A Retrospective Study of Chemotherapy with and without Pemetrexed in Malignant Pleural Mesothelioma

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1 A Retrospective Study of Chemotherapy with and without Pemetrexed in Malignant Pleural Mesothelioma MASAYOSHI HIGASHIGUCHI, HIDEKAZU SUZUKI, TOMONORI HIRASHIMA, MASASHI KOBAYASHI, SHO GOYA, NORIO OKAMOTO, YUKA MATSUURA, MOTOHIRO TAMIYA, NAOKO MORISHITA, TEPPEI TSUMORI and ICHIRO KAWASE Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan Abstract. Background: The current standard first-line chemotherapy for malignant pleural mesothelioma (MPM) is pemetrexed and cisplatin. However, other regimens, with or without a platinum agent, are reported to be effective in the treatment of MPM. Patients and Methods: Patients who were diagnosed with MPM and treated with chemotherapy between January 1999 and June 2010 at the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases were studied, and the outcomes of these patients were retrospectively analyzed in relation to therapy. Results: In total, 48 patients with MPM (42 men and 6 women) treated with chemotherapy were included in the current analysis. The median survival time (MST) and one-year survival rate in the pemetrexed-containing group were 541 days and 63.2%, respectively. The MST and one-year survival rate in the nonpemetrexed group were 516 days and 66.7%, respectively. Overall survival did not differ significantly with respect to the pemetrexed-containing regimen. Conclusion: The superiority of pemetrexed-containing regimens is equivocal. Nonpemetrexed-containing regimens may be potent alternatives. Malignant pleural mesothelioma (MPM) is a rare form of malignancy that originates from the mesothelium. It is known to be associated with asbestos exposure (1). Despite recent advances, the prognosis of this disease remains poor, and a median survival of 6-12 months is reported (2-4). Surgery, radiation, chemotherapy, and multimodal therapy are treatment options for MPM, but evidence for the efficacy of these treatments is insufficient (1, 2, 5). Correspondence to: Masayoshi Higashiguchi, MD, Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino Habikino-shi, Osaka, Japan. Tel: , Fax: , puer_aeternus_0308@goo.jp Key Words: Malignant pleural mesothelioma, pemetrexed, cisplatin. A recent phase III trial revealed that in patients with MPM, combination chemotherapy with pemetrexed and cisplatin was superior to single-agent cisplatin treatment with respect to overall survival, response rate, and time to progression (6). In this trial, the response rate and median survival time (MST) of pemetrexed-cisplatin were 41.3% and 12.1 months, respectively. The current standard first-line chemotherapy for MPM based on this result is pemetrexed plus cisplatin. Other active agents include raltitrexed, gemcitabine, and vinorelbine, but these agents were evaluated mainly in phase II studies (7-15). In this study, we retrospectively analyzed the outcomes of patients who were diagnosed with MPM and treated with chemotherapy in our facility. We aimed to examine the efficacy of pemetrexed by comparing it with other agents. Patients and Methods Patients who were diagnosed with MPM pathologically and treated with chemotherapy between January 1999 and June 2010 at the Osaka Prefectural Medical Center for Respiratory and Allergic Diseases were identified, and medical records of these patients were reviewed. Age, sex, history of asbestos exposure, Eastern Cooperative Oncology Group Performance Status (PS), histologic classification, stage, the prescribed chemotherapy, and survival time were recorded. This staging was based on the International Mesothelioma Interest Group (IMIG) staging system (16). The survival period was measured between the date of diagnosis with MPM and the date of death, or October 30, Histological classification the disease categorized against as epithelioid or nonepithelioid. Patients who were treated with pemetrexed were compared patients who were treated with other agents. Statistical analysis. The Kaplan Meier method was used for the estimation of survival time. The log-rank test was used to compare the survival of groups. Univariate Cox proportional hazards regression was performed for each factor. Variables found to be significant (p 0.1) were included in a multivariate analysis using a Cox model. All analyses were calculated with R [version ; R Development Core Team (2011). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN , URL: /2012 $

