reports of long-term survival following external-beam irradiation or intracavitary instillation of radioisotopes Most reviews of RT for mesothelioma, however, have concluded that it produced no significant effect on disease control or survival.45'66,67,86,90 Many of these reviews were based on older literature and ignored issues such as dose response45'85'86 336s or the prognostic importance of subhistology. Tumoricidal doses of irradiation, however, are limited by the extent of disease and organ toxicity in the lung, heart, and possibly liver.91 Nevertheless, RT is frequently used for palliation of local pain and, despite the lack of trials to prove its utility, has been added to surgical series in order to reduce the high incidence of local recurrence. In one report,92 21 Gy delivered in 3 fractions prevented tumor recurrence in the wound after thoracoscopy or thoracotomy in 24 patients; whereas in the authors' prior experience, 61% of 33 patients developed tumors at the wound site without irradiation. RT thus has the potential to reduce the high incidence of local failures following pleurectomy and to improve local control following extrapleural pneumonectomy. Chemotherapy The role of chemotherapy in the management of malignant mesothelioma also remains uncertain. In the past, small numbers of patients with mesothelioma were included in broad phase II trials or in trials for soft-tissue sarcomas; many agents were thus inadequately tested. The relative inability to define measurable parameters for assessing response also compounded the problem. To overcome these limitations, small series were often combined in overviews to define the activity of individual agents and combinations.93'94 This approach, however, perpetuated the possibility of a positive results publication bias. In the last decade, studies of chemotherapy have been designed specifically for mesothelioma. Table 5 shows the activity of various individual chemotherapeutic agents, as reported in both overviews and individual trials.94'154 Doxorubicin, probably the most extensively studied single agent, has achieved a modest composite response rate of 16%94 but a somewhat lower response in trials of adequate size. There was a 14% response rate in one trial of 51 patients,101 and no responses among 15 patients in another trial.102 Several other anthracyclines have been adequately studied as single agents, including detorubicin107 with 9 of 35 responders (26%), pirarubicin with 12 of 100 responders (12%), epirubicin112'113 with 8 of 69 responders (12%), and mitoxantrone114'115 with 3 of 62 responders (5%). Among the alkylating agents, cyclophosphamide has shown a composite activity of 13%; however, in the only trial with a sufficient number (16) of evaluable patients,102 no responses were seen. Among the classic alkylating agents, only mitomycin in one study with 19 patients123 achieved a response rate of 21%. Both cisplatin and carboplatin have been adequately tested with composite responses of 13% and 11%, respectively.124'136 A recent small study by Planting et

6 Table 5-Response Rates for Single Agents Adequately Evaluated in Malignant Mesothelioma* No. Class Evaluable No. Agent Patients Responders % Anthracyclines Doxorubicin Detorubicin Pirarubicinl Epirubicin112, Mitoxantrone114" Alkylating agents Cyclophosphamide95"02, Ifosfamide Mitomycin Cisplatinl Carboplatinl3l' (2 CR) Antimetabolites High-dose methotrexate137, (1 CR) Trimetrexatel Edatrexate Di-deazafolic acid (CB3717)135, Fluorouracil96" Dihydro-azacytidinel43, (1 CR) 4 7 Nitrosoureas PCNU Vinca alkaloids & podophyllotoxins Vincristine Vindesinel47, Etoposidel Miscellaneous Amsacrine Aziridinylbenzoquinone *From Aisner and Antman.94 CR=complete response. al'30 suggested that weekly doses of cisplatin may be more effective, but this observation needs further accrual and confirmation. The antifolate compounds may be particularly interesting for the treatment of mesothelioma. Highdose methotrexate was initially suspected to have some antitumor activity in a small study of 6 patients,'37 and this finding was confirmed by Solheim et al'38 in a larger study with a 37% response rate among 60 assessable patients. Other antifolate agents have been tested, but results have not been consistent. Vogelzang et al'39 reported a 12% response rate with little toxicity using trimetrexate, while Belani et al140 reported a 25% response rate with considerable toxicity using edatrexate. Because the lower response rates seen with antifolate drugs like trimetrexate and dideazafolic acid'35"14' may be related to a dose effect, further testing of this class of agents seems appropriate. The other antimetabolites, including 5-fluorouracil and 5-dihydroazacytidine, have not shown consistent activity. Similarly, most of the other chemotherapeutic agents either have been inadequately tested or do not show much promise. The testing of new agents in advanced mesothelioma thus remains an important priority. Combination chemotherapy for mesothelioma has similarly been tested in small and often inadequate trials. The basis for using some combinations was derived in the past from composites of these small series.93'94 Newer studies now focus on mesothelioma alone and include sufficient numbers of patients. The modern trials have the added benefit of routine use of CT scans to define response. Because of the early composite data for single agents, most combination regimens included doxorubicin, cyclophosphamide, or cisplatin. A composite overview of many of the combination chemotherapy regimens is shown in Table 6 according to their inclusion of doxorubicin,94,99, other anthracyclines,94'110' cyclophosphamide,30'94'164 cisplatin,94,110, or other agents.94"17' Similar to the problem seen for the single agents, the composite response rate of 21% for doxorubicin-based combinations appears to be greater than the response rate seen in contemporary trials that include larger numbers of patients. One large study of doxorubicin plus cyclophosphamide with or without dacarbazine for example, showed a composite response rate of only 7%.155 Three studies CHEST / 107 / 6 / JUNE, 1995 / Supplement 337S

