Peritoneal mesothelioma is a relatively rare disease, with an estimated annual incidence of approximately 1 per one million. Its incidence is still increasing and a peak is expected in many developed countries within the next two decades due to the long latency period from asbestos exposure, the main known etiologic factor, to the development of clinical symptoms.¹²#

The tumor is most often confined to the peritoneal cavity at the time of initial diagnosis and remains there for much or all of the subsequent clinical course. Hence, aggressive local-regional therapy has been attempted to try to improve the survival of patients with this disease. Intensive multimodality approaches that combine cytoreductive surgery with intraperitoneal chemotherapy, with or without radiotherapy, have been evaluated at several institutions with encouraging results in selected small cohorts of patients.² However, these therapeutic strategies, often associated with high morbidity and mortality rates, are only feasible in a minority of cases. For those patients not suitable for curative resection, the prognosis is rather poor with median survival ranging from 6 to 9months.¹#

The role of chemotherapy in this setting continues to be challenging. Evaluation of efficacy of antineoplastic agents is hampered by the limited number of patients and by the difficulties inherent to radiological assessment of response because of the diffuse spreading nature of this disease and the variable volumes of ascitic fluid that obscure its actual extent. Numerous single-drug and combination regimens have been tested over the past decades with modest results. In addition, data concerning mesothelioma of peritoneal origin are particularly scarce. For these reasons we present an overview of the role of systemic chemotherapy in the management of malignant mesothelioma regardless of its site of origin, with particular emphasis on the emerging role of antifolates.#

Original data for inclusion in this review was obtained through a MEDLINE search of the literature. All reports from 1966 through February 2005 were identified by the following search terms: “mesothelioma”, “peritoneal”, “chemotherapy”, “antifolates”, “cancer therapy”. All original research and review papers related to the role of systemic chemotherapy were selected. This search was supplemented by a manual search of the Proceedings of the Annual Meetings of the American Association for Cancer Research, American Society of Clinical Oncology, and the American Association for Cancer Research (AACR)–European Organization for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI) Symposium, on New Anticancer Drugs.#

Most available cytotoxic agents have been tested in patients with malignant mesothelioma with rather disappointing results. Early clinical trials generally included small heterogeneous patient populations. A systematic review published in 2002 performed a meta-analysis of all prospective clinical trials published in the literature from 1965 to 2001 relative to the treatment of malignant mesothelioma of pleural or peritoneal origin.³ All trials with at least 14 patients that had observed at least one objective response to therapy were included. This systematic review comprised over 2300 patients included in 80 single-arm and 3 randomized phase II trials. Trials were divided in four groups: Group 1 were those trials testing cisplatin without doxorubicin; Group 2 were trials evaluating doxorubicin without cisplatin; Group 3 were studies assaying the combination of cisplatin and doxorubicin; and Group 4 included all other trials. Results of the meta-analysis are summarized in Table 1. Overall response rates were greater for Group 3 (cisplatin and doxorubicin) than for Group 1 (cisplatin) (29% versus 23%, p=0.22) or Group 2 (doxorubicin) (29% versus 11%, p<0.001). Polychemotherapy regimens had greater response rates than single agent therapy (23% versus 12%, p<0.001). Response rates observed for patients treated with cisplatin (23%) were significantly greater (p<0.001) than those observed for patients treated with doxorubicin (11%) or treatment regimens not including any of these two drugs (12%), whereas no significant differences were observed between patients belonging to Group 2 (doxorubicin) and Group 4 (other agents). Cisplatin-containing regimens were also more active than carboplatin-containing regimens (24% versus 12%, p=0.004). Doxorubicin showed greater response rates than epirubicin (18% versus 9%, p=0.02), although this difference was vanished when studies containing cisplatin were withdrawn from the comparison (11% versus 9%, p=0.7). In terms of antitumoral response rate, thus, this meta-analysis suggested Cisplatin to be the most active single agent, and the combination of Cisplatin with Doxorubicin the most active regimen. However, these results should be interpreted with caution, as the validity of these comparisons was not warranted by a randomization procedure. Also, conclusions were based solely on response rates as a meta-analysis on survival or quality of life issues could not be performed because these other more important endpoints were poorly reported in most trials.#

