From Medscape Today Management of Mesothelioma Ramaswamy Govindan, MD Introduction Malignant mesothelioma is a locally invasive disease with a dismal outcome and limited treatment options. Indeed, the median survival of patients treated in 10 consecutive prospective Cancer and Leukemia Study Group B (CALGB) studies was only 7 months, although more recent data show that treatment regimens with newer agents, such as the combination of cisplatin and pemetrexed, is associated with better survival outcomes. Nevertheless, because the incidence of malignant mesothelioma is expected to peak around 2010 before declining, continued improvements are still necessary. No significant breakthroughs in the systemic therapy of mesothelioma were reported at the 10th World Conference on Lung Cancer, but a number of interesting preclinical studies were presented that could lead to improved treatment options. Systemic Therapy Single-agent chemotherapy regimens have not shown great promise in the past, so there has been an attempt to identify active and tolerable combinations. In a multi-institutional phase 2 study of gemcitabine (1000 mg/m2 on days 1,8, and 15) and carboplatin (AUC 5), 26% of patients had a partial response, with a median response duration of 55 weeks. Median survival was 66 weeks, with a 2-year survival rate of 30%. The most common side effects were hematologic, with 11% of patients experiencing grade 3/4 leukopenia. Slightly lower response rates were noted with the combination of mitomycin, vinblastine, and cisplatin (MVP), which was associated with an overall response rate of 15% in 150 patients. However, 69% of patients reported symptom improvement, and no treatment-related deaths were seen with the use of MVP chemotherapy. Median survival in this study was 7 months, with a 1-year survival rate of 31%. In a multivariate analysis, low hemoglobin, weight loss, and nonepithelioid histology were associated with poor prognosis. The use of newer agents either singly or in combination with older agents is also being explored. For example, raltitrexed produced a partial response rate of 21% in patients with malignant mesothelioma in a prospective EORTC study. However, as noted in the studies conducted by Pavlakis and colleagues, combination therapy might be slightly more effective than monotherapy. Preliminary results were reported in 2 parallel nonrandomized phase 2 studies in which patients received either thalidomide alone or thalidomide in combination with cisplatin and gemcitabine. Of 16 evaluable patients, thalidomide monotherapy resulted in partial response in 1 patient (6%), stable disease in 8 patients (50%), and progressive disease in 7 patients (44%). By contrast, the combination of cisplatin, gemcitabine, and thalidomide resulted in 3 partial responses (14%), 12 stable disease (55%), and 7 progressive disease (32%). Thalidomide was well tolerated except for mild constipation, dry mouth, and paresthesias. An alternative novel combination studied by investigators from the United Kingdom consisted of irinotecan (100 mg/m2 days 1 and 15), cisplatin (40 mg/m2 days 1 and 15), and mitomycin C (6 mg/m2 day 1) on a 28-day cycle in patients with previously untreated malignant mesothelioma. Of 43 evaluable patients, partial responses were seen in 15 patients (43%) and stable disease was noted in an additional 23 patients (53%), with progression-free survival and overall survival of 6.5 months and 10.1 months, respectively. The most common toxicities were hematologic, with 25 patients experiencing grade 3 or 4 neutropenia. Of note, when the same regimen was tested in a group of previously treated patients with malignant mesothelioma, partial responses were seen in 3 of 10 evaluable patients. Vinorelbine was the most commonly used therapy in the first-line setting in these patients. Symptom Improvement Results of a phase 3 trial published earlier this year showed that the addition of pemetrexed to cisplatin improves survival in patients with malignant mesothelioma compared with cisplatin alone (median survival 12.1 months vs 9.3 months). As a follow-up to the survival data, Boyer and colleagues reported the results of health-related quality of life (QOL) assessments performed in this study. QOL was evaluated at baseline and on a weekly basis using a modified Lung Cancer Symptom Scale (LCSS-meso). Nearly 90% of patients completed the LCSS scores. Results showed that pain scores were significantly improved in the combination chemotherapy arm beginning with cycle 3 (P < .05 for cycles 3-6). At the same time, dyspnea scores stabilized in the combination arm while they worsened in the monotherapy arm. Anorexia and fatigue worsened in both arms at the beginning, but there was an improvement in fatigue scores in the combination chemotherapy arm by cycle 6 (P = .039). While there was progressive decline in global QOL up to cycle 3 in both arms, there was an improvement in the global scores by cycle 6 in the combination chemotherapy arm. Thus, the combination of cisplatin and pemetrexed appears to improve QOL in patients with malignant mesothelioma. In addition, the combination chemotherapy used in this study improved pulmonary function tests compared with single-agent cisplatin therapy. Combined-Modality Therapy The preliminary results of a neoadjuvant therapy from the Swiss Group for Clinical Cancer Research (SAKK) were reported at this meeting. Patients with potentially resectable malignant mesothelioma were enrolled in order to assess resectability rates and to evaluate the toxicity of combined-modality therapy. Patients underwent preoperative mediastinoscopy to rule out N2 disease, but any histologic subtype of malignant mesothelioma was allowed. Patients received 3 cycles of cisplatin (80 mg/m2 on day 1) and gemcitabine (1000 mg/m2 on days 1, 8, and 15) administered every 28 days. Preoperative therapy was well tolerated, with no grade 4 toxicities noted. Of 30 evaluable patients, 24 underwent surgery and 22 underwent pleuropneumonectomy, for a resectability