Update on Malignant Mesothelioma

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Oncology, ONCOLOGY Vol 19 No 10, Volume 19, Issue 10

Mesotheliomas are uncommon in the United States, with an incidenceof about 3,000 new cases per year (or a risk of about 11 per million Americansper year). Incidence and mortality, however, are probably underestimated.Most are associated with asbestos, although some have arisen inports of prior radiation, and a reported association with simian virus (SV)40remains controversial. About 85% of mesotheliomas arise in the pleura,about 9% in the peritoneum, and a small percentage in the pericardiumor tunica vaginalis testis. The histology of about half of mesotheliomas isepithelial (tubular papillary), with the remainder sarcomatous or mixed.Multicystic mesotheliomas and well-differentiated papillary mesotheliomasare associated with long survival in the absence of treatmentand should be excluded from clinical trials intended for the usual rapidlylethal histologic variants of the disease. The median survival isunder a year, although longer median survivals for selected patients,particularly those with epithelial histology, have been reported in somecombined-modality studies. Recent randomized trials have shown significantimprovement in time to progression and survival for the additionof new antifolates to platinum-based chemotherapy.

Mesotheliomas are uncommon in the United States, with an incidence of about 3,000 new cases per year (or a risk of about 11 per million Americans per year). Incidence and mortality, however, are probably underestimated. Most are associated with asbestos, although some have arisen in ports of prior radiation, and a reported association with simian virus (SV)40 remains controversial. About 85% of mesotheliomas arise in the pleura, about 9% in the peritoneum, and a small percentage in the pericardium or tunica vaginalis testis. The histology of about half of mesotheliomas is epithelial (tubular papillary), with the remainder sarcomatous or mixed. Multicystic mesotheliomas and well-differentiated papillary mesotheliomas are associated with long survival in the absence of treatment and should be excluded from clinical trials intended for the usual rapidly lethal histologic variants of the disease. The median survival is under a year, although longer median survivals for selected patients, particularly those with epithelial histology, have been reported in some combined-modality studies. Recent randomized trials have shown significant improvement in time to progression and survival for the addition of new antifolates to platinum-based chemotherapy.

Mesotheliomas are uncommon in the United States, with an incidence of about 3,000 new cases per year (or a risk of about 11 per million Americans per year, Figure 1).[1] A fundamental issue for research in mesothelioma is the lack of accurate statistics. Available statistics probably underestimate mortality. The pathologic diagnosis is often difficult and may be inaccurate as well. Death certificates often cite lung cancer or heart failure as the cause of death. The disease is rare and thus physicians are inexperienced, leading to a delay in diagnosis and wide vari ations in care. Except at the few centers with research and treatment programs, few tissues are available for research studies. Epidemiology About 50% to 70% of mesotheliomas are associated with exposure to asbestos. In Turkey, mesothelioma, endemic in some areas, is associated with an asbestiform mineral, erionite, in white soil used as a whitewash.[2,3] Familial susceptibility may also be a factor.[4,5] In addition, mesothelio delivered for a prior malignancy or after extravasation of thorium dioxide contrast (Thorotrast).[6-8] Smoking and asbestos exposure substantially increases the risk of lung cancer, but smoking is not implicated in the etiology of mesotheliomas. Of uncertain significance, simian virus (SV)40 DNA fragments have been detected in mesotheliomas in some but not other studies.[9,10] SV40-contaminated polio vaccine was distributed in the 1950s. SV40 sequences have been found in microdis sected tumor cells but not in stroma in a substantial fraction of US mesothelioma patients. SV40 can cause mesothelioma in hamsters. The oncoproteins of SV40 bind to Rb and p53. A causal link in human mesothelioma, however, remains controversial.[9,10]

Asbestos