More recently, newer agents have shown promise of greater efficacy. Among them, antifolates deserve particular mention due to their emerging role in the treatment of this traditionally chemoresistant disease. Other cytotoxic agents that have shown to be active in this setting include gemcitabine and vinorelbine, either alone or combined with platinum compounds. A number of other drugs, including alkylating agents, fluoropyrimidines, taxanes or camptothecins, have also been evaluated in malignant mesothelioma patients with poor results and will therefore not be commented further.#

Clinical trials have been recently initiated to evaluate the antitumor activity of different drugs targeting vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as they are known autocrine growth factors in malignant mesothelioma, and epidermal growth factor receptor (EGFR), which is also highly overexpressed.³² VEGF inhibitors currently in clinical trials include SU5416, bevacizumab, and thalidomide. A National Cancer Institute (NCI)-sponsored phase II trial of SU5416 has been concluded and antitumor activity has been observed. A U.S. nationwide double-blind, placebo-controlled phase II trial of cisplatin/gemcitabine with or without bevacizumab in patients with malignant mesothelioma has been launched. Thalidomide, however, has already shown negative preliminary results, as have some EGFR or PDGF inhibitors such as gefitinib or imatinib.³² Many other targeted agents are currently under evaluation.#

In light of the aforementioned data, the pemetrexed-cisplatin combination has become the new standard of care for patients with unresectable malignant pleural mesothelioma. This chemotherapy combination is the first systemic treatment that demonstrates a clear survival improvement in this patient population. Given the absence of more solid data in patients with mesothelioma of peritoneal origin, and considering that results of uncontrolled studies with this treatment regimen in peritoneal mesothelioma patients are in the range of those observed for mesothelioma of pleural origin, we believe that pemetrexed-cisplatin would also be the preferred chemotherapy option for peritoneal mesothelioma patients not suitable for curative surgery. Folic acid and vitamin B12 supplementation is mandatory in pemetrexed-treated patients as it notably reduces toxicity, including drug-related deaths, while improving efficacy. For patients with poor performance status or impaired cardiovascular or renal functions, pemetrexed alone with or without carboplatin are acceptable alternatives. Other cytotoxic agents that have shown to be active in this setting include raltitrexed combined with cisplatin or oxaliplatin, gemcitabine alone or combined with platinum compounds, and vinorelbine. Evidence supporting their use, however, is less compelling.#

Future strategies shall incorporate these novel agents into multimodality approaches at earlier stages of the disease, both in patients with pleural and peritoneal mesothelioma. Further insights into the molecular biology of this malignant tumor shall help us identify new targets for drug development and teach us how to best integrate new targeted therapies with conventional chemotherapy. In this regard, Bueno et al. recently showed that the human alpha folate receptor is consistently overexpressed in 72% of mesothelioma tumor specimens compared to normal tissues, a finding that provides some molecular basis for the consistent antitumor activity observed with antifolates in this disease and may improve our ability for adequate patient selection for specific therapies.³³ Further, defective core-apoptosis signaling seems to play an important role in resistance to treatment.³⁴ On the other hand, deletions of chromosome regions 1p, 3p, 9p and 6q, as well as loss of chromosome 22, are commonly found in mesothelioma. These regions contain putative tumor suppressor genes such as NF2, p14 or p16.³⁵ Improving our understanding of the molecular basis of this disease, as well as the mechanisms involved in response and resistance to therapy, will be essential tools that will help us develop newer more rationally designed treatment strategies that will potentially change the natural history of malignant mesothelioma. Finally, given the low incidence of malignant mesothelioma in the general population, encouraging physicians to refer these patients to specialized centers and patients themselves to participate in clinical trials is of utmost importance.#