Mesothelioma

The diagnosis and management of malignant pleural mesothelioma are major challenges that often frustrate both patient and clinician alike. Occupational asbestos exposure to crocidolite or amosite forms of the fiber is the most important known risk factor in North America and Western Europe. Other mineral fibers such as erionite, a naturally occurring fibrous zeolite crystal, are associated with mesothelioma in volcanic tuffs of the Cappadocia region of central Anatolia in Turkey. In addition, other possible factors such as the presence of simian virus 40 and genetic susceptibility have been associated recently with the development of mesothelioma in animal models. These latter findings are increasing our understanding of this disease. In addition, the discovery of elevated levels of various markers such as folic acid receptor [alpha], cyclooxygenase 2, and multidrug resistance proteins 1 and 2 in mesothelioma tissue have opened up new areas of potential diagnostic and therapeutic importance. However, traditional treatment modalities--surgery, radiotherapy, and chemotherapy--have evolved slowly, and few gains in therapeutic efficacy have occurred. Recently, however, continuing research efforts have led to novel treatment strategies that are changing the way clinicians view a disease that has traditionally been managed with almost universal therapeutic nihilism. This review explores our current knowledge of this disease and presents current and novel therapeutic strategies.

Key words: chemotherapy; epidemiology; gemcitabine; mesothelioma; pathogenesis; pemetrexed; treatment

Abbreviations: CALGB = Cancer and Leukemia Group B; COX-2 = cyclooxygenase-2; DHFR = dihydrofolate reductase; EORTC = European Organization for Research and Treatment of Cancer; EPP = extrapleural pneumonectomy; GARFT = glycinamide ribonucleotide formyltransferase; IMIG = International Mesothelioma Interest Group; MPM = malignant pleural mesothelioma; P/D = pleurectomy/decortication; SV = simian virus; TS = thymidylate Synthetase; VEGF = vascular endothelial growth factor.

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There has been no consensus in the literature guiding the appropriate management of patients with malignant pleural mesothelioma (MPM). This has been due primarily to a lack of convincing data identifying any single treatment modality or combination that might offer a clinically meaningful and significant improvement in survival or quality of life over best supportive care. (1,2) While many believe that radical surgical resection may offer the only chance of cure or meaningful improvement in survival, the majority of patients presenting with MPM are not candidates for radical surgical resection due to unresectable, locally advanced disease or comorbid medical illness. This intervention, even when applied to highly selected patient populations, is associated with a relatively high risk of severe morbidity and mortality and has not yet been clearly proven to have a significant beneficial impact on survival. (3) Many chemotherapeutic agents have been studied in patients with MPM, either as single agents or as part of a combination chemotherapy regimen. Response rates have ranged from 0 to 48%, with the highest response rates generally achieved using multiagent regimens. However, no dear standard of care using available agents has emerged due to a lack of clearly demonstrated survival or palliative benefit in the setting of well-designed, randomized, and controlled clinical trials. This article will review the epidemiology and biology of this disease as well as the evidence for benefit of various current and investigational treatments for MPM.

EPIDEMIOLOGY

Wagner et al (4) initially reported 33 cases of mesothelioma in a South African asbestos mining community in 1960. Since then, data have been collected through various databases in the United States, Western Europe, some Eastern European countries, and the United Kingdom. Mesothelioma is usually diagnosed in the fifth to seventh decades of life, with a strong male predominance where occupational exposure to asbestos is involved. (5) There are approximately 2,500 new eases of mesothelioma annually in the United States, of which 2,000 are in men and 500 are in women. (5,6) The incidence in the United States appears to be rising, mainly in men aged [greater than or equal to] 75 years, with the maximum lifetime risk in the from 1925 to 1929 birth cohort of men. (5) The incidence in women and in men < 75 years of age appears to have been stable since 1983. (5) This coincides with restrictions and regulations of the US Occupational Safety and Health Administration and the Environmental Protection Agency, enacted in the 1970s, regarding uses and permissible exposure limits for asbestos in the workplace. (5) The incidence of mesothelioma is also rising in Europe, from 5,000 men dying in 1998 to a projected 9,000 men dying by 2018, with the highest incidence in the from i945 to 1950 birth cohort of men. (7)

