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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 7  |  Page : 82-85
 

The efficacy of pemetrexed and bevacizumab intrapleural injection for malignant pleural mesothelioma-mediated malignant pleural effusion


Department of Oncology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China

Date of Web Publication27-Mar-2015

Correspondence Address:
N Du
Department of Oncology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.154058

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 » Abstract 

Objective: The aim of the present study was to evaluate the efficacy and safety of pemetrexed chemotherapy combined with intrapleural injection of pemetrexed and bevacizumab in the treatment of malignant pleural mesothelioma (MPM)-mediated malignant pleural effusion, and analyze the objective response rate (ORR), the median progression-free survival (PFS) and the median overall survival (OS). Methods: We analyzed the clinical data of 23 MPM patients with pleural effusion who were treated with a combination chemotherapy of pemetrexed at 500 mg/m 2 , on day 1 plus cisplatin (DDP) at 20 mg/m 2 on day 1-5 of each 21 days cycle, and concurrently, intrapleural injection of pemetrexed 0.5 g and bevacizumab 300 mg was administered on day 3 or day 4 after complete effusion drainage. ELISA test was applied to detect the vascular endothelial growth factor (VEGF) level in the pleural effusion and serum, and assess the ORR and survival. Results: In the 23 evaluable patients, the VEGF level in the pleural effusion and serum was significantly decreased, P < 0.01, pleural effusion of 20 patients (86.96%) was controlled effectively. There were 8 complete responses, 7 partial responses, 5 stable disease and 3 progressive disease, the ORR was 65.21%, the disease control rate was 86.96%, the median PFS was 6 months, the median OS was 14.5 months, and the 1-year survival rate was 41.22%. Toxicities were generally mild and manageable; the major toxicities included myelosuppression, fatigue, and anemia, mainly were grade 1-2 which could be managed by symptomatic treatments. Conclusion: The combination of pemetrexed chemotherapy with intrapleural injection of pemetrexed and bevacizumab is efficacious and safe for MPM pleural effusion, and results of the present study demonstrate some improvement in the PFS and OS. The expression of VEGF in the pleural effusion and serum plays a guiding role in monitoring the efficacy of bevacizumab in the treatment of malignant pleural effusion.


Keywords: Bevacizumab, intrapleural chemotherapy, malignant pleural effusion, malignant pleural mesothelioma, vascular endothelial growth factor


How to cite this article:
Chen D, Li X, Zhao H, Fu Y, Yao F, Hu J, Du N. The efficacy of pemetrexed and bevacizumab intrapleural injection for malignant pleural mesothelioma-mediated malignant pleural effusion. Indian J Cancer 2014;51, Suppl S3:82-5

How to cite this URL:
Chen D, Li X, Zhao H, Fu Y, Yao F, Hu J, Du N. The efficacy of pemetrexed and bevacizumab intrapleural injection for malignant pleural mesothelioma-mediated malignant pleural effusion. Indian J Cancer [serial online] 2014 [cited 2020 Sep 19];51, Suppl S3:82-5. Available from: http://www.indianjcancer.com/text.asp?2014/51/7/82/154058



 » Introduction Top


Malignant pleural mesothelioma (MPM) is a diffuse malignant cancer that arises in the pleura, given an extremely long latency period about 20 years, the incidence is increasing worldwide in the recent years. MPM carries a poor prognosis by a median survival of 12 months. [1] MPM with pleural effusion is hardly removed by surgery and recurs much more often. Excessive amounts of pleural effusion can cause chest distress, shortness of breath, difficulty breathing, and seriously affects the patient's quality-of-life (QOL). Therefore, active treatment of malignant pleural effusion is of great significance. The nonspecific local treatment is still the major option, but it can only occasionally alleviate symptoms rather than improving survival, and >50% recur. In this setting, there is no reliable separate treatment for most patients. Vascular endothelial growth factor (VEGF) is indicated to be a key medium for the formation of malignant pleural effusion. [2] VEGF levels in the blood of patients with MPM is higher, and VEGF concentration was positively associated with microvascular density and poor prognosis, therefore, the local rise of VEGF in MPM malignant pleural effusion may be caused by the interaction between VEGF and its receptors which promotes the secretion of cancer cells and mesothelial cells. Current researches show that bevacizumab (anti-VEGF antibody) is capable to directly inhibit proliferation, migration, and differentiation of vascular endothelial cell, promote apoptosis of endothelial cells, suppress VEGF-induced neoangiogenesis and vascular permeability, [3] effectively block the generation of pleural effusion, and produce good synergy with chemotherapy drugs. [4] However, the efficacy of bevacizumab combination chemotherapy seems to have no obvious correlation with serum VEGF level, high dose high frequency is needed but the result is disappointing. [5] Intrapleural injection after drainage of pleural effusion with a high level of VEGF can make bevacizumab less invalid but more conducive to the tumor-infiltrating pleura. Given, there is no effective treatment options and such injection has not yet been reported, we performed this study to investigate the efficacy of the combination of pemetrexed and bevacizumab to MPM pleural effusion, and look for a more effective clinical treatment for malignant pleural effusion.