7 Table 6-Combination Chemotherapy for Malignant Mesothelioma* No. Combination Evaluable No. Chemotherapy Patients Responders % Doxorubicin-based9499, Other anthracycline-based94,110, Cyclophosphamide-based30, Cisplatin-based94,110" Other941l7' *From Aisner et al.'8 of doxorubicin plus cisplatin showed a composite response of 27%, but the recent Cancer and Leukemia Group B (CALGB) study showed only a 13% response rate for the same combination.157 The combination of doxorubicin, cyclophosphamide, and cisplatin showed a response rate of 26% in one small study.159 Several other anthracyclines including piparubicin, epirubicin, and rubidazone, have been studied in combination.110, The results for each of these trials were disappointing with a composite response rate of only 9%. There are few contemporary trials of cyclophosphamide-based combinations other than those that include cyclophosphamide as part of doxorubicin-based regimens. The composite response rate reported in these small, older trials was only 14%.94 The cisplatin-based combinations exclusive of doxorubicin and cyclophosphamide have also been disappointing with a composite response rate of only 18%. The combination of cisplatin and mitomycin appeared highly synergistic in a mesothelioma nude mouse xenograft.168 However, the composite response rates for-this combination and the response from the prospective study by the CALGB were only 25% and 26%, respectively.'57"68"70 Other miscellaneous combinations used in malignant mesothelioma have shown a composite response rate of 22%, but the total number of patients evaluated is small and the composite response is weighted by 6 responses among 9 patients in an unconfirmed trial by Dimitrov et al'7l using vincristine and highdose methotrexate. The response in this trial brings to mind the response rate (four of nine) seen in the initial single-agent study of high-dose methotrexate.137 The paucity of active combination regimens currently available underscores the need to test new chemotherapeutic agents and develop new combinations. Intrapleural Therapy Mesothelioma develops superficially along pleural and peritoneal cavities. Therefore, intracavitary chemotherapy with radionuclides or biologic agents may 338S be beneficial in patients with early superficial disease. Anecdotal reports of prolonged survival with certain radioisotopes helped to stimulate interest in this approach.87'172 Intrapleural therapy, however, is limited to relatively early disease since the pleural space disappears progressively with the advancing rind of disease (Fig 1). Another limitation of this approach is the shallow penetration of chemotherapy (usually only a few millimeters) into the tumor. Among the agents instilled into the abdominal and thoracic cavities, cisplatin has been the most extensively studied.173'l75 Pharmacokinetics show that the total exposure (area under [the plasma X concentration X time] curve) and peak levels are greater with intracavitary than with intravenous cisplatin administration.173'175 While intraperitoneal cisplatin administration has met with some success in patients with peritoneal mesothelioma,175 intrapleural administration has been far less successful. The efficacy of intracavitary administration of other agents such as doxorubicin, cytarabine, and mitomycin is even less well established Recently, several studies have evaluated intrapleural administration of biologic response modifiers such as the interferons, interleukin-2 (IL-2), and specific RNA segments;46"181'189 response rates for these trials are shown in Table 7. While there is as yet only limited experience with most of these agents, the preliminary results are interesting with dramatic responses reported. In one study using recombinant gamma interferon, Boutin et al'87 reported a pleuroscopy-documented total response rate of 24% and a complete response rate of 7% among 99 patients with early stage disease. Among those patients with disease confined only to the parietal pleura, there was a greater than 45% complete response rate and an apparent improvement in survival. In the United States, primary care physicians are reluctant to order early invasive diagnostic procedures. Consequently, it may be difficult to identify patients with early- Table 7-Biologic Response Modifiers in the Treatment of Malignant Mesothelioma* No. Evaluable No. Agent Patients Responders % BCG (after surgery)'82 30 NE NE RNA (intrapleural) Interferons Alpha' (1 CR) 12 Beta18, Gamma (intrapleural)t46,186, (7 CRs) 24 IL-2 (intrapleural)188, *From Aisner et al.84 texcluded fibrosarcoma subtype. NE=not evaluable; CR=complete response.