PATHOGENESIS AND BIOLOGY

Exposure to asbestos, a family of naturally occurring silicate minerals, is the main risk factor for the development of MPM. The association between asbestos exposure and cancer was first established in a case-control study of lung cancer patients in 1955. (8) Several varieties of asbestos fibers occur naturally; those that are narrow and needle-like (amphiboles such as crocidolite and amosite) appear to be more carcinogenic and mutagenic in animal models and tissue culture than those that are curled and more pliable (chrysotile). In addition, asbestos fibers are commonly seen in excised surgical specimens from patients with MPM. Similar to coal dust in coal miners, asbestos fibers are trapped in distal parts of the lung and concentrate to form black spots in the parietal pleura, the main anatomic site of mesothelioma in the chest. (9) The latency period between initial exposure and death has been reported up to 72 years (mean, 48.7 years; range, 14 to 72 years), with wide variability linked to the type of fibers and intensity of exposure. (10)

Although approximately 80% of patients with MPM have a history of asbestos exposure, only approximately 10% of those with asbestos exposure acquire mesothelioma, (11,12) suggesting that other factors may be important either independently or as cofactors in the development of this malignancy. Human mesothelioma cells are highly susceptible to infection by simian virus (SV)-40 in vitro and in animal models and often express virus sequences. (13-14) Furthermore, studies have demonstrated that SV-40 is a poor prognostic factor in MPM. (15) Some research has shown that asbestos and SV-40 can function as co-carcinogens, since the presence of asbestos fibers leads to an increase in the number of transformation loci that develop with SV-40 in tissue culture.

Chromosomal abnormalities such as deletions of chromosome regions 1p, 3p, 9p, and 6q, as well as loss of chromosome 22, are commonly found in MPM. These recurrent genomic losses are consistent with the loss of both defined and putative tumor suppressor genes important in the development of MPM, including the CDKN2A locus in chromosomal location 9p21 containing p16 and [p14.sup.ARF], and neurofibromatosis 2 in chromosome 22. (16,17)

Genetic susceptibility may also contribute to the etiology of malignant mesothelioma. Two small villages in file central Anatolia region of Turkey share a rare environmental pathogen for malignant mesothelioma (erionite exposure). While 50% of the men in one village died of malignant mesothelioma, only one case of malignant mesothelioma was reported in the other village, and that ease occurred in a woman who was originally from the former village.)s Six families have been identified with an obvious familial clustering of malignant mesothelioma, and these could be linked to one large six-generation pedigree, suggesting a founder effect and an autosomal dominant pattern of inheritance with incomplete penetrance.

CLINICAL MANIFESTATIONS AND NATURAL HISTORY

Dyspnea and nonpleuritic chest wall pains are the most common presenting complaints of patients with MPM. (19) Examination may show signs of a unilateral pleural effusion with dullness to percussion and decreased air entry at one base, with a slight right-sided predominance. Patients may also be asymptomatic, with evidence of a pleural effusion noted only incidentally on physical examination or by chest radiography. A pleural mass is often present but may be obscured by pleural fluid on chest radiography. Metastatic disease is uncommon at presentation, and contralateral pleural abnormalities are often due to asbestos-related pleural disease rather than metastatic disease.

Median survival time from symptom onset is approximately 1 year, depending on the initial stage and various prognostic factors. (19-21) Shortness of breath and chest pain become progressively worse, often followed by weight loss, anorexia, and night sweats. (19) Local invasion of the chest wall and surrounding structures can cause increasing pain as well as functional abnormalities including dysphagia, superior vena cava syndrome, Horner syndrome, vocal cord paralysis, and diaphragmatic paralysis. Death is rarely a result of metastatic disease; it is usually due to infection or respiratory failure along with constitutional symptoms associated with progressive malignancy.

