TREATMENT


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Patients with MPM should be managed by an experienced multidisciplinary team. Treatment options include surgery, radiation therapy (RT), and chemotherapy. Selected patients with clinical stages I–III with operable disease and a good performance status may be candidates for multimodality therapy.

Chemotherapy

Most patients with MPM are not candidates for aggressive surgery due to the extent of disease or an inadequate functional status. In those patients unable or unwilling to have surgery, and with an acceptable performance status, chemotherapy is a reasonable treatment option. Platinum analogs, selected anti-metabolites (pemetrexed [Eli Lilly and Company, Indianapolis, IN, USA], raltitrexed [AstraZeneca, London, UK], methotrexate [multiple manufacturers]), gemcitabine (Eli Lilly and Company), vinorelbine (Pierre Fabre, Parsippany, NJ, USA), and doxorubicin (multiple manufacturers) have activity in MPM with single-agent response rates of 7%–20%.37 Only one randomized trial has evaluated the impact of first-line single-agent chemotherapy on survival in this disease. A Phase III comparison of weekly vinorelbine with best supportive care in patients with previously untreated MPM closed early due to poor accrual, and was therefore underpowered, but demonstrated a trend toward improved progression-free and overall survival in the vinorelbine arm.38

The role of combination chemotherapy has also been evaluated in MPM. Vogezang et al performed a randomized Phase III comparison of cisplatin and pemetrexed versus cisplatin (multiple manufacturers) alone in 456 treatment-naïve patients with MPM who were not surgical candidates. There was a statistically significant improvement in median overall survival (12.1 versus 9.3 months, P=0.02) and progression-free survival (5.7 versus 3.9 months, P=0.001) that favored the combination arm.39 As a result of this trial, the combination of cisplatin and pemetrexed received the US Food and Drug Administration (FDA) approval as first-line treatment for MPM and has been the preferred regimen over the past decade in the USA. A similar Phase III trial performed in Europe compared the combination of cisplatin and raltitrexed with cisplatin alone. The primary end point was median overall survival, and a statistically significant improvement was seen in the combination arm (11.4 versus 8.8 months, P=0.048).40

The combination of carboplatin (Bristol-Myers Squibb, Princeton, NJ, USA) and pemetrexed has also been evaluated in three Phase II trials in patients with untreated MPM with reported median overall survivals of 12.7–14 months.41–43 In addition, in a non-randomized comparison of 1,704 patients treated with cisplatin and pemetrexed or carboplatin and pemetrexed as part of an expanded access program, the median time to progression (7 versus 6.9 months) and 1-year survival rates (63.1% and 64%) were similar between the two regimens.44 The combination of carboplatin and pemetrexed is therefore a reasonable alternative for those patients unable to receive cisplatin. In addition, the combination of cisplatin and gemcitabine has been assessed in two Phase II trials with reported median survivals of 9.6 and 11.2 months, suggesting that it may be a useful option for MPM patients who cannot receive pemetrexed.45,46

The benefit of second-line chemotherapy in MPM has only been evaluated to a limited extent. Jassem et al randomized 243 patients with previously treated MPM who had not received prior pemetrexed to pemetrexed or best supportive care. A significant improvement in median time to progression was seen in the pemetrexed arm (3.7 versus 1.5 months, P=0.0002), but no difference in overall survival or mean change in quality of life was observed.47 The authors speculated that the lack of improvement in overall survival may have resulted from a significant imbalance in post-discontinuation chemotherapy between the two arms. Nonetheless, these results suggest that pemetrexed is a reasonable second-line option for those patients who did not receive it first-line. Additional second-line options in MPM include vinorelbine and gemcitabine, but both have demonstrated limited activity in this setting.48,49

Until recently, prior studies of molecularly targeted therapy in MPM had failed to demonstrate significant promise. Specifically, multiple prior attempts to target the vascular endothelial growth factor pathway in MPM had met with limited success.50,51 However, a recent multicenter Phase III trial (IFCT-CFPC-0701 MAPS) compared the addition of the vascular endothelial growth factor monoclonal antibody bevacizumab (Genentech Inc., South San Francisco, CA, USA) to cisplatin and pemetrexed followed by maintenance bevacizumab with cisplatin and pemetrexed alone in 448 untreated, unresectable MPM patients with a good performance status. A statistically significant increase in the median overall survival was observed in the bevacizumab-containing arm compared with the chemotherapy-only arm (18.8 versus 16.1 months, P=0.012). Higher rates of grade 3 hypertension, proteinuria, and arterial thrombotic events were also observed in the bevacizumab arm.52 Though not yet formally approved for use in MPM, this regimen could be considered an emerging standard of care for appropriately selected patients who are candidates for bevacizumab.