Comparison of Two Chemotherapy Regimens for Malignant Pleural Mesothelioma
ABSTRACT & COMMENTARY
By William B. Ershler, MD
Synopsis: In a randomized, Phase 2 trial conducted in Egypt comparing gemcitabine/cisplatin vs pemetrexed/carboplatin for the primary treatment of malignant pleural mesothelioma, the latter resulted in a slightly improved response rate and less toxicity but no significant difference in survival.
Source: Habib EE, Fahmy ES. Chemotherapy management of malignant pleural mesothelioma: A phase II study comparing two popular chemotherapy regimens. Clin Transl Oncol 2013;15:965-968.
The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide and the prognosis remains poor. Currently, the standard of care involves a multimodal approach including chemotherapy, surgery, and radiation. Evidence has suggested that single-agent chemotherapy is not sufficient, as no single drug has been shown to have a beneficial response in > 20% of patients.1,2 However, of the single chemotherapy agents tested, a meta-analysis revealed that cisplatin is the most active, with a response rate of 13-14%.2,3 Recently, a Phase 2 trial showed activity of the anti-fol pemetrexed in patients with MPM.4 A Phase 2 trial of combination therapy with pemetrexed and cisplatin compared to cisplatin alone demonstrated significant improvements in response rates in those who received both drugs (41.3% vs 16.7%, P < 0.0001), as well as in median survival (12.1 months vs 9.3 months, P = 0.020).5 As a result, this combination of pemetrexed and cisplatin has been established as the standard of care for MPM. However, because of its lower toxicity profile, carboplatin is often selected as the preferred platinum agent, and when combined with pemetrexed, it produced comparable results in terms of MPM disease response and overall survival.6
Habib and colleagues conducted a prospective, Phase 2 clinical trial to investigate the effectiveness of two different chemotherapy regimens, gemcitabine and cisplatin vs pemetrexed and carboplatin, in patients with non-resectable MPM. Forty patients with histologically proven untreated MPM were enrolled at a single institution in Egypt from May 2008 through May 2011 and were blindly randomized to one of two treatment groups. Twenty-one patients were randomized to Group 1 and received six cycles of cisplatin 80 mg/m2 on day 1 and gemcitabine 1 g/m2 on days 1, 8, and 15. Nineteen patients were randomized to Group 2 and received six cycles of pemetrexed 500 mg/m2 on day 1 and carboplatin at an AUC of 5 mg/mL/min on day 1. All patients received folic acid and vitamin B12 supplementation with the aim of decreasing toxicity. The only significant differences between the patients in the two groups were age and gender. The mean age of the patients in this cisplatin group was 62.2 years (SD ± 8.9 years) vs 49.5 years (SD ± 11.7 years) in the pemetrexed group (P < 0.001). There were 19 males and 2 females in the cisplatin group and 10 males and 9 females in the pemetrexed group (P = 0.012).
Patient evaluations included a medical history, physical examination, and laboratory studies at baseline and prior to each cycle of chemotherapy. Chest x-rays were done monthly, and CT scans of the chest and abdomen were done at baseline and every 3-6 months after treatment completion, depending on symptoms or other clinical indications. Response was determined based upon assessment of clinical symptoms and radiographic data. The median follow-up was 18 months (range 6-30 months).
Overall toxicity (grades 1-4) appeared to be worse in patients who received the cisplatin regimen. Specifically, more patients experienced thrombocytopenia (66.6% vs 26.3%, P = 0.014), nausea/vomiting (100% vs 5.3%, P < 0.001), diarrhea (47.6% vs 0.0%, P = 0.001), and hearing loss (42.9% vs 5.3%, P = 0.001).
Of the 19 patients in the pemetrexed treatment group, one had a complete response (CR), 14 had a partial response (PR), three had progressive disease (PD), and one had stable disease (SD). Of the 21 patients in the cisplatin treatment group, there were no patients who had a CR, 10 had a PR, two had PD, and nine had SD. Overall response rate (CR + PR) was superior in the pemetrexed treatment group vs the cisplatin group (78.9% vs 47.6%, respectively, P = 0.041). Overall survival at 1.5 years appeared to be better for patients treated with pemetrexed (57.8% vs 41%). However, this difference was not statistically significant (P = 0.0599).
Thus, the combination of pemetrexed and carboplatin was demonstrably active for patients with MPM, comparable in response rate and less toxic than cisplatin/gemcitabine. Although responses were better than those reported for single-agent treatment, there remains much need for improvement. n
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