8 stage disease in this country. These approaches, however, hold considerable promise for patients who have undergone a radical debulking surgical procedure such as extrapleural pneumonectomy. Combined-Modality Therapies The limitations of the individual treatment modalities used in patients with malignant mesothelioma have led some to suggest supportive care alone for these patients. However, surgery, radiotherapy, chemotherapy, and biologic response modifiers could potentially be combined to improve outcome. Experience with combined-modality therapies has been relatively limited,596870'82'83'90'94 and the results can not be compared because of differences in patient selection, disease heterogeneity, and end points. Chemotherapy has been infrequently combined with RT despite the potential for some agents such as cisplatin to act as radiosensitizers. Doxorubicin plus RT has been studied in two small trials.160'190 In South Africa, where the composite overall median duration of survival has been poor,90 a small number of patients who were treated with doxorubicin and RT achieved a median duration of survival of 22.6 months.'90 Even when radical surgical resections are attempted, local and systemic recurrences are common in malignant mesothelioma. Thus, adjuvant therapies to improve local control and prevent systemic recurrence are often tried. The high local failure rate among patients undergoing pleurectomy alone has led most investigators to add postoperative RT. Rusch et al'93 attempted to give intracavitary cisplatin and mitomycin chemotherapy to patients following pleurectomy; postoperative systemic cisplatin and mitomycin chemotherapy were also added subsequently.72 This approach yielded a high intracavitary drug concentration but the high drug plasma levels produced systemic chemotherapy toxicities. Sugarbaker et a159 added chemotherapy and chest irradiation following extrapleural pneumonectomy. The results of this approach compare favorably to most other series. In a very similar approach at the University of Maryland Cancer Center, we administered radiation boosts to the surgical scar and needle tracts. Recently, we have also instilled cisplatin into the cavity at the completion of resection. Our results are similar to those reported by Sugarbaker et al,59 wherein 45% of those having resection and no mediastinal lymph node involvement were alive at 2 years. Several unique approaches to combining treatment modalities have recently been described. Pass et al'92 recently completed the initial phase I trial of intracavitary therapy using a photoactivated protoporphyrin derivative. The protoporphyrin dye is preferentially absorbed by the tumor so that a light source placed in the hemithorax after surgery activates the dye and preferentially kills the residual tumor cells. The results of phase II testing of this approach are awaited. Pogrebniak et al'9' combined cisplatin, interferon-a, and tamoxifen with the latter agent used to modify drug resistance. The results of this feasibility trial were not striking, but further testing of such combined modalities is under investigation. CONCLUSIONS Malignant mesothelioma remains a clinical problem to diagnose and treat. The disease is of interest because of its association with asbestos exposure. Because of the rarity of this tumor, however, a systematic means for studying patients with this disease would be most desirable. Early diagnosis using pleuroscopy offers a good opportunity to employ possibly more effective therapies like intrapleural chemotherapy or extirpative surgery. Further evolution in chemotherapy is needed. Today we can identify some of the patients at risk on the basis of asbestos exposure. Following such patients and implementing early diagnostic procedures for pleural effusion offers the best chance for early intervention. Identifying at-risk patients early for specific therapy and avoiding sclerosis will help to define better treatment options for this very difficult disease. REFERENCES 1 Wagner JC, Sleggs EA, Marchand P. Diffuse pleural mesothelioma and asbestos in the North Western Cape Province. Br J Ind Med 1960; 17: Fowler PBS, Sloper JC, Warner EC. Exposure to asbestos and mesothelioma of the pleura. BMJ 1964; 2: Newhouse ML, Thompson H. Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Br J Ind Med 1993; 50: Selikoff IJ, Churg J, Hammond EC. Asbestos exposure and neoplasia. JAMA 1964; 188: Walker AM, Loughlin JE, Freidlander ER, et al. Projections of asbestos-related disease J Occup Med 1983; 25: Enterline PE, Henderson VL. Geographic patterns for female pleural mesothelioma deaths for 50 states. 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