rate of 73%. No pathologic complete responses were seen in any patients. The most common postoperative complication was atrial arrhythmia, with 1 death in the immediate postoperative period attributed to respiratory failure. The investigators concluded that induction chemotherapy was well tolerated in patients with potentially resectable mesothelioma. Molecular Biology Considerations Manganese-containing superoxide dismutase (MnSOD), a primary antioxidant enzyme, plays a key role in detoxification of superoxide radicals and protects tissue from free-radical damage. The formation of superoxide radicals is considered to be important in asbestos-induced carcinogenesis. A major genetic polymorphism of the MnSOD gene (MnSOD Ala9Val) could interfere with the mitochondrial transport of this enzyme and its anti oxidant properties. Of note, in a preliminary report from Australian investigators, there were significant differences in allelic frequencies between those with pleural plaque only and those with malignant mesothelioma. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death in various cancer cell lines. TRAIL binds to 2 proapoptotic (DR4 and DR5) and antiapoptotic (DcR1 and DcR2) receptors. Aberrant methylation of DcR1 was demonstrated in 44 of 66 samples of malignant mesothelioma (66%) and aberrant methylation of DcR2 was noted in 39% of primary mesotheliomas. No significant methylation was found in normal tissues. Of note, treatment with 5-aza-2-L-deoxycytidine restored DcR1 and DcR2 expression. The methylthioadenosine phosphorylase (MTAP) gene is homozygously co-deleted with CDKN2A in pleural mesothelioma. MTAP encodes an enzyme that is essential in the salvage of cellular adenine and methionine and is co-deleted with CDKN2A (encoding the p16 protein). In 2 separate fluorescent in situ hybridization (FISH) assays performed in frozen tissue from 58 cases of pleural mesothelioma, investigators from Memorial Sloan-Kettering Cancer Center in New York, NY, reported homozygous co-deletion of CDKN2A in 39 cases (67%). MTAP co-deletion was demonstrated in 87% of those who had deletion of CDKN2A, and no case of MTAP deletion was found in those without CDKN2A deletion. A novel immunohistochemistry method revealed very strong correlation with FISH analysis. This development is significant, as MTAP represents a potential target for therapy. It has been shown that loss of heterozygosity of tumor suppressor genes, such as NF2, p16INK4A, and TP53, is common in malignant mesothelioma, and the development of mesothelioma in NF2 knockout mice further enforces this concept. Kratzke and colleagues previously reported that loss of p16 INK4a is the most common molecular lesion in malignant mesothelioma. Re-expression of p16INK4a using a first-generation adenovirus gene therapy resulted in cell-cycle arrest, apoptosis, and tumor regression in xenograft models. This group of investigators also observed cell death in treated mesothelioma cell lines using synthetic TATp16INK4a, while the control peptide had no effect. Further studies examining this approach in mesothelioma xenograft models in mice are ongoing. Prognostic and Predictive Markers In order to better identify patients who will respond to therapy and to improve outcomes overall, researchers have attempted to identify prognostic and predictive markers in patients with malignant mesothelioma. Hypoxia-inducible factor 1 alpha (HIF-1a) is a subunit of a heterodimeric transcription complex that regulates a number of genes associated with tumor proliferation and inhibition of apoptosis. Expression of HIF-1a was seen 79% of mesothelioma specimens and a third of these patients had intense expression of HIF-1a, but none of the specimens from the normal mesothelium expressed HIF-1a. Unfortunately, no correlation was seen between HIF-1a expression and response to chemotherapy or survival. Because mesothelioma is classically seen as a tumor that does not respond well to systemic chemotherapies, Italian investigators sought to identify key genetic factors that might help predict which patients would respond more favorably. They theorized that overexpression of thymidylate synthase (TS) mRNA, the primary target for the antifolate pemetrexed, might correlate with resistance to pemetrexed, and that overexpression of nucleotide excision repair genes, such as ERCC1, might be associated with resistance to the cytotoxic agent cisplatin. After studying the TS and ERCC1 expression profiles in 38 paraffin-embedded specimens, they found that more than 50% of samples had low levels of TS expression and low to medium levels of ERCC1 expression, and that median mRNA expression levels did not differ significantly between the epithelial and nonepithelial types. An arbitrary cut-off value of 8 for ERCC1 was associated with trend toward better survival (437 days vs 318 days, P = .2), suggesting that ERCC1 expression might show a small predictive value. Focusing more on clinical factors, a number of research groups have been able to identify a few markers that help predict better outcomes. A 20-year cohort of 553 patients with malignant mesothelioma was analyzed for factors that could predict survival. The mean survival of the cohort was only 8 months (range, 1 month-11 years), with only 3 patients surviving longer than 5 years. The 2 most important prognostic factors favoring better survival were young age and epithelioid subtype. The EORTC had previously reported a prognostic model based on age, sex, histology, and white blood cell count. This prognostic model was tested in 3 consecutive prospective phase 2 studies conducted by EORTC, and validated the model by finding trends toward worse survival associated with a prognostic score of > 1.27. Of note, in a retrospective analysis, Rusch and colleagues reported that postoperative adjuvant therapy (radiotherapy or chemotherapy) had a favorable impact on survival apart from other known prognostic markers, such as stage and histology. 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