Even though mesothelioma remains without cure, improvements in the traditional mesothelioma treatments have led to an increase in median survival times for many types of patients. The success of the chemotherapy agent pemetrexed, marketed as Alimta by Eli Lilly, has been one of these notable improvements. Whereas previous chemotherapy regimens had not demonstrated any real success in treating pleural mesothelioma or slowing disease progression, a number of studies have confirmed the efficacy of pemetrexed in combination with the platinum compound cisplatin in the treatment of the disease. The United States Food and Drug Administration (US FDA) approved pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma in 2004 because of these studies and the combination remains the only FDA-approved treatment for mesothelioma in the United States.

Researchers from Japan began a study in 2005 about the use of pemetrexed and cisplatin for Japanese patients with malignant pleural mesothelioma and they have recently released their results. As with many of the other published studies, these researchers found moderate therapeutic activity and some survival benefit to the use of pemetrexed.

This article summarizes their findings.

Overview of the Study

The researchers began their study in 2005 with the identification of two phases of research: the first phase would investigate the recommended clinical dose of pemetrexed and cisplatin, while the second phase would analyze how effective the treatment at recommended dose was in controlling disease growth and progression.

To be eligible for study, patients had to meet a number of criteria. The major factors governing patient inclusion were:

• Chemonaive—patients were not allowed to have undergone a previous course of chemotherapy.
• Patients must have received histological confirmation of their disease.
• Patents must not have been eligible for curative surgery.
• Patient age between 20–74, performance status of 0 or 1, with adequate organ and lung function.

Results

A total of 25 patients were evaluated in the study. The majority of patients were male with an average age of 61. Most patients were Stage IV when the study began, with a performance status of 1. 60% of the patients presented with epithelial subtype.

The first phase of the study was an investigation of the recommended clinical dose. Four sets of dosing instructions were initially investigated and a fifth track at a smaller dose was also studied:

• Pemetrexed at 500 mg/m² with cisplatin at 75 mg/m² (Level 1)
• Pemetrexed at 700 mg/m² with cisplatin at 75 mg/m² (Level 2)
• Pemetrexed at 900 mg/m² with cisplatin at 75 mg/m² (Level 3)
• Pemetrexed at 1000 mg/m² with cisplatin at 75 mg/m² (Level 4)
  
• Pemetrexed at 500 mg/m² with a lower dose of cisplatin at 60 mg/m² (Level -1)

During the dose escalation phase, these various administrations were evaluated for causing toxicity events and the administrations which failed the study’s toxicity-evaluation algorithm were then removed from final consideration. The recommended dose was eventually decided as the Level 1 administration—pemetrexed at 500 mg/m² with cisplatin at 75 mg/m², which matches the average for pemetrexed treatment worldwide.

During the second phase of the study, the researchers investigated tumor response at the recommended dose level of 500 mg/m², with cisplatin at 75 mg/m². 19 patients received the Level 1 dose during this phase of the trial. 6 patients completed the smaller-dose Level -1 administration during the first phase and their results were also reported. The authors list the individual group statistics and a set of combined statistics. The Level -1 group scored better than the Level 1 group in nearly all categories, but the researchers speculate the cause of this was that all of those patients presented with epithelial mesothelioma, while only about half of the recommended dose cohort presented with epithelial histology.

Of the 19 patients who received the recommended dose, 7 patients experienced a partial response to treatment, 5 patients had stable disease, six had progressive disease and one was not evaluated. Thus, the response rate for the Level 1 cohort was 36.8%, or 7/19. Each member of the Level -1 group showed some partial response, so the overall response rate was 52%, or 13/25. The median duration of response for both groups was 5.2 months, while progression free survival was 4.7 months for the Level 1 cohort and 10.1 months for the Level -1 group, for a combined figure of 4.8 months. The 1-year survival rate for the Level -1 group was 66.7%, while the 1-year rate for the Level 1 group was 36.8%.

The overall median survival time was 9.2 months for both groups.

Conclusion

Pemetrexed and cisplatin represent the chemotherapy standard of care in the treatment of pleural mesothelioma. This study is the latest to show the treatment’s efficacy for extending survival times, even if the treatment—as all mesothelioma treatments do—falls short of being a true cure. However, these results do show treatments have improved and they offer hope that the improvements will continue in the future.

The authors report that Japan approved the use of pemetrexed and cisplatin in 2007.

Labels: mesothelioma