Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: A phase II study of the Southwest Oncology Group (SWOG 9810)☆
Introduction
Malignant pleural mesothelioma (MPM) is an uncommon, neoplastic disorder of the pleural lining of the lung, usually presenting at an advanced stage and generally considered resistant to conventional chemotherapy treatment. The majority of cases (60–80%) occur in male patients, and are attributed to asbestos exposure, with a long latency between exposure and presentation [1], [2]. Although the incidence of the disease may have peaked in the United States, it continues to rise throughout much of the world where it is not expected to peak until sometime between 2010 and 2020 [3], [4].
The median survival of patients with unresectable MPM averages approximately 12 months [5], [6]. Numerous chemotherapy agents have been tested in phase II trials. Single agent chemotherapy has generally yielded response rates between 0 and 20%. Combination chemotherapy has resulted in somewhat higher response rates of 10–40% [7]. An impact on survival has been difficult to demonstrate until the recent phase III trials using cisplatin and the newer antifolates (i.e., pemetrexed and raltitrexed) which have now demonstrated a significant improvement in response rate and a survival advantage compared to cisplatin alone [5], [6].
In a murine mesothelioma model, gemcitabine has shown additive anti-tumor effects when administered in combination with cisplatin [8]. This combination was initially studied in Australia with promising results in MPM [9], [10]. In these studies cisplatin was administered at a dose of 100 mg/m2 on day 1, with gemcitabine at 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle. This Southwest Oncology Group (SWOG) study was designed to confirm and extend these results by using the same dose of gemcitabine, but dividing the cisplatin into three weekly doses to reduce the toxicity. The additional hypothesis was that this weekly dosing regimen might make allow greater synergism between the two agents.
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Patients and methods
Between February 1999 and August 2000, 57 patients with unresectable MPM were enrolled onto this study at participating institutions from the SWOG. Patients were required to have histologically confirmed MPM of the pleura with bidimensionally measurable disease, SWOG performance status 0–2, and no prior chemotherapy or radiotherapy for any reason. Patients may have undergone prior surgery at least 4 weeks before study enrollment, and should have recovered from all side effects associated with
Results
Fifty-seven patients were registered on this study. Seven patients were found to be ineligible due to insufficient documentation of disease (two patients), inadequate baseline hematologic or renal function (three patients) and no measurable disease (two patients). Eleven patients were removed from protocol therapy before progression of disease, completion of treatment, or toxicity for reasons not specified in the protocol. This included worsening of disease not qualifying as disease progression
Discussion
This multicenter cooperative group study has failed to confirm the response rate seen with this combination in two prior trials in Australia [9], [10]. Although the response rates were lower, the median survival appears to be equivalent to the other trials. In the first single institution study by Byrne et al., 10 of the 21 enrolled patients (47%) exhibited a partial response. Nine of the 10 patients had epithelioid mesothelioma, and 1 patient had a mixed histology. The estimated median
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This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA38926, CA32102, CA14028, CA35192, CA42777, CA20319, CA46441, CA35176, CA35128, CA67575, CA45807, CA35178, CA67663, CA63848, CA12213, CA58882, CA35262, CA35431, and supported in part by Eli Lilly and Company. Dr. Petrylak receives research funding for his clinical research from Eli Lilly and Company.