 » Materials and Methods Top


Materials

Totally, 23 histologically confirmed MPM patients with pleural effusion between October 2008 and May 2012 were enrolled, including 13 men, 10 women, with a mean age of 53.4 years (range 36-72) [Table 1]. All had to have normal liver and kidney function, blood routine before treatment, an expected lifetime >3 months, and measurable lesions to assess response. 30 patients with nonmalignant pleural effusion from the Department of Pneumology served as normal controls, (16 male and 14 female), at a mean age of 63.60 (range 55-81), of which 15 patients have tuberculous exudative pleurisy, 7 had cardiac insufficiency and pleural effusion, 8 had pneumonia and pleurisy, all had typical clinical manifestation and were confirmed by imaging and related laboratory tests. This study was approved by the ethical committees at the First Affiliated Hospital of Chinese PLA General Hospital, and informed consent was obtained from each patient.
Table 1: Clinical characteristics of 23 MPM patients

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Reagents and medicine

Vascular endothelial growth factor (VEGF-A) ELISA Kit was purchased from R and D Company, cisplatin from Qilu Pharmaceutical; pemetrexed from Lilly, and Bevacizumab from Roche.

Instrument

550 ELIASA (BIO-RAD Company), refrigerated centrifuge (Sigma Company).

ELISA detection of pleural effusion and serum vascular endothelial growth-factor expression

Pleural effusion was collected in centrifuge tube before the treatment and 1 week after intrapleural injection, and centrifuged at 2500 rpm for 10 min at 4°C, the supernatant was separated into EP tube and stored in refrigerator at −20°C for inspection. Likewise, 10 ml peripheral blood was taken before chemotherapy and 1 week after intrapleural injection, supernatant was separated into EP tube after centrifugation, and stored in the refrigerator at −20°C for inspection. ELISA test was made with reference to the instructions.

Treatment

Chemotherapy

Patients enrolled were given pemetrexed 500 mg/m 2 , intravenously on day 1 and cisplatin (DDP) 20 mg/m 2 , intravenously on day 1-5 of a 2l days cycle, for a mean of 5 cycles. All of the patients received intravenous infusion of dexamethasone 5 mg on 1 day before and 2 days after the treatment, folic acid and Vitamin B12 (Centrum), orally 1 tablet/day 2 days before the chemotherapy, and muscle injection of Vitamin B12 1000 mg once every 9 weeks until the end of chemotherapy. All patients completed >2 cycles of treatment.

Intrapleural injection chemotherapy

Thoracocentesis and central venous catheter were performed after B ultrasonic locating, and after drainage of pleural effusion as much as possible, a suitable amount of pleural effusion was collected in a centrifuge tube for ELISA test. Intrapleural injection was given 2 days after cisplatin chemotherapy. Bevacizumab group: Pemetrexed 0.5 mg and bevacizumab 300 mg were dissolved in 20 ml normal saline, respectively, for intrapleural injection, sealed by the heparin cap. Then patients were required for a bed rest of 2 h and turnover once every 15 min to ensure full access of drugs with the chest wall to improve drug bioavailability. Doses were administered every 3 weeks for an average of 3 times. VEGF expression in the pleural effusion and serum was checked before and after the first cycle. Detailed records were made of the response, and blood routine and B ultrasonic were weekly reviewed, liver and kidney function, and the response was evaluated after the treatment. Patients with nonmalignant pleural effusion did not have chest treatment.