2 Table I. Characteristics of all the patients. N=48 Age (year) Median 67 Range Gender Male 42 Female 6 PS Histological type Epithelioid 33 Sarcomatous 9 Biphasic 4 Desmoplastic 1 Unclassifiable 1 Stage I 21 II 3 III 16 IV 8 History of asbestos exposure Yes 35 No 13 Presence of chest pain Yes 18 No 30 Surgery EPP 6 P/D 2 No surgery 40 N: Patient number, PS: performance status, EPP: extrapleural pneumonectomy, P/D: pleurectomy/decortications. Table II. Patient characteristics (pemetrexed-containing group vs. nonpemetrexed-containing group). Pemetrexed- Non-pemetrexed- p-value containing containing group (N=23) group (N=25) Age (year) Median (range) 67 (54-81) 67 (49-81) > Gender Male Female 3 3 PS Histological type Epithelioid Non-epithelioid 6 9 Stage I or II III or IV History of asbestos exposure Yes No 5 8 Presence of chest pain Yes No Surgery Yes No Wilcoxon rank sum test was used for age and Fisher s exact test for other variables. Results In total, 48 MPM patients (42 men and 6 women) treated with chemotherapy were included in the current analysis. Their backgrounds are listed in Table I. The median age at diagnosis was 67 years. The epithelioid type was predominant. Most of the patients had good performance score. Twenty-three patients were treated with chemotherapy containing pemetrexed (pemetrexed-containing group) and the remaining patients were treated with chemotherapy that did not contain pemetrexed (non-pemetrexed-containing group). Baseline characteristics of each group did not differ significantly (Table II). The first line regimens used in each group are listed in Tables III and IV. Survival analysis for chemotherapy. The MST and one-year survival rate in the pemetrexed-containing group were 541 days and 63.2%, respectively, while those in the nonpemetrexed group were 516 days and 66.7%, respectively (Figure 1). Overall survival did not differ significantly between the two groups (p=0.65). Surgical therapy. Surgery was performed in eight patients. Six patients were treated with extrapleural pneumonectomy (EPP), and two patients were treated with pleurectomy/ decortication (P/D). Neoadjuvant chemotherapy with gemcitabine cisplatin was administered to both of the patients treated with P/D, and neoadjuvant chemotherapy with pemetrexed cisplatin was administered to all of the patients treated with EPP. Survival did not differ significantly between the patients treated with surgery and those treated without surgery (p=0.19). However, there was a trend for improved survival in patients who underwent surgery (Figure 2). Survival analysis for histologic type. Survival of the patients with the epithelioid type was significantly better than the one of patients with the non-epithelioid type (p=0.0038). The MST and one-year survival rate of the patients with the epithelioid type were 789 days and 76.7%, respectively, and 610

3 Higashiguchi et al: Chemotherapy with and without Pemetrexed in MPM Table III. The first-line chemotherapy regimens in the pemetrexedcontaining group. N=23 Cisplatin plus pemetrexed 21 Pemetrexed alone 2 Table IV. The first-line chemotherapy regimens in the non-pemetrexedcontaining group. N=25 CDDP+GEM 10 CBDCA+GEM 4 CPT+MTX+DXR 2 GEM+VNR 4 GEM 4 VNR 1 CDDP: Cisplatin, GEM: gemcitabine, CBDCA: carboplatin, CPT: irinotecan, MTX: methotrexate, DXR: doxorubicin, VNR: vinorelbine. Figure 1. Kaplan-Meier survival curves of the patients in the pemetrexed-containing and non-pemetrexed-containing groups (p=0.65). these of patients with the non-epithelioid type were 306 days and 38.3%, respectively (Figure 3). Univariate and multivariate analysis. The results of univariate analysis are presented in Table V. Significant factors of poor prognosis include non-epithelioid type, advanced stage, and presence of chest pain. Factors demonstrating p<0.1 in univariate analysis were included in multivariate analysis using the Cox model; none of the factors reached statistical significance (Table VI). Discussion In this retrospective study, survival was similar in patients receiving pemetrexed and in patients receiving other agents. There was a trend for improved survival with surgery, which did not reach statistical significance. On univariate analysis, non-epithelioid type, advanced stage, and presence of chest pain were suggested to be related to poor survival outcome, although in multivariate analysis, these factors did not reach statistical significance. The current standard first-line chemotherapy is pemetrexed plus cisplatin. In a systematic review by Ellis et al. which included 119 trials (8 randomized trials and 111 phase II trials), it was suggested that response rates with combination chemotherapy are higher than those with single agents and that platinum-containing regimens lead to higher response rates compared with non-platinum-containing regimens. This review concluded that chemotherapy with pemetrexed and cisplatin is recommended for patients with advanced MPM (14). However, most of the studies included in this systematic review are noncomparative phase II trials, and pemetrexed cisplatin has only been demonstrated to be superior to cisplatin monotherapy. Some other agents, used with or without platinum, are reported to be effective in the treatment of MPM. Among non-pemetrexed-containing regimens, gemcitabine cisplatin is also often administered. The response rate and MST of this regimen are reported to be 12-48% and months, respectively(7, 8). Lee et al. retrospectively analyzed data for 81 patients with MPM who were treated with pemetrexed cisplatin or gemcitabine cisplatin and reported that survival outcomes of patients treated with these regimens did not differ (17). Carboplatin is considered to be a potent alternative to cisplatin. In a phase II study, the response rate and MST of gemcitabine carboplatin were reported to be 24% and 10.6 months, respectively (9). Gemcitabine was also found to have some single-agent activity in MPM. In a phase II study of single-agent gemcitabine, gemcitabine monotherapy was reported to have response rates between 0% and 7% (10, 11). Vinorelbine, a semisynthetic vinca alkaloid, has also been shown to be effective in the treatment of MPM. In a phase II study of 29 chemotherapy-naïve patients, the response rate and MST of single-agent vinorelbine were 24% and 10.6 months, respectively (12). Vinorelbine may be used in combination with platinum agents. Sørensen et al. evaluated the efficacy of vinorelbine cisplatin and reported MST and median time to progression to be 16.8 months and 7.2 months (response rate, 29.6%), respectively (13). Recently, in a randomized phase III trial of 409 patients from 76 centers performed by the Medical 611

