Malignant mesothelioma is an aggressive but rare malignancy that principally affects the pleura and peritoneum. The pleura and peritoneum are lining that cover the lung (pleura) and the abdominal cavity (peritoneum). In recent years, a steady proportional increase in pleural tumors has been matched by a proportional decrease in peritoneal tumors.[1]

Roughly 80% of cases are believed to derive from occupational or paraoccupational exposure to primary asbestos fiber types (thus the high mesothelioma asbestos claim numbers); namely, crocidolite, amosite, and chrysotile in a ratio of 500:100:1, respectively, and, less commonly, by exposure to tremolite (which has little commercial value and is therefore mined in limited quantities). These are the cases most associated with mesothelioma lawsuits and claims across the country requiring the assistance of a mesothelioma lawyer. According to recent mesothelioma statistics from Great Britain's Health and Safety Executive's Epidemiology and Medical Statistics Unit, risk appears to be highest among workers associated with the following broad areas of asbestos use: shipbuilding, railway carriage and locomotive building, and installation/maintenance of insulation materials in buildings or industrial plants.

Epidemiologic Trends

By contrast, during the same time period when asbestos was banned in the United States, asbestos imports were peaking in the United Kingdom. This accounts for the currently increasing incidence rate, from a current total of 1300 cases annually to a projected total of more than 3000 cases annually by the year 2021. In Western Europe -- specifically, Britain, France, Germany, Italy, The Netherlands, and Switzerland, which account for 75% of the entire Western European population -- asbestos use remained high until 1980, and substantial quantities are still used in several countries.

Prognosis

Diagnosis

A thorough history with a focus on occupational aspects and presenting signs and symptoms, coupled with computed tomography (CT) and thorascopic pleural biopsy, are generally effective in disease diagnosis.

The Role of Surgery and Radiotherapy

The role of surgery and radiotherapy (RT) in mesothelioma management is quite limited. Neither is backed by evidence from randomized, controlled trials that establish their efficacy as single-modality therapies.

Surgery, while used successfully for palliative control of symptoms, has only minimal effect on median survival times when used as a radical treatment. Extrapleural pneumonectomy, defined as a "radical treatment" is associated with a median survival of 15-24 months. Extrapleural pneumonectomy involves resection of the pleura, lung, and pericardium, and often the diaphragm. Debulking parietal pleurectomy is associated with minimal morbidity and 90% effusion control at 12 months. Thoracoscopy with palliative pleurodesis is generally reserved for patients for whom pneumonectomy and other procedures (ie, pleural decortication, resection of the parietal/visceral pleura with lung preservation) are contraindicated.

RT has only been studied in limited numbers of patients, and its utility is restricted by both the volume of the tumor to be treated and by normal tissue toxicities. Like surgery, there may be a palliative role for RT, as it appears to be effective in alleviating pain. However there are no data suggesting that RT improves survival compared with best supportive care.

Single-Agent Chemotherapy

Because most patients with mesothelioma are not candidates for surgery or RT, chemotherapy or palliative care are often the only options. To date, single-agent regimens utilizing commercially available cytotoxic agents such as cisplatin, doxorubicin, trimetrexate, or the taxanes docetaxel or paclitaxel have yielded modest results with average response rates no higher than 10% to 20%. Although doxorubicin has been the most frequently investigated, results of a recent meta-analysis suggest that cisplatin is the most active.

Single-agent chemotherapy with newer compounds, such as liposomal anthracyclines (ie, liposomal doxorubicin, daunorubicin), gemcitabine, and pemetrexed, have, likewise, yielded modest results. While the former have proven mostly inactive, phase 2 data with the nucleoside analogue gemcitabine demonstrated response rates ranging from 0% to 31%, while the overall response rate is 14% for the antifolate pemetrexed.

Combination Chemotherapy

To date, combination regimens using traditional agents (eg, doxorubicin/cisplatin, doxorubicin/cisplatin/cylophosphamide, cisplatin/etoposide, cisplatin/DHAC) have not yielded substantially higher response rates than single-agent regimens.[19] By contrast, doublets utilizing novel cytotoxic agents such as pemetrexed, gemcitabine, and raltitrexed in combination with a platinum have shown more encouraging results.