DIAGNOSIS AND STAGING

Biopsy

Patients presenting with a clinical picture consistent with MPM require further investigation to establish a pathologic diagnosis and the stage of disease. Thoracentesis is often the initial diagnostic intervention. Cytologic diagnosis of MPM from pleural fluid is, however, unreliable since reactive mesothelial cells and cells flout other malignant tumors such as sarcomas and adenocarcinomas are often very difficult to distinguish from malignant mesothelial cells. (22) As a result, histologic assessment is preferred, with samples obtained either as a CT-guided pleural biopsy or by biopsy under direct vision via thoracoscopy. CT-guided biopsy has a yield of 60% with a single attempt and up to 85% with repeat biopsies. (23) Thoracoscopic biopsy using video-assisted thoracoscopy has a yield of > 90% and carries a relatively low risk of complications (10%), including persistent air leak, hemorrhage, and infection. (24-26) Seeding of the tumor biopsy tract occurs in up to 40% of eases but may be prevented by prophylactic local radiation to the site. (25) Open thoracotomy is the last resort for obtaining adequate tissue for pathologic diagnosis.

Pathology

Mesothelioma is classified into three types: epithelial, sarcomatoid, and mixed. The epithelial type (50% of eases) can be further subdivided into subtypes such as tubular, papillary, giant/large cell, small cell, myxoid, and others that reflect morphologic similarities to carcinomas of other origins. The sarcomatoid type (15% of cases) is characterized pathologically by spindle-shaped cells similar to those seen in fibrosarcomas, and clinically by a poorer prognosis compared with epithelial or mixed pathological types. The mixed type contains elements of both the sarcomatoid and epithelial types. (27,28)

Immunohistochemical assays developed for specific antigens are often helpful in differentiating mesothelioma from metastatic adenocarcinoma of various origins. Such antigens include carcinoembryonic antigen, CD15 (Leu-M1), and epithelial membrane antigen. (29) Carcinoembryonic antigen and CD15 are typically absent in MPM. MPM stains for epithelial membrane antigen with a distinctive membrane-associated staining pattern, contrary to the cytoplasmic pattern seen in adenocarcinomas. (29) Staining for cytokeratin 5, cytokeratin 6, and calretinin are also relatively specific for MPM. (30,31) Electron microscopy remains the "gold standard" and should be used for difficult cases where morphologic assessment by immunostaining is equivocal. Mesothelioma can usually be distinguished from adenocarcinoma by the presence of long and branching microvilli as well as the relatively higher quantity of tonofilaments and desmosomes found in the former. (32) The most valuable asset to the diagnosis of mesothelioma is an experienced pathologist who sees a relatively high volume of this disease.

Staging

Several staging systems for MPM have been proposed, and none have been accepted universally. The oldest staging system, introduced by Butchart et al, (33) has largely been abandoned due to a la& of prognostic value, in favor of TNM-based systems. (34) Recently, the International Mesothelioma Interest Group (IMIG) proposed a TNM-based staging system based on an analysis of information about the impact of tumor and node status on survival, shown in Table 1. (34) CT scan or MRI are necessary for accurate clinical staging. However, using the IMIG system, surgical staging has been shown to be superior to clinical staging where feasible. (35)

Prognostic Factors

Stage of disease is but one of the known variables that may influence survival. Two prognostic scoring systems have been developed for MPM on the basis of data collected from patients entered into large cooperative group trials. (20,21)

The Cancer and Leukemia Croup B (CALGB) examined the individual and combined effects of a number of pretreatment clinical characteristics on survival of patients with MPM, (20) including poor Eastern Cooperative Oncology Group performance status, chest pain, dyspnea, platelet count > 400,000/[micro]L, weight loss, serum lactate dehydrogenase level > 500 IU/L, pleural involvement, low hemoglobin level, high WBC count, and age > 75 years. Multivariate Cox analysis of these variables demonstrated that pleural involvement, lactate dehydrogenase > 500 IU/L, poor performance status, chest pain, platelet count > 400,000/[micro]L, nonepithelial histology, and age > 75 years were independent predictors of reduced survival time. Performance status (0 vs 1, 2) produced the most significant prognostic split in the resulting regression tree. Six distinct prognostic subgroups were subsequently defined using this tree, with survival times ranging from 1.4 to 13.9 months. The best survival time was in patients < 49 years old, with a performance status of 0 and hemoglobin [greater than or equal to] 14,6 g/dL, The worst survival time was in patients with a performance status of 1 or 2 and a WBC [greater than or equal to] 15.6/[micro]L. In a similar study undertaken by the European Organization for Research and Treatment of Cancer (EORTC), 13 factors were entered into a Cox proportional hazards regression model. Poor prognosis was independently associated with poor performance status, a high WBC, a probable/possible histologic diagnosis of mesothelioma, male gender, and sarcomatoid histologic type. (21) Using these factors, the EORTC group then classified patients into two prognostic groups: a good prognosis group (1-year survival of 40%) having two or fewer poor prognostic factors, and a poor prognosis group (1-year survival of 12%) having three or more poor prognostic factors. A subsequent retrospective analysis of an independent cohort of patients confirmed the prognostic value of both the CALGB and EORTC scoring systems. (36)

Certain biological markers have been reported to be elevated in mesothelioma compared with normal mesothelium, including overexpression of the [alpha]-folate receptor, (37) cyclooxygenase-2 (COX-2), (38) and the multidrug resistance proteins 1 and 2. (39) Of these, COX-2 has been correlated with other prognostic factors and contributed significantly to both the EORTC and CALGB prognostic scoring systems.

These developments are particularly interesting, as these molecules may represent important targets for future therapies.

TREATMENT

Palliative Care

Given that the prognosis for patients with mesothelioma has been historically poor regardless of the type of anticancer treatment, palliation of symptoms has been the primary goal of most therapy to date. Palliative therapy focuses on two major symptoms, dyspnea and chest wall pain. All previously described modalities may contribute to the palliation of patients with MPM. Radiation has shown palliative benefit in reducing pain and symptoms of dyspnea, (40) surgical pleurodesis can reduce the symptoms associated with recurrent or persistent pleural effusions, (41) and chemotherapy has demonstrated palliative benefit in terms of overall quality of life. (42) Judicious use of these treatments in combination with adequate pain control and attention to respiratory function has formed the basis of effective palliation in MPM. Use of these modalities for palliation will be discussed in more detail below.

Treatment of MPM with more than palliative intent remains inadequate at all stages of presentation. (1,2) Generally, surgery as a single modality has failed to improve survival, and several investigators (43,44) have explored the use of combined modality therapy incorporating radiation and chemotherapy in conjunction with surgery. In advanced disease, chemotherapy remains the main therapeutic modality, although either surgical intervention or local radiation therapy may be useful for the local eontrol of pain or symptoms often associated with pleural fluid accumulation. (40,41) Chemotherapy has generally failed to significantly impact survival. (1,2) This has been due both to the lack of control subjects in most studies and the lack of statistical power in those randomized trials that have been done. However, recently presented data from a large, well-powered phase III trial (45) comparing the combination of pemetrexed and cisplatin with cisplatin alone are encouraging, and may represent a standard chemotherapeutic regimen against which future treatments can be measured.

Surgery

Three procedures are used in the surgical management of MPM: thoracoscopy with pleurodesis, pleurectomy/decortication (P/D), and extrapleural pneumonectomy (EPP). EPP is the most aggressive procedure. It involves the en bloc resection of the visceral and parietal pleura, lung, pericardium, and ipsilateral diaphragm. (27) Patient selection for EPP is critical, as is the experience of the surgeon and institution at which the procedure is performed. Early series showed a prohibitively high mortality rate. (33) However, more recently, the 30-day postoperative mortality and morbidity in a center with extensive experience with the procedure are 3.8% and 50%, respectively. (43)

P/D involves the removal of the visceral, parietal, and pericardial pleura from the apex of the lung to the diaphragm. Complete resection is usually only possible at a very early stage of the disease, and local recurrence occurs in the majority of these patients. In comparison to EPP, postoperative radiation doses are limited dim to the retained lung.

Thoracoscopy is useful not only in obtaining tissue for a diagnosis but also for pleurodesis to palliatively treat recurrent or symptomatic pleural effusions. Several sclerosing agents can be used (ie, bleomycin, tetracycline, and talc) with no significant differences in efficacy. (41,46) Talc is generally the least expensive and can be administered via a thoracoscope or instilled as slurry through a chest tube. (47)

While often attempted with curative intent, neither EPP nor P/D appear to offer a significant improvement in survival. (3,48) Efforts have therefore focused on a multimodality approach. Brigham and Women's hospital has conducted the largest study evaluating multimodality treatment of MPM. (43) A single cohort of patients underwent EPP and adjuvant chemotherapy with cyclophosphamide/doxornbicin and/or cisplatin and/or carboplatin/paclitaxel. Those who survived surgery achieved 2-year and 5-year survival rates of 38% and 15%, respectively. A subset of patients with good prognostic parameters (ie, epithelial histology, no nodal involvement, and clear resection margins) achieved a median survival of 51 months and g-year and g-year survival rates of 68% and 46%, respectively. Other approaches to multimodality therapy have been tried, including combinations of P/D or EPP with either brachytherapy and external beam radiation or intrapleural and systemic chemotherapy, achieving improved survival compared with historical controls. (49-51) More effective chemotherapeutic regimens may further impact survival in this setting by decreasing the incidence of distant metastasis in addition to improving local control. However, randomized, controlled trials are necessary in order to provide sufficient evidence to consider any one or more of these approaches as a standard of therapy.

Radiation

To encompass all known disease and areas at high risk, radiation therapy usually requires a prohibitively large field, as the entire pleural surface is at risk. In addition to the lung parenchyma itself, other thoracic structures can be dose limiting, further complicating treatment planning. Retrospective reviews (1,2) have shown no suggestion of a clear survival benefit for extensive radiation therapy.

A report from the Joint Center for Radiation therapy in Boston suggests a minimum effective dose of 40 Gy in order to achieve palliation. (40) In the post-EPP setting, higher doses of radiation therapy can be delivered safely and are associated with a very, low risk of local recurrence, with distant metastasis being the most common form of relapse. (44) hi a study by Boutin et al, (25) dosing to small fields was found to be highly effective at decreasing malignant seeding along biopsy tracts. (25) Radiation therapy, therefore, seems to have a role in disease palliation but has no real impact on survival.

Chemotherapy

Most single agents have been tested in MPM (Table 2). (52) In general, single-agent response rates are < 20%, and survival benefit for single-agent chemotherapy has not been suggested in single cohort studies.

In the past, doxorubicin was regarded as the standard for single-agent chemotherapy for malignant mesothelioma. However, this anthracycline and other anthracycline analogues and formulations, including epirubicin and liposomal doxorubicin, have achieved response rates of <20% as single agents. (53,54,68,69)

Platinum analogues have been extensively studied in MPM both as single agents and in combined regimens. Cisplatin demonstrated an overall response rate of 14% and 36% when administered at a dose of 100 mg/[m.sup.2] every 21 days and 80 mg/[m.sup.2] weekly, respectively. (56,57) Carboplatin, a better tolerated and easier-to-deliver analog of cisplatin, demonstrated response rates similar to cisplatin when used with a conventional dosing regimen (7 to 16%). (58,70)

Taxanes, such as paclitaxel and docetaxel, also have very, low response rates and therefore do not appear to be effective as single-agent treatments of MPM. (61,62,71) Vinorelbine is unique among the vinca alkaloids for its single-agent activity in MPM. Weekly vinorelbine treatment at standard doses had a partial response rate of 24% and an improvement in overall quality of life in 41% of patients examined in a single cohort phase II study. (63) Gemcitabine appears to have limited activity as a single agent in MPM based on a single phase II study (64) showing a response rate of only 7% among 27 patients. Antifolates have demonstrated single-agent activity in MPM; such activity may be related to the overexpression of the [alpha]-folate receptor gent in up to 72% of MPM tumors. (37) High-dose methotrexate demonstrated a response rate of 37% in a phase II trial (60); this result requires confirmation in a randomized, controlled clinical trial. CALGB demonstrated a response rate of 25% for edatrexate but with a considerable degree of toxicity. (72) A single-agent phase II trial of raltitrexed has been completed but not yet reported. (73) Raltitrexed is also currently being evaluated in combination with oxaliplatin and cisplatin in two separate randomized trials. (73,74) Pemetrexed is a novel multitargeted antifolate that has been studied as a single agent in a phase II study (67) and in a combination regimen with cisplatin compared to cisplatin alone in a phase III trial. (45)

Combination chemotherapy regimens have been extensively evaluated in MPM (Table 3). (52) The majority of these regimens are anthracycline based, platinum based, or both. With few exceptions, however, response rates are [less than or equal to] 20%, and median survival remains largely unaffected in the range of 6 to 12 months.

