A Multicenter Phase II Study of Gemcitabine and Oxaliplatin for Malignant Pleural Mesothelioma

Second Medical Department, City hospital Martha-Maria Halle-Doelau, Halle, Germany.
Clinical Lung Cancer (Impact Factor: 3.1). 04/2003; 4(5):294-7. DOI: 10.3816/CLC.2003.n.009
Source: PubMed


We conducted a phase II multicenter trial to evaluate the activity of combined gemcitabine and oxaliplatin in malignant pleural mesothelioma. Twenty-five patients were recruited between May 1999 and December 2001 and received gemcitabine 1000 mg/m2 intravenously over 30 minutes and oxaliplatin 80 mg/m2 intravenously over 3 hours on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0-2 and no prior chemotherapy. Best objective responses achieved were as follows: partial response, 10 patients (40%, 95% CI, 21%-61%); stable disease, 6 patients (24%, 95% CI, 9%-45%); and progressive disease, 9 patients (36%, 95% CI, 18%-57%). Median time to disease progression was 7 months, and median survival was 13 months. One-year survival was 60% (95% CI, 31%-72%). There were 2 deaths from disease progression. Toxicity was mainly hematologic. Grade 3/4 nausea and vomiting occurred in 8% of patients, neuropathy occurred in 8% of patients, and diarrhea occurred in 4% of patients. The combination of gemcitabine and oxaliplatin was shown to be active in malignant pleural mesothelioma and to exhibit tolerable toxicity in an outpatient setting.

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    • "The toxicities of the combination oxaliplatin/gemcitabine as well as of the monotherapy with oxaliplatin were very acceptable in our study – in accordance with the low toxicities reported in the first line therapy [17]. In general, chemotherapy was tolerated well by all patients. "
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    ABSTRACT: The aim of this study was to investigate the efficacy and safety of oxaliplatin +/- gemcitabine in patients with diffuse malignant pleural mesothelioma (MPM) pretreated with pemetrexed. The study enrolled consecutive patients with relapsed MPM, all of them pretreated with a platin-pemetrexed-based chemotherapy. Oxaliplatin 80 mg/m2 was administered as monotherapy or in combination with gemcitabine 1000 mg/m2 given on day 1 and 8. Cycles were repeated every 21 days. The primary endpoints were response rate and disease control rate. Secondary endpoints included overall survival (OS), time to tumour progression (TTP), progression-free survival (PFS), time to treatment failure (TTF), and toxicity. Between February 2005 and September 2007 29 patients (median age: 65.0 years, World Health Organisation (WHO) performance status: 0-3) were enrolled. The follow-up period encompassed 5.4 to 97.4 weeks (median: 24.3 weeks). Out of these 29 patients, 15 were treated in second, 10 in third, 3 in fourth and 1 in fifth line, respectively. The majority of the patients received the combination oxaliplatin and gemcitabine (n = 25 vs. 4; 86.2 vs. 13.8%).The median overall survival (OS) was 71.7 weeks (30.6-243.3 weeks), whereas survival from the start of oxaliplatin/gemcitabine-treatment was 24.3 weeks (5.4-97.3 weeks). Median time to tumour progression (TTP) was 9.3 weeks (3.0-67.6 weeks).Partial response (PR) was observed in 2 patients (6.9%), stable disease (SD) for at least three courses of treatment in 11 patients (37.9%). Thus, disease control rate was 44.8%, whereas 16 of 29 patients exhibited progressive disease (55.2%).The toxicity profile was favourable, with no WHO grade 4-toxicities, only few dose-reductions were performed due to non-symptomatic haematotoxicities (neutropenia, thrombopenia). Mild WHO grade 2 neurotoxicity was seen in 6 patients. Pemetrexed-pretreated patients with progressive MPM may benefit from a consecutive chemotherapy with oxaliplatin and gemcitabine without significant toxicity.
    Full-text · Article · Jan 2009 · Journal of Occupational Medicine and Toxicology
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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 [28], and gemcitabine plus oxaliplatin, which produced a response rate of 40% and a median survival of 13 months in a 25-patient study [31]. The combination of gemcitabine plus pemetrexed is no more active than either agent alone, but has greater toxicity [32]. "
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    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.
    Preview · Article · Sep 2008 · Current Treatment Options in Oncology
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