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Mesothelioma Medical Information
John R. Eckardt,
MD Board Certified Oncologist Member of: American Society of Clinical Oncology American Association of Cancer Research
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.
| Drug | Mechanism | Investigator(s) |
|---|---|---|
| SU5416 | Inhibits tyrosine kinase activity of flk-1 | University of Chicago Consortium (phase 2) |
| Talidomide | Inhibits fibroblast growth factor-induced angiogenesis mediated by VEGF and tumor necrosis alpha | Royal North Shore Hospital, Sydney and Royal North Shore Hospital, Brisbane, Australia (phase 2)University of Maryland (phase 2)Netherlands Cancer Institute |
| PTK787/ZK222584 | Inhibits VEGF receptor tyrosine kinases and platelet-derived growth factor receptor beta tyrosine kinase | Cancer and Leukemia Group B (phase 2, not yet recruiting) |
| Bevacizumab | Blocks VEGF receptor binding | University of Chicago Consortium (randomized phase 2, gemcitabine/cisplatin ± bevacizumab) |
Several trials are underway examining thalidomide activity 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.