Reports of activity with other agents in combination have been highly variable. For example, response rates as high as 48% have been reported with the combination of gemcitabine and cisplatin (75); however, a trial of similar design but slightly higher planned dose intensity of gemcitabine failed to duplicate this result, demonstrating a response rate of only 16%. (76) Oxaliplatin, a platinum analog available throughout Europe since 1999 and recently approved by the US Food and Drug Administration for the treatment of advanced colon cancer, has been studied in several regimens, including combination with gemcitabine. Schuette et al (77) reported a response rate of 40% with this promising combination. Its toxicity profile is reported as favorable, and responses were noted in patients previously identified as platinum refractory. By contrast, preliminary data in 26 patients receiving the combination of vinorelbine and oxaliplatin yielded a response rate of only 23%, a result nearly identical to that mentioned above for single-agent vinorelbine. (78)

Halme et al (79) studied 26 patients with localized MPM treated with high-dose methotrexate and leucovorin rescue in combination with [alpha]-interferon. This regimen was well tolerated and demonstrated a response rate of 29%, a median survival of 17 months, and 1-year and 2-year survival rates of 62% and 31%, respectively. Although the combination of irinotecan and docetaxel in patients with IMIG stage III-IV was slightly efficacious (overall response rate of 15%), its high toxicity profile (50% incidence of neutropenic fever and 40% of grade 3-4 diarrhea) makes it an improbable candidate for the treatment of MPM. (80)

Overall, despite the testing of a variety of older and newer agents in combination, treatment for MPM with currently marketed agents remains inadequate. The incorporation of new targeted therapies into the most promising cytotoxic regimens of presently marketed agents needs to be tested extensively within more novel strategies of drug delivery.

NOVEL THERAPIES

Several novel approaches to the treatment of MPM that incorporate new chemotherapeutic, biological, and targeted therapies are under development. Pemetrexed is a multitargeted antifolate that inhibits multiple enzymes important in folate metabolism, including thymidylate synthetase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase. (81,82) The key enzyme targets for pemetrexed are TS, DHFR, and GARFT (Fig 1). (83) TS and DHFR are targets of the known antineoplastic agents 5-flurouracil and methotrexate, respectively, while GARFT is not targeted by any currently used chemotherapeutic agent.

[FIGURE 1 OMITTED]

Pemetrexed as a single agent administered at a dose of 500 mg/[m.sup.2] every 21 days has demonstrated promising activity in several malignancies, including non-small cell lung cancer, breast cancer, previously untreated colorectal cancer, bladder cancer, cervical cancer, and cancer of the head and neck. (82,84-87) In a phase I trial of pemetrexed combined with cisplatin, 5 of 11 evaluable patients (45%) with MPM achieved a partial response, (88) while a second phase 1 trial of pemetrexed combined with carboplatin in patients with MPM showed partial response in 8 of 25 assessable patients (32%). (89) In the initial stages of development, pemetrexed therapy was complicated by severe toxicities, thought to be due to deficiencies of folate and/or vitamin [B.sub.12] pools. (90,91) Subsequent supplementation of all patients with vitamin [B.sub.12] and folate significantly reduced severe toxicities associated with the drug. (67,92) An open-label, multi-institutional phase II trial of pemetrexed as a single agent involving 64 patients with MPM showed an overall response rate of 16% and a median survival of 13 months in patients supplemented with folic acid and vitamin [B.sub.12]. (67) The initial encouraging results of pemetrexed in phase I and II studies led to the largest randomized trial (45) conducted to date for MPM, comparing pemetrexed/cisplatin vs cisplatin. Pemetrexed/cisplatin was more effective than cisplatin alone in terms of median survival (12.1 months vs 9,3 mouths, p = 0.020), median time to disease progression (5.7 months vs 3.9 months), and response rate (41% vs 17%). As expected, the pemetrexed/cisplatin arm had a higher incidence of laboratory toxicities than cisplatin alone, including grade 3/4 neutropenia (28%) and leukopenia (18%), and rare nonlaboratory toxicities. Supplementation improved the efficacy and toxicity profiles. Finally, pemetrexed/cisplatin showed significant improvement in both pulmonary function tests and major disease-related symptoms such as dyspnea and pain. (93,94)

As a 10-min infusion administered every 21 days, pemetrexed is easy to administer; when administered with appropriate folate and vitamin [B.sub.12] supplementation, severe toxicity is controlled. Based on these data, pemetrexed in combination with cisplatin should be considered as a major component of standard care of patients with unresectable MPM.

