Malignant peritoneal mesothelioma—Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent
Introduction
Malignant peritoneal mesothelioma (PM) is a relatively rare cancer that develops in the cells lining the peritoneum. There is a clear statistical relationship between mesothelioma and a particularly heavy exposure to airborne asbestoses fibers, and pleural plaques are seen in approximately 50% of patients with peritoneal primaries [1], [2]. With a latency period of 20–40 years between occupational asbestos exposure and development of disease [1], mesothelioma typically affects older men in their fifth, sixth, or seventh decade of life [2], [3].
Yearly incidence of PM is about 1–2 cases per million in Europe, while the incidence of pleural mesothelioma is 3- to 30-fold higher in different countries, depending on the level of industrialization [4]. The incidence of mesothelioma appears to be increasing in the EU, and PM now accounts for 25–33% of all mesotheliomas [5], [6].
Due to its low incidence, few studies have been conducted in patients with PM specifically. Treatment has often followed that recommended for pleural mesothelioma. Intensive multi-modality approaches that combine cytoreductive surgery with intraperitoneal chemotherapy, with or without radiotherapy, have been evaluated at several institutions with encouraging results in small cohorts of patients. However, this therapeutic strategy is only feasible in the minority of cases. For those patients not suitable for curative resection, the prognosis is rather poor. They can be palliated with systemic intravenous chemotherapy, although no standard treatment has been approved by any regulatory agency. Patients with pleural mesothelioma have a median survival time of 10–17 months from symptom onset and 9–13 months from diagnosis [3]. Median survival time for untreated PM ranges from 5 to 12 months [7]. For patients not suitable for curative resection, median survival ranges from 6 to 9 months have been reported [8].
Chemotherapy for peritoneal mesothelioma continues to be challenging. Evaluation of efficacy of anticancer agents is hampered by the limited number of patients and by the difficulties inherent to the assessment of radiologic response. The diffuse spreading nature of this disease, as well as the variable volumes of ascetic fluid, can obscure the actual extent of the disease and can hinder tumor assessment.
In general, the most common single-agent drugs used for mesothelioma have been the anthracyclines, platinum agents, and antimetabolites. Investigational treatments alone or in combination with other compounds in Phase 2 studies have included doxorubicin, epirubicin, mitomycin, cisplatin (CIS), carboplatin (CARBO), methotrexate, irinotecan, trimetrexate, gemcitabine, raltitrexed, edatrexate, vinorelbine, and paclitaxel [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. These compounds have been evaluated for the treatment of pleural mesothelioma and have also been used for PM. However, no chemotherapeutic agent, either alone or in combination, has demonstrated a consistent survival advantage in PM. Currently, there is no approved treatment for PM.
Pemetrexed (ALIMTA®, PEM) is a multitargeted antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that PEM inhibits dihydrofolate reductase (DHFR), thymidylate synthase (TS), and glycinamide ribonucleotie formyltransferase (GARFT), all of which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides [19], [20]. Preclinical studies have shown that PEM inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) [3].
In 2004, PEM was approved worldwide to be used in combination with CIS for the treatment of malignant pleural mesothelioma in patients whose disease is not resectable [19], [21]. A major study that facilitated this approval was a phase III trial of PEM 500 mg/m2 and CIS 75 mg/m2 versus CIS 75 mg/m2 alone. The median survival time for PEM/CIS was 12.1 months compared to 9.3 months for CIS alone (p = 0.020) [22].
After this phase III trial showed improved overall survival in patients with pleural mesothelioma, but before the approval of the regimen, there was a demand for patient access to pemetrexed. The International Expanded Access Program (EAP) was created by Eli Lilly and the FDA to facilitate compassionate use of PEM for patients with mesothelioma prior to approval by regulatory agencies. In this program, 109 patients with malignant PM were enrolled.
Because of the limited clinical data available for PM – PM is a rare disease not often studied because of the difficulty of finding adequate numbers of patients to enroll in trials – and because there is no approved treatment regimen for PM, it was considered important to report on this patient population and to evaluate a more comprehensive safety and efficacy profile when PM patients were treated with pemetrexed with or without a platinum agent.
Section snippets
Regulatory
The protocol and consent document were approved by a local institutional review board at each participating site. This study was conducted according to the principles of good clinical practices, applicable laws and regulations, and the Declaration of Helsinki. Patients provided signed informed consent prior to undergoing any study procedure or receiving any study treatment.
Patients
Under the International EAP, patients in European countries diagnosed with mesothelioma were provided access to PEM while
Baseline characteristics and patient disposition
This study of patients participating in the EAP program was conducted at 310 study centers in 13 countries in Europe and Canada. Fig. 1 displays patient disposition. Of the total number of patients enrolled in the study (N = 3255), 113 eligible patients with PM entered the study, 109 of whom received at least 1 dose of PEM alone or in combination with CIS or CARBO, and were evaluable for safety. Among these 109 patients, 91 had at least 1 post-baseline tumor assessment and were evaluable for
Discussion
The number of previous studies evaluating the role of systemic anticancer therapy in PM patients is limited, especially randomized clinical trials adequately powered to reach statistical significance. Table 4 lists peritoneal mesothelioma studies using various chemotherapy options [10], [11], [13], [14], [27].
The EAP reported here represents the largest known study (N = 109) of patients with PM to date. This study showed an overall response rate of 18.7%, an overall disease control rate of 68.1%,
Conclusion
The results of this study confirm previous findings that PEM combined with a platinum agent shows antitumor activity and has an acceptable safety profile for the treatment of malignant PM. In conclusion, our observations showed that PEM with or without a platinum agent was both active and well tolerated in chemo-naïve and previously treated patients with peritoneal mesothelioma, with an overall response rate of 18.7%, disease control rate of 68.1%, and 1-year OS rate of 47.4%.
Conflict of interest
C. Visseren-Grul and J. Blatter are employees of Eli Lilly and Company. Y. Liu is an employee of i3 Statprobe, a CRO employed by Eli Lilly and Company. G. Carteni, C. Manegold, G. Martin Garcia, S. Siena, C.C. Zielinski, D. Amadori, and R. Stahel were investigators who participated in the study conduct.
Acknowledgements
Rhonda Anderson provided writing assistance for the manuscript. Ms. Anderson is an employee of i3 Statprobe, who received payment from Eli Lilly for this service.
Funding: Study H3E-MC-JMFL was funded by Eli Lilly and Company.
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