Asbestos, a silicate mineral of magnesium, calcium, and iron, occurs as fibrous rock, which is mined and milled. Asbestos fibers are either needle-like (amphiboles including amosite, tremolite and crocidolite) or spiral (chrysotile). Risk of mesothelioma varies by asbestos type broadly in the ratio of 1:100:500 for chrysotile, amosite, and crocidolite, respectively.[ 11] Although chrysotile is associated with the lowest risk, it nevertheless appears to result in some risk in animals and humans.[12] The word "asbestos" is derived from a Greek root for inextinguishable or indestructible. Asbestos use is documented for more than 6,000 years. Persians burned bodies in asbestos cloth to preserve the ashes. Pliny the Elder observed that the asbestos quarry slaves died young and thus recommended they not be purchased. Modern recognition of the health effects of asbestos exposure were initially complicated by the high incidence of tuberculosis in sweatshops in Europe. In 1930, however, Merewether convincingly demonstrated pulmonary fibrosis in asbestos workers, coining the term "asbestosis." In 1955, Doll recognized lung cancer arising in asbestos workers,[13] and in 1960, Wagner et al described 47 cases of mesothelioma in South Africa in a crocidolite (blue amphibole asbestos) mining community, and established the diagnosis (which until then had been debated) as well as both occupational and bystander risk.[14] Asbestos fibers in lung tissue are found as either uncoated fibers or ferruginous bodies, fibers coated by macrophages with iron substance. Because fibers persist once in situ, exposure continues decades after fibers were initially inhaled. Pleural calcified plaques may develop decades after a significant asbestos exposure. Asbestos is not carcinogenic in the Ames test; however, it induces reactive oxygen species and damages DNA, producing chronic inflammation and eventual fibrosis. Because of the pattern of asbestos use, mesothelioma incidence will likely peak in Europe[15,16] in about 2020. Surveillance, Epidemiology, and End Results (SEER) data in the United States show that the incidence peaked in 1994-1995 at 1.2 cases per 100,000, with a small nonsignificant decline to 1.0 cases per 100,000 in 2000-2002.[1] The incidence varies considerably by location, being highest along coastal towns associated with shipyards and in states with industrial asbestos textile mills (Figure 2). At- risk occupations include asbestos miners and millers, but also insulation, shipyard, and maintenance workers,[ 17] as well as auto mechanics.[18] Workers manufacturing cigarette filters were exposed due to asbestos in the filter paper.[19] Incidence is lower for African-Americans than for European- Americans (Figure 1) because of work place patterns favoring whites for employment. Few women were employed in these industry jobs at the time.[1] Presentation About 85% of mesotheliomas arise in the pleura, about 9% in the peritoneum, and a small percentage in the pericardium or tunica vaginalis testis.[1] Peritoneal mesotheliomas may develop more frequently in men with heavier asbestos exposure. Women comprise only about 18% of patients with pleural mesothelioma, but 42% of those with peritoneal mesothelioma. Risk is highest at about age 80 to 84 (Figure 3).[1] The median age in reported clinical trials is frequently a decade or more younger than the median age of patients in the SEER database. Patients with pleural mesothelioma initially complain of shortness of breath or chest pain, whereas those with peritoneal mesothelioma present with increased abdominal girth or abdominal pain.[20,21] Fine-needle biopsy can be used to document recurrence or metastases but is not sufficiently reliable for primary diagnosis.[22] The histology of about half of mesotheliomas is epithelial (tubular papillary), with the remainder being sarcomatous, or mixed.[20,21] Multicystic mesotheliomas and welldifferentiated papillary mesotheliomas are associated with a long survival in the absence of treatment. Thus, these patients should be excluded from clinical trials intended for the usual rapidly lethal histologic variants of mesothelioma.[23-25] Prognostic Variables and Survival The median survival in the Surveillance, Epidemiology, and End Results (SEER) database is approxi mately 7 months and has not improved over the past 2 decades, for either pleural or peritoneal mesotheliomas (Figure 4).[1]

Poor-prognostic variables include sarcomatous histology, pleural as opposed to peritoneal primaries, older age, pain at diagnosis, male gender, poor performance status, and perhaps high lactate dehydrogenase (LDH), white blood cell, and platelet levels.[ 20,26] In a recent European Organization for Research and Treatment of Cancer (EORTC) analysis, poor prognosis was associated with a poor performance status, elevated white blood cell (WBC) count, lack of a definitive histologic diagnosis of mesothelioma, male gender, and sarcomatous histologic subtype.[27] In a Cancer and Leukemia Group B (CALGB) multivariate analysis, poor performance, pleural involvement, LDH > 500 IU/L, chest pain, platelets > 400,000/μL, sarcomatous or mixed histology, and age older than 75 years predicted poor survival.[28] Grouping prognostic variables, the group with the best survival (14 months) had a performance status of 0, and were ei- ther younger than 49 years or aged 50 or more with a hemoglobin of 14.6 or more. Those with a performance status of 1 or 2 and WBC more than 15.6/μL had a median survival of only 1.4 months.[28]

Surgical and Radiologic Treatment of Localized DiseasePleural Mesothelioma
In the SEER 9 regions from 1987 to 2002, pleural mesothelioma constituted 74% of all mesotheliomas in women and 88% in men.[1] Computed tomography (CT), magnetic resonance imaging (MRI), and 18Ffluorodeoxyglucose (FDG) imaging provide assessment of extent of disease.[29,30] Surgical alternatives include biopsy only, pleurodesis, pleurectomy, and pleuropneumonectomy. Optimal management of localized disease with surgery, radiation, or both is not established. In studies of thoracoscopic talc pleurodesis, the median survival was 7 to 9 months-not significantly different from survivals in the SEER database. After pleurectomy, the median survival ranges from 5 to 20 months. Extrapleural pneumonectomy results in median survivals of 9 to 21 months in various series. Certainly, selection of patients healthy enough to undergo surgery accounts for some or all of this difference. Of 76 patients assessed with contrast- enhanced MRI in Leicester, United Kingdom, 51 underwent extrapleural pneumonectomy or radical pleurectomy/decortication. Pathologic stage was correlated with radiologic staging, with particular emphasis on tumor resectability. On MRI, 17 patients (22%) had unresectable disease that was not visible on CT scan. Fiftyone patients (67%) underwent surgery; pathologic nodal data were incomplete in three who were excluded from further analyses. The median interval from MRI to surgery was 17 days. MRI correctly predicted resectability in 97%. (Two patients had unexpected extensive disease at thoracotomy.) MRI tumor stage was accurate in 48%, and understaged in 50%, largely due to pericardial involvement, which significantly affected neither resectability nor prognosis. Nodal stage was correctly identified in 60% of patients. Thus, MRI is unlikely to contribute significantly to nodal staging, but it remains valuable for selection of patients for surgery.[30] In a Dana-Farber/Brigham and Women's Hospital series (Table 1) of 52 selected patients who received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy, perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The median survival was 16 months. One- and twoyear survival rates were 77% and 50% for patients with epithelial histology and 45% and 7.5% for those with sarcomatous and mixed variants (P < .01); all of the latter patients died by 25 months. Patients with negative regional mediastinal lymph nodes survived longer than those with positive nodes (P < .01). Of the subset of patients with epithelial histology and negative mediastinal lymph nodes, 45% were alive at 5 years.[31] Of 132 patients with malignant pleural mesothelioma who underwent surgery in a Leicester, UK, study, 53 underwent extrapleural pneumonectomy, and 79, less radical resections. Mortality at 30 days was similar for the two groups (Table 1). Time to disease progression and survival favored extrapleural pneumonectomy, although selection bias may account for the difference. Nodal involvement of N2 nodes compared with N0/1 involvement was associated with shorter survival (197 vs 358 days, P = .02).[32] Radiation series described symptom control in some but not all patients. Conformal radiotherapy is currently under evaluation and would at least theoretically deliver a higher dose to the pleura while avoiding heart and lung tissue. Recent studies of surgery, radiation, or combined-modality therapy are shown in Table 1. After invasive procedures, the risk of tumor masses growing out of needle or incision scars was diminished by radiation in one study[42] but not a second randomized study (Table 2).[43] Peritoneal Mesothelioma
The second most common site for the development of mesothelioma is the peritoneum. Though overall more men than women develop peritoneal mesothelioma, a higher proportion of women than men develop the disease in the peritoneal cavity. In the SEER 9 regions from 1987 to 2002, peritoneal mesothelioma comprised 19% of all mesotheliomas in women and 7% in men. Typically, patients with peritoneal mesothelioma present with increasing abdominal girth, abdominal pain, ascites, fever, and night sweats. CT scan findings are varied and include ascites, localized tumor masses, or diffuse peritoneal involvement. Some long-term survivors have been described in a Dana-Farber Cancer Institute study of surgical debulking, intraperitoneal chemotherapy, and radiotherapy.[51,52] In a National Cancer Institute series, 49 patients underwent laparotomy, tumor resection, hyperthermic intraperitoneal (IP) cisplatin, and postoperative IP fluorouracil and paclitaxel. The median progression-free survival was 17 months and the medi an survival was 92 months. Patients with debulking surgery, superficial tumor, minimal residual disease after resection, and age less than 60 years survived longer.[53] Given patient selection, the contribution of any of these modalities to prolonged survival is unknown.