Criteria for efficacy evaluation

Response Evaluation Criteria in Solid Tumors was utilized to evaluate the response, complete response (CR): Effusion and symptoms disappeared, and stay stable more than 4 weeks. Partial response (PR): Effusion reduced by 50%, symptoms improved, and residual effusion did not grow through 4 weeks observation; response not obvious: Pleural effusion decreased <50% or did not change; progress disease: Pleural effusion increased than before, CR and PR totaled up the objective response. Progression-free survival (PFS) was calculated from study entry until documented disease progression or death. Overall survival (OS) was defined from the day of study entry to death or last day of follow-up. Toxicities were classified grade 0-4 according to the WHO standard. All of the patients were followed-up by outpatients, telephone and letter. The median follow-up period was 12 months. The survival was calculated from the date when the treatment began.

Statistical analysis

We used SPSS 16.0 software for statistical data processing, Kaplan-Meier method for survival analysis, P < 0.05 was considered to indicate a statistically significant difference.


 » Results Top


Vascular endothelial growth factor expression in the pleural effusion and serum of all 23 patients was detected before and after the treatment [Figure 1], and a significant difference (P < 0.01) between the MPM patients with malignant pleural effusion and nonmalignant pleural effusion group was seen. VEGF expression after treatment decreased, significantly lower than the level before treatment, and similar to the control group, but no statistically significant difference was observed (P > 0.05).
Figure 1: Vascular endothelial growth factor (VEGF) in pleural effusion (a) and serum (b) before and after the treatment. (a) VEGF in pleural effusion decreased obviously after treatment, P < 0.01; (b) VEGF in serum decreased obviously after treatment, P < 0.01. *Compared with the level after treatment, P > 0.05, **Compared with the level before treatment, P < 0.01

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Response evaluation of 23 patients evaluable for response after an median of 3.3 cycles (range 2-6) treatment, pleural effusion of 20 patients (86.96%) were effectively controlled, 8 (34.78%) had CR, 3 (30.43%) had PR, 5 (21.74%) had stable disease, and 3 (13.04%) had progressive disease. The objective response rate and the disease control rate (DCR) were 65.21% and 86.96%, respectively. Upon May 2014, the median follow-up was up to 14 months (range 3-18 months), the median PFS was 7.0 months, the median OS was 13.5 months, and 1-year survival rate was 41.22% [Figure 2].
Figure 2: Progression-free survival (PFS) (a) and median overall survival (OS) (b) of 23 malignant pleural mesothelioma patients. (a) The median PFS was 7.0 months, (b) the median OS was 13.5 months

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Quality-of-life 18 (78.26%) patients were found to have an improved QOL, 4 (17.39%) kept stable, and 1 (4.35%) got worse.

Toxicities major toxicities observed of bevacizumab were bleeding and high pressure, nausea, and vomiting were reported as the major adverse events for cisplatin, and pemetrexed related toxicities included anemia and fatigue [Table 2].
Table 2: Major toxicities of 23 patients

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 » Discussion Top


Malignant pleural mesothelioma is a rare, highly invasive and fatal diffuse cancer that arises from cells of the pleural mesothelium, most commonly caused by exposure to asbestos, the incidence elevates worldwide over these decades of years. [6] More than 60% MPM patients were diagnosed with malignant pleural effusion which has been considered as a predictor for poor prognosis. Patients with malignant pleural effusion suffer a higher fatality rate and short survival time. Given the disease often causes chest distress and short of breath, patients cannot lay down, and a large consumption of body fluid and protein causes great pain and even life-threatening, the diagnosis and treatment of MPM with malignant pleural effusion has been attached with a great significance. At present, insertion of an intercostal drain and medicine intrapleural injection is likely the most prevalent in the treatment of malignant ascites or pleural effusion, and cisplatin intrapleural injection is preferred currently in clinical practice since cisplatin can kill tumor cells directly, stimulate chemical pleurisy, and reduce pleural effusion leakage, with a response rate from 50% to 70%. [7] However, there still are no standard guidelines for the treatment of malignant pleural effusion.

This study inspected the treatment of pemetrexed chemotherapy combined with intrapleural injection of pemetrexed and bevacizumab for MPