Phase II Trial of Pemetrexed and Gemcitabine in Chemotherapy-Naive Malignant Pleural Mesothelioma
ABSTRACT Pemetrexed and gemcitabine have single-agent activity in malignant pleural mesothelioma (MPM). The combination of pemetrexed/gemcitabine has not previously been studied in MPM to our knowledge.
Patients with histologic or cytologic diagnosis of MPM were included. Cohort 1 received gemcitabine 1,250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) on day 8, and cohort 2 received gemcitabine 1,250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) on day 1. Cycles were repeated every 21 days; all patients were supplemented with folic acid and vitamin B(12) and received dexamethasone.
One hundred eight patients (cohort 1, n = 56; cohort 2, n = 52) with pleural mesothelioma were enrolled. Among assessable patients, response rate was 26.0% in cohort 1 and 17.1% in cohort 2. Median time to disease progression was 4.34 months for cohort 1 and 7.43 months for cohort 2. Median survival was 8.08 months for cohort 1 (1-year survival = 31.14%) and 10.12 months for cohort 2 (1-year survival = 45.80%). In cohorts 1 and 2, incidence of grade 4 neutropenia was 25.0% and 29.4%, grade 4 thrombocytopenia was 14.3% and 3.9%, grade 3 or 4 anemia was 5.4% and 5.9%, and grade 3 or 4 fatigue was 23.2% and 15.7%, respectively.
The combination of pemetrexed and gemcitabine resulted in moderate clinical activity in MPM. However, the median survival times are similar to those with single-agent pemetrexed and inferior to outcomes observed with cisplatin in combination with an antifolate.
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- "Other gemcitabine doublets with activity in mesothelioma include gemcitabine plus carboplatin, which achieved a 26% response rate and a median survival of 15.1 months in a 50-patient trial , and gemcitabine plus oxaliplatin, which produced a response rate of 40% and a median survival of 13 months in a 25-patient study . The combination of gemcitabine plus pemetrexed is no more active than either agent alone, but has greater toxicity . "
ABSTRACT: Opinion statementSystemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.Current Treatment Options in Oncology 09/2008; 9(2-3):171-9. DOI:10.1007/s11864-008-0071-3 · 3.24 Impact Factor
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ABSTRACT: Malignant pleural mesothelioma is a neoplasm that is commonly fatal and for which there are no widely accepted curative approaches. Mesothelioma is unresponsive to most chemotherapy and radiotherapy regimens, and it typically recurs even after the most aggressive attempts at surgical resection. Multimodality approaches have been of some benefit in prolonging survival of very highly selected subgroups of patients, but they have had a relatively small impact on the majority of the patients diagnosed with this disease. As the incidence of pleural mesothelioma peaks in the United States and Europe over the next 10 to 20 years, new therapeutic measures will be necessary. This review will discuss the roles of chemotherapy, radiotherapy, surgery, and combined modality approaches in the treatment of pleural mesothelioma, as well as scientific advances made in the past decade that have led to the development of experimental techniques, such as photodynamic therapy, immunotherapy, and gene therapy, that are currently undergoing human clinical trials. These promising new avenues may modify the therapeutic nihilism that is rampant among clinicians dealing with mesothelioma.Chest 09/1999; 116(2):504-20. DOI:10.1378/chest.116.2.504 · 7.48 Impact Factor