Pemetrexed/Cisplatin

Pemetrexed's primary mechanism of action is the inhibition of 3 enzymes involved in purine and pyrimidine synthesis: thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Although other drugs, such as raltitrexed and 5-fluorouracil, also target TS, no other agent currently available targets all 3 enzymes.

Encouraging results from phase 1 and 2 trials, in which up to 45% of evaluable patients receiving pemetrexed/cisplatin experienced a partial response (PR), led to the largest phase 3 trial ever undertaken among mesothelioma patients. Vogelzang and colleagues[35,36] randomized 456 eligible patients to pemetrexed 500 mg/m2 intravenous bolus over 10 minutes plus cisplatin 75 mg/m2 administered every 3 weeks (n = 226) or to single-agent cisplatin 75 mg/m2 plus saline (to preserve blinding) administered every 3 weeks (n = 222). The majority of trial patients had stage III or IV disease. Previous reports had documented severe toxicities (eg, grade 4 neutropenia and diarrhea) due to elevated baseline serum homocysteine and methylmalonic acid resulting from folic acid and vitamin B12 deficiencies. Therefore, the 2 treatment arms were modified early during trial recruitment to include supplementation with 350 to 1000 mcg folic acid daily and 1000 mcg intramuscular vitamin B12 every 9 weeks.

A statistically significant longer median survival time was observed in all patients receiving the combination therapy vs all patients receiving cisplatin alone (12.1 months vs 9.3 months, respectively; hazard ratio [HR] = 0.77; P = .020).

Median time to progressive disease was also significantly longer for patients in the pemetrexed/cisplatin arm compared with those in the cisplatin-only arm (5.7 months vs 3.9 months; HR = 0.68, P = .001). Tumor response (PR only), as measured by CT scan, was observed in 41.3% of patients in the pemetrexed/cisplatin arm vs 16.7% of patients in the cisplatin-only arm (P <.001).

Although treatment with pemetrexed/cisplatin resulted in a greater incidence of drug-related serious adverse events (22.5% vs 7.2%, respectively) as well as more grade 3/4 neutropenia, nausea, and vomiting, supplementation with folic acid and vitamin B12 resulted in consistent declines in toxicity. Indeed, significant differences in some toxicities were observed between those who were fully or partially supplemented and those who were never.

Finally, Gralla and colleagues analyzed quality-of-life (QOL) parameters as measured by the LCSS-meso instrument for roughly 96% of patients (n = 448) enrolled in this trial. In addition to the survival advantage noted by Vogelzang, the pemetrexed/cisplatin combination was associated with statistically significant improvements in global QOL and symptom relief in most parameters by week 18, compared with cisplatin only; significant improvements were noted in pain, dyspnea, and cough by week 15 (P < .001). Notable improvements in QOL and symptoms occurred within 6 to 9 weeks of starting treatment.

Gemcitabine/Cisplatin

Gemcitabine is a pyrimidine antimetabolite that is related to cytosine arabinoside. It has been shown to have broad activity in mesothelioma and a variety of other solid tumors. While its activity as a single agent is limited, response rates generally have been higher when used in combination with cisplatin.

Byrne and colleagues observed a 47.6% response rate among 21 patients receiving cisplatin 100 mg/m2 intravenously on day 1 and gemcitabine 1000 m/m2 intravenously on days 1, 8, and 15 of a 28-day cycle for 6 cycles. Ninety percent of patients experienced substantial or complete symptom relief. However, despite these favorable findings, median survival was only 9.4 months. Toxicity was mainly confined to the gastroenterologic and hematologic systems: grade 3 nausea and vomiting occurred in 33% of patients and leukopenia occurred in 38%, while grade 4 thrombocytopenia occurred in 19%.

