A rare neoplasm, malignant mesothelioma mostly develops on the mesothelial surfaces of the pleural cavity, on the peritoneal surface in a few cases, and seldom in the pericardium or tunica vaginalis. The condition has an exceptionally poor prognosis irrespective of the therapeutic approach, with median survival being 4 to 13 months in case of untreated patients and around 6-18 months in case of patients who receive treatment.
A variety of factors have made it difficult to develop systemic treatment approaches for pleural mesothelioma. These factors include the relatively fewer number of patients; difficulty in assessing the treatment benefits, if any, being derived by an individual patient; and the poor prognosis linked with advanced disease.
The best way to assess the effectiveness of a new agent or combination drug therapy among mesothelioma patients is the evaluation of survival benefit through a randomized trial.
Both the objective response rate (which is demonstrated on CT scan by a reduction of >30% in the width of the pleural rind located perpendicular to the rib cage) as well as the progression-free survival rate have been used as alternative ways to determine effectiveness in all phase III clinical trials till date. In comparison to the objective response as evaluated using computed tomography alone, the use of positron emission tomography in combination with CT scanning (PET/CT) to ascertain a reduction in the tumor’s metabolic activity may be a better indicator of time to progression. In phase III trials however, the PET/CT factor has never been corroborated.
The interpretation of results has been limited by the diversity of study populations in various studies. Analysis from the European Organization for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) have enabled the proper identification of the primary prognostic factors and enhanced the ability to evaluate and generalize results among clinical trials.
Emerging techniques, for instance gene expression profiling, can eventually allow further classification of patients into diverse prognostic subgroups.
Benefits associated with chemotherapy
Analysis from three randomized clinical studies have helped establish that cisplatin-based doublet chemotherapy considerably increases survival as compared to single agent chemotherapy or active supportive care (ASC).
The sole randomized clinical trial, which directly evaluated chemotherapy in comparison to ASC, failed to show any major improvement in survival irrespective of the treatment involving single agent Vinorelbine or a conventional regimen of low-dose cisplatin, mitomycin, and vinblastine. However, the study was discontinued prematurely due to poor accrual after the initial enrollment of 409 patients. The two chemotherapy groups that were still active were put together for a survival analysis. The survival among those who were treated with both chemotherapy and ASC was slightly prolonged. However, this difference was not significant in statistical terms (8.5 as opposed to 7.6 with ASC alone).
As opposed to the above finding, two trials that compared present-day doublets (high dose cisplatin – 75-80 mg/m2) in combination with an anti-folate (cisplatin plus raltitrexed and cisplatin plus pemetrexed) demonstrated considerable increase in survival in comparison to cisplatin alone. With cisplatin alone, the median survival was nine months in both these trials, something which was also demonstrated in the other randomized trial with ASC alone.
Single agent chemotherapy
For several different agents, phase II trials have demonstrated clinical activity, as made evident through response rates. While single agent chemotherapy has not demonstrated to increase survival in previously untreated patients, it is possible that these agents may be useful as second-line therapy in certain patients.
Discussed below are some of the agents that have shown significant activity in phase II trials:
- Cisplatin – The meta-analysis of almost all phase II trials published during 2001 showed that cisplatin was the most effective single agent. As far as combination chemotherapy regimens are concerned, cisplatin can be described as its backbone. Carboplatin can also demonstrate activity, although the available data is significantly less.
- Pemetrexed – As a single agent, pemetrexed demonstrated considerable activity in phase II trials and had an expanded access program. The results derived thereon have prompted the use of pemetrexed in combination with cisplatin, which has become the standard approach for preliminary systemic chemotherapy in mesothelioma patients. This agent may also be useful in the role of second-line therapy for patients who were not treated with this agent earlier.
Other antifolates that have demonstrated single agent activity include edatrexate, raltitrexed, and methotrexate.
- Gemcitabine – This has demonstrated activity in phase II trials and may be useful, especially when used in combination with cisplatin.
- Anthracyclines – Several studies have demonstrated significant response rates with doxorubicin. Clinical activity may also be possible with the use of epirubicin and pegylated liposomal doxorubicin.
- Vinca alkaloids – Vinca alkaloids such as vinorelbine and vinflunine have demonstrated objective responses in phase II trials.