Pericardial Mesothelioma
Pericardial mesothelioma is a rare but lethal malignancy for which treatment options are limited.[54,55] Patients present with symptoms of constrictive pericarditis. MRI may demonstrate the extent of infiltration of the myocardium or cardiac vessels. Misdiagnosis is common, with the correct diagnosis frequently made at surgery or autopsy. Occasionally, patients survive disease-free after complete resection, but myocardial invasion usually precludes complete resection. Surgery is often useful to relieve effusions, pericardial tamponade, or constriction. Chemotherapeutic regimens established in pleural mesotheliomas, as well as intracavitary chemotherapy or irradiation and photodynamic therapy treatments, have been reported with modest benefit.[54,55]

Mesothelioma of the Tunica Vaginalis Testis
Men typically present with scrotal masses that include a hydrocele. Age at diagnosis varies widely. Staging should include CT of the chest and abdomen, as disease is frequently found intra-abdominally. The optimal primary surgical approach appears to be inguinal orchiectomy. Intra-abdominal disease found at diagnostic laparotomy may be effectively treated by surgery or abdominal radiotherapy. Testicular mesotheliomas are frequently indolent with a long interval from initial treatment to clinical recurrence. Testicular mesotheliomas have responded to chemotherapy reported to be effective for pleural and peritoneal primaries.[56] Systemic TreatmentRandomized Trials
Two recent randomized trials (Table 2) have both demonstrated significantly higher response rates for the addition of newer antifols to cisplatin therapy. Eligibility was confined to pleural mesotheliomas. Survival was significantly improved in one study,[45] with a trend in the other.[46] In another randomized trial of ranpirnase (Onconase) vs doxorubicin, ranpirinase produced similar survival to that associated with doxorubicin; however, whether doxorubicin improves survival over best supportive care is unknown.[47] Thus, based on a survival advantage in one randomized trial and a trend in a smaller European trial (Table 2), and a significantly increased response rate in both trials, the combination of cisplatin and pemetrexed (Alimta), or possibly cisplatin and raltitrexed (Tomudex), would be an appropriate initial palliative regimen for patients with pleural mesothelioma. Phase I/II Trials
Reported response rates for single chemotherapy agents prior to the advent of CT scanning were up to 30% for methotrexate, cyclophosphamide, and doxorubicin; however, using CT scan measurements, response rates were considerably lower (10%-15%). Certainly platinum and antifol combinations again appear to be effective based on response data. Platinum and gemcitabine (Gemzar) regimens are also associated with reasonable response rates. Raltitrexed or weekly vinorelbine, with reported response rates of 21% and 24%, respectively, provide attractive single- agent regimens.[57,58] Some biologics, particularly those delivered intrapleurally, also provide reasonable reported response rates.[59-62] Interferon alfa and gamma (Actimmune) have resulted in respectable response rates, particularly when delivered intrapleurally. Gemcitabine, temozolomide (Temodar), liposomal doxorubicin (Doxil), and topotecan (Hycamtin) produce response rates in the single digits. Future Directions in Systemic Treatment
Potential targets in mesothelioma include platelet-derived growth factor (PDGF)-A and -B, vascular endothelial growth factor (VEGF), p53 mutations, mesothelin, and epidermal growth factor receptor (EGFR); therefore, evaluating targeted therapies in mesothelioma is totally appropriate.[ 63-65] Mesothelin, a cell surface glycoprotein present on normal mesothelial cells, is overexpressed in the majority of epithelial mesotheliomas.[ 66] SS1(dsFv)PE38 (SS1P) is a recombinant antimesothelin immunotoxin that is currently undergoing phase I clinical evaluation at the National Institutes of Health.[67] Tumor Markers No reliable serum tumor markers are available for screening or diagnosis of mesothelioma or to monitor response to treatment. However, soluble mesothelin- related proteins could be a useful marker. Of 44 patients with mesothelioma in Perth, Australia, 37 (84%) had elevated serum-soluble mesothelin- related protein levels, compared with 3 (2%) of 160 patients with other cancers or other inflammatory lung or pleural diseases, and with none of 28 controls. Soluble mesothelinrelated protein levels correlated with tumor size and disease progression. Seven of 40 asbestos-exposed participants had increased concentrations of soluble mesothelin-related proteins. Of these, three developed mesothelioma and one developed lung cancer within 5 years.[68] Thus, soluble mesothelinrelated proteins could potentially be developed to screen asbestos-exposed individuals for mesothelioma. Quality of Life In a University of Sydney study, 53 patients treated with cisplatin and gemcitabine completed quality-of-life studies. At baseline, role and social function were impaired and symptoms included cough, fatigue, dyspnea, pain, insomnia, and anorexia. Dyspnea, pain, insomnia, and cough improved with chemotherapy, although chemotherapy- related symptoms increased.[69] Dyspnea scores correlated strongly with measured forced vital capacity.[69] Conclusions In summary, the median survival after a diagnosis of mesothelioma is short and has not changed over the past 2 decades for which statistics are available. Available treatments offer modestly improved survival, with few long-term disease-free survivors. Welldesigned clinical trials are essential.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Ries L, Eisner M, Kosary C, et al: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md; National Cancer Institute. Available at http://seer.cancer.gov/csr/1975_2002. Accessed July 5, 2005.
2. Metintas S, Metintas M, Ucgun I, et al: Malignant mesothelioma due to environmental exposure to asbestos: Follow-up of a Turkish cohort living in a rural area. Chest 122:2224- 2229, 2002.
3. Zeren EH, Gumurdulu D, Roggli VL, et al: Environmental malignant mesothelioma in southern Anatolia: A study of fifty cases. Environ Health Perspect 108:1047-1050, 2000.
4. Bianchi C, Brollo A, Ramani L, et al: Familial mesothelioma of the pleura-a report of 40 cases. Ind Health 42:235-239, 2004.
5. Roushdy-Hammady I, Siegel J, Emri S, et al: Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet 357:444-445, 2001.
6. Antman KH, Corson JM, Li FP, et al: Malignant mesothelioma following radiation exposure. J Clin Oncol 1:695-700, 1983.
7. Antman KH, Ruxer RL Jr, Aisner J, et al: Mesothelioma following Wilms’ tumor in childhood. Cancer 54:367-369, 1984.
8. Maurer R, Egloff B: Malignant peritoneal mesothelioma after cholangiography with thorotrast. Cancer 36:1381-1385, 1975.
9. Shah KV: Causality of mesothelioma: SV40 question. Thorac Surg Clin 14:497-504, 2004.
10. Cacciotti P, Strizzi L, Vianale G, et al: The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor. Am J Respir Cell Mol Biol 26:189-193, 2002.
11. Hodgson JT, Darnton A: The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 44:565-601, 2000.
12. Suzuki Y, Yuen SR: Asbestos tissue burden study on human malignant mesothelioma. Ind Health 39:150-160, 2001.
13. Doll R: Mortality from lung cancer in asbestos workers. Br J Ind Med 12:81-86, 1955.
14. Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med 17:260-271, 1960.
15. Peto J, Decarli A, La Vecchia C, et al: The European mesothelioma epidemic. Br J Cancer 79:666-672, 1999.
16. Bianchi C, Brollo A, Ramani L, et al: Asbestos exposure in malignant mesothelioma of the pleura: a survey of 557 cases. Ind Health 39:161-167, 2001.
17. Yeung P, Rogers A: An occupation-industry matrix analysis of mesothelioma cases in Australia 1980-1985. Appl Occup Environ Hyg 16:40-44, 2001.
18. Wong O: Malignant mesothelioma and asbestos exposure among auto mechanics: appraisal of scientific evidence. Regul Toxicol Pharmacol 34:170-177, 2001.
19. Talcott JA, Thurber WA, Kantor AF, et al: Asbestos-associated diseases in a cohort of cigarette-filter workers. N Engl J Med 321:1220-1223, 1989.
20. Antman KH: Current concepts: Malignant mesothelioma. N Engl J Med 303:200- 202, 1980.
21. Suzuki Y: Pathology of human malignant mesothelioma-preliminary analysis of 1,517 mesothelioma cases. Ind Health 39:183- 185, 2001.
22. Yu GH, Soma L, Hahn S, et al: Changing clinical course of patients with malignant mesothelioma: Implications for FNA cytology and utility of immunocytochemical staining. Diagn Cytopathol 24:322-327, 2001.
23. Sawh RN, Malpica A, Deavers MT, et al: Benign cystic mesothelioma of the peritoneum: A clinicopathologic study of 17 cases and immunohistochemical analysis of estrogen and progesterone receptor status. Hum Pathol 34:369-374, 2003.
24. Meister T, Birkfellner T, Poremba C, et al: Papillary mesothelioma of the peritoneum in the absence of asbestos exposure. Z Gastroenterol 41:329-332, 2003.
25. Galateau-Salle F, Vignaud JM, Burke L, et al: Well-differentiated papillary mesothelioma of the pleura: A series of 24 cases. Am J Surg Pathol 28:534-540, 2004.
26. Antman KH: Clinical presentation and natural history of benign and malignant mesothelioma. Semin Oncol 8:313-320, 1981.
27. Curran D, Sahmoud T, Therasse P, et al: Prognostic factors in patients with pleural mesothelioma: The European Organization for Research and Treatment of Cancer experience. J Clin Oncol 16:145-152, 1998.
28. Herndon JE, Green MR, Chahinian AP, et al: Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 113:723-731, 1998.
29. Gerbaudo VH, Sugarbaker DJ, Britz- Cunningham S, et al: Assessment of malignant pleural mesothelioma with (18)F-FDG dualhead gamma-camera coincidence imaging: Comparison with histopathology. J Nucl Med 43:1144-1149, 2002.
30. Stewart D, Waller D, Edwards J, et al: Is there a role for pre-operative contrast-enhanced magnetic resonance imaging for radical surgery in malignant pleural mesothelioma? Eur J Cardiothorac Surg 24:1019-1024, 2003.
31. Sugarbaker DJ, Strauss GM, Lynch TJ, et al: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11:1172-1178, 1993.
32. Stewart DJ, Martin-Ucar A, Pilling JE, et al: The effect of extent of local resection on patterns of disease progression in malignant pleural mesothelioma. Ann Thorac Surg 78:245-252, 2004.
33. Rusch VW, Rosenzweig K, Venkatraman E, et al: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 122:788-795, 2001.
34. Yajnik S, Rosenzweig KE, Mychalczak B, et al: Hemithoracic radiation after extrapleural pneumonectomy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 56:1319-1326, 2003.
35. Ahamad A, Stevens CW, Smythe WR, et al: Promising early local control of malignant pleural mesothelioma following postoperative intensity modulated radiotherapy (IMRT) to the chest. Cancer J 9:476-484, 2003.
36. Forster KM, Smythe WR, Starkschall G, et al: Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 55:606-616, 2003.
37. Lee TT, Everett DL, Shu HK, et al: Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 124:1183-1189, 2002.
38. Weder W, Kestenholz P, Taverna C, et al: Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 22:3451- 3457, 2004.
39. Friedberg JS, Mick R, Stevenson J, et al: A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma. Ann Thorac Surg 75:952-959, 2003.
40. van Ruth S, Baas P, Haas RL, et al: Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 10:176-182, 2003.
41. van Ruth S, van Tellingen O, Korse CM, et al: Pharmacokinetics of doxorubicin and cisplatin used in intraoperative hyperthermic intrathoracic chemotherapy after cytoreductive surgery for malignant pleural mesothelioma and pleural thymoma. Anticancer Drugs 14:57- 65, 2003.
42. Boutin C, Rey F, Viallat JR: Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 108:754-758, 1995.
43. Bydder S, Phillips M, Joseph DJ, et al: A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br J Cancer 91:9-10, 2004.
44. Pass HI, Temeck BK, Kranda K, et al: Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 4:628-633, 1997.
45. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636- 2644, 2003.