Ranpirnase, a ribonuclease derived from leopard frog eggs, has been extensively studied in mesothelioma. In a phase II trial of 105 patients with MPM, it demonstrated a response rate of only 5% but was noted to produce stable disease in 43% of patients. (95) Overall survival was 6 months for the intent-to-treat group and 8.3 months in a subset of patients with a good prognosis based on CALGB criteria. A phase III trial (96) suggested that ranpirnase may have higher efficacy than doxorubicin in certain small subgroups of patients with unresectable malignant mesothelioma, but these retrospective observations had insufficient power to draw any reliable conclusions on efficacy. Larger studies of such subgroups are needed.

Various cytokines, alone or in combination, also have been studied in MPM. (97-99) A phase II trial investigating [alpha]-2b interferon in combination with cisplatin and doxorubicin showed a response rate of 29% and a median survival of 9.3 months in patients with advanced MPM. (97) Severe myelosuppression and fatigue were significant limiting toxicities. Intrapleural interleukin-2 was also examined for the treatment of malignant pleural effusions with promising results. (98,99)

A variety of new approaches are under investigation for the treatment of mesothelioma, based on the targeting of specific markers. SV-40 has been identified as a possible cause of MPM, (15) and a candidate vaccine of the SV-40 T-antigen has shown early evidence of efficacy. (100) Vascular endothelial growth factor (VEGF) is an autocrine growth factor important in the pathogenesis of MPM. (100) Three potential inhibitors of VEGF are being investigated for activity against the disease: bevacizumab (rhuMAbVEGF), SU5416, and thalidomide. (73,101) Bevacizumab, a recombinant anti-VEGF antibody, is in phase II trials in combination with chemotherapy (gemcitabine/ cisplatin). ZD1839 (gefinitib), an inhibitor of the epidermal growth factor receptor, and STI-571 (imatinib), an inhibitor of the platelet derived growth factor receptor, were unsuccessful as monotherapies in epidermal growth factor receptor-positive malignant mesothelioma and MPM, respectively. (102,103) Since COX-2 is overexpressed in MPM and may constitute a poor prognostic factor, COX-2 inhibitors may have therapeutic potential. (38) Photodynamic therapy has also been investigated, but a randomized trial (104) failed to show any benefit in either survival or local control.

CONCLUSION

Despite a long history of therapeutic nihilism in the treatment of MPM, recent advances have renewed enthusiasm for aggressive management of the disease in all stages. The combination of pemetrexed with cisplatin, which demonstrated a positive benefit on multiple outcomes including survival, time-to-progressive disease, and quality of life, will likely become a major component of the standard of care for patients with advanced disease, and has provided renewed hope for the development of other effective standards of care for this disease. This regimen should now be tested in clinical trials in the adjuvant and neoadjuvant setting as well. Based on a rapidly emerging understanding of the biology of MPM, continued research on novel molecular targets and their respective targeted therapies will be very important for further advances to occur in the treatment of this disease.

* From the Department of Medicine (Dr. Rusthoven), McMaster University, Hamilton, ON, Canada; and Department of Critical Care (Dr. Pistolesi), University of Florence, Firenze, Italy,.

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Dr. Pistolesi is a consultant of Eli Lilly and Company in the phase III study of pemetrexed in malignant pleural mesothelioma.

Dr. Rusthoven is a consultant and former employee of Eli Lilly and Company.

Manuscript received October 1, 2003; revision accepted December 5, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Massimo Pistolesi, MD, Section of Respiratory Medicine, Department Critical Care, University of Florence, Viale G.B. Morgagni 85, 50134 Firenze, Italy; e-mail: massimo@unifi.it

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