4 Figure 2. Kaplan-Meier survival curves of the patients treated with and without surgery (p=0.19). Figure 3. Kaplan-Meier survival curves of the patients with epithelioid and non-epithelioid types (p=0.0038). Table V. Results of Cox univariate analysis. Variable HR (95% CI) p-value Age>70years 0.87 ( ) 0.75 PS ( ) 0.23 Epithelioid type 0.31 ( ) Stage III or IV 3.84 ( ) Male gender 0.36 ( ) 0.11 History of asbestos exposure 1.70 ( ) 0.25 Presence of chest pain 2.63 ( ) Pemetrexed-containing regimens 0.83 ( ) 0.65 Platinum-containing regimens 0.82 ( ) 0.63 Surgery 0.45 ( ) 0.20 HR: Hazard ratio, CI: confidence interval. Table VI. Results of multivariate analysis. Variable HR (95% CI) p-value Epithelioid type 0.44 ( ) Stage III or IV 2.53 ( ) Presence of chest pain 1.98 ( ) HR: Hazard ratio, CI: confidence interval. Research Council, active symptom control (ASC) alone was compared to ASC plus chemotherapy (mitomycin vinblastine cisplatin, or weekly vinorelbine) (18). In this study, the additional benefit of chemotherapy on ASC was not demonstrated, but a survival advantage was suggested for ASC plus vinorelbine compared to ASC alone, although it was not statistically significant. The authors concluded that the efficacy of vinorelbine deserves further investigation. Standard surgical options in the treatment of MPM include EPP and P/D. Lower local recurrence rate and higher distant recurrence rate of EPP compared to P/D are reported. The role of surgical resection for the treatment of MPM and the optimal surgical procedure remain controversial since microscopically complete resection is difficult, and these surgical treatments have relatively high rates of morbidity and mortality (4). No randomized trial has evaluated the efficacy of surgical treatment in MPM. Lee et al. performed phase II trials in 77 MPM patients, evaluating the efficacy of adjuvant pemetrexed plus cisplatin followed by EPP and radiation. In this study, patients who completed all therapy had a good prognosis, with an MST of 29.1 months and a two-year survival rate of 61.2% (19). Limitations of the current study include its retrospective design and small sample size. In addition, non-pemetrexedcontaining regimens were mostly used prior to 2007, when pemetrexed became available in Japan. Moreover, in this study, the response to chemotherapy was not evaluated. In conclusion, the superiority of pemetrexed-containing regimens is equivocal. As some agents other than pemetrexed have been shown to be effective in the treatment of MPM, nonpemetrexed-containing regimens may be potent alternatives, particularly for patients unable to tolerate pemetrexedcontaining chemotherapy. Chemotherapy in MPM may not be necessarily confined to pemetrexed-containing regimens. 612

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