46. Van Meerbeeck JP, Manegold C, Gaafar R, et al: A randomized phase III study of cisplatin with or without raltitrexed in patients (pts) with malignant pleural mesothelioma (MPM): An intergroup study of the EORTC Lung Cancer Group and NCIC (abstract 7021). J Clin Oncol 22(14S):7021, 2004.
47. Vogelzang N, Taub R, Shin D, et al: Phase III randomized trial of onconase vs doxorubicin in patients with unresectable malignant mesothelioma: Analysis of survival (abstract 2274). Proc Am Soc Clin Oncol 19:577a, 2000.
48. Chahinian AP, Antman K, Goutsou M, et al: Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B. J Clin Oncol 11:1559-1565, 1993.
49. Samson MK, Wasser LP, Borden EC, et al: Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: A Sarcoma Intergroup Study. J Clin Oncol 5:86-91, 1987.
50. Sorensen PG, Bach F, Bork E, et al: Randomized trial of doxorubicin versus cyclophosphamide in diffuse malignant pleural mesothelioma. Cancer Treat Rep 69:1431-1432, 1985.
51. Antman KH, Osteen RT, Klegar KL, et al: Early peritoneal mesothelioma: A treatable malignancy. Lancet 2:977-981, 1985.
52. Antman KH, Pomfret EA, Aisner J, et al: Peritoneal mesothelioma: Natural history and response to chemotherapy. J Clin Oncol 1:386-391, 1983.
53. Feldman AL, Libutti SK, Pingpank JF, et al: Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 21:4560-4567, 2003.
54. Eren NT, Akar AR: Primary pericardial mesothelioma. Curr Treat Options Oncol 3:369-373, 2002.
55. Vigneswaran WT, Stefanacci PR: Pericardial mesothelioma. Curr Treat Options Oncol 1:299-302, 2000.
56. Antman K, Cohen S, Dimitrov NV, et al: Malignant mesothelioma of the tunica vaginalis testis. J Clin Oncol 2:447-451, 1984.
57. Baas P, Ardizzoni A, Grossi F, et al: The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: An EORTC phase II study (08992). Eur J Cancer 39:353-357, 2003.
58. Steele JP, Shamash J, Evans MT, et al: Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol 18:3912-3917, 2000.
59. Parra HS, Tixi L, Latteri F, et al: Combined regimen of cisplatin, doxorubicin, and alpha- 2b interferon in the treatment of advanced malignant pleural mesothelioma: A phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP). Cancer 92:650-656, 2001.
60. Altinbas M, Er O, Ozkan M, et al: Ifosfamide, mesna, and interferon-alpha2a combination chemoimmunotherapy in malignant mesothelioma: Results of a single center in central Anatolia. Med Oncol 21:359-366, 2004.
61. Mendes R, O’Brien ME, Mitra A, et al: Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma. Br J Cancer 86:336-341, 2002.
62. Castagneto B, Zai S, Mutti L, et al: Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients. Lung Cancer 31:303-310, 2001.
63. Nowak AK, Lake RA, Kindler HL, et al: New approaches for mesothelioma: Biologics, vaccines, gene therapy, and other novel agents. Semin Oncol 29:82-96, 2002.
64. Kindler HL: Moving beyond chemotherapy: Novel cytostatic agents for malignant mesothelioma. Lung Cancer 45(suppl 1):S125- S127, 2004.
65. Fennell DA, Rudd RM: Defective coreapoptosis signalling in diffuse malignant pleural mesothelioma: Opportunities for effective drug development. Lancet Oncol 5:354-362, 2004.
66. Hassan R, Bera T, Pastan I: Mesothelin: A new target for immunotherapy. Clin Cancer Res 10(12 pt 1):3937-3942, 2004.
67. Hassan R, Bullock S, Kindler H, et al: Updated results of the phase I study of SS1(dsFv)PE38 for targeted therapy of mesothelin expressing cancers. Eur J Cancer 2(suppl 8):280a, 2004.
68. Robinson BW, Creaney J, Lake R, et al: Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362:1612-1616, 2003.
69. Nowak AK, Stockler MR, Byrne MJ: Assessing quality of life during chemotherapy for pleural mesothelioma: Feasibility, validity, and results of using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire and Lung Cancer Module. J Clin Oncol 22:3172-3180, 2004.