New Therapeutic Pathways

Although relatively little is known about the biology of malignant mesothelioma, there is growing interest in the multiple factors involved in angiogenesis. One target of particular interest is the vascular endothelial growth factor (VEGF) signal transduction pathway. VEGF is considered the best-characterized proangiogenic factor; upon expression, VEGF binds to receptors on endothelial cells and initiates a signaling cascade that stimulates new blood vessel formation. In vitro data demonstrate that VEGF is one of the various autocrine growth factors that play an important role in the aggressive growth and metastasis of mesothelioma, such that VEGF, VEGF-C, and its receptors are expressed by mesothelioma cell lines.[40] Note that VEGF expression through the receptor flk-1 correlates with microvessel density, which, in turn, is associated with poor survival.

The presence of both VEGF and VEGF-C autocrine activity in mesothelioma cells suggests that the development of therapies that ultimately target both may confer the greatest activity. Another potential avenue lies in incorporating the VEGF blockade into current cytotoxic regimens. Agents currently being studied for their anti-VEGF potential include SU5416, thalidomide, PTK787/ZK222584, and bevacizumab VEGF, vascular endothelial growth factor.

Several trials are underway examining thalidomide a

ctivity in malignant mesothelioma. Thalidomide is thought to inhibit VEGF-, tumor necrosis alpha-, and basic fibroblast growth factor-induced angiogenesis.

PTK787/ZK222584 is an inhibitor of both VEGF receptor tyrosine kinases and platelet-derived growth factor receptor beta tyrosine kinase. In vitro data demonstrate dose-dependent inhibition of malignant mesothelioma cells lines and patient cell lines that are both sensitive and resistant to conventional therapy. Furthermore, PTK787/ZK222584 inhibits VEGF-induced migration of cells across the extracellular matrix. Phase 1 study data demonstrated disease stabilization in up to 50% of patients receiving up to 1000 mg daily.[45] No significant clinical toxicities were noted. A phase 2 trial examining its efficacy in malignant mesothelioma will soon open within the CALGB.

Bevacizumab is a recombinant monoclonal antibody that blocks VEGF from binding to its receptors and is the first antiangiogenesis agent to prove effective in a phase 3 trial. In combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin), bevacizumab increased survival, progression-free survival, and response rate and duration in 800 patients with metastatic colorectal cancer vs bolus IFL alone. A randomized phase 2 trial, sponsored by the University of Chicago Consortium, is currently underway to evaluate the effectiveness of gemcitabine/cisplatin with or without bevacizumab in 106 patients with malignant mesothelioma.

Epidermal growth factor receptor (EGFR) represents an additional angiogenic target of particular interest. Its expression, which is activated via aberrant signaling and ligand binding, has been reported in 68% of paraffin-embedded mesothelioma specimens, and 4 of 4 mesothelioma cell lines. However, Govindan and colleagues demonstrated that the EGFR-targeting agent gefitinib 500 mg daily was inactive in malignant mesothelioma and did not correlate with failure-free survival in patients expressing EGFR.

Summary and Conclusions

Although malignant mesothelioma has long been considered one of the more uncommon cancers in the Western hemisphere, a steady increase in case numbers, particularly in the United Kingdom, has created an urgency to find new treatments that offer fewer toxicities, better symptom control, increased antitumor activity, improved survival, and better overall QOL. Until recently, these goals remained elusive, and the strength of the evidence supporting any single treatment modality was weak.

Fortunately, the tide appears to be turning and the sense of nihilism surrounding mesothelioma treatment is dissipating. Greatly encouraging results from clinical trials suggest that combination chemotherapy utilizing at least one novel agent has an important, definitive role in disease management. At present, phase 3 data demonstrating significant improvements in survival, favorable tolerability, good antitumor activity, and increased QOL support the use of pemetrexed plus cisplatin as first-line therapy for malignant pleural mesothelioma. Other combinations, including gemcitabine plus cisplatin or carboplatin, and raltitrexed plus oxaliplatin, may, likewise, become standard therapy in the near future.

As evidence continues to mount that more firmly establishes the role of combination chemotherapy, researchers are beginning to make inroads into greater understanding of the biology of mesothelioma. Ultimately, new insights may provide novel therapeutic targets and a means to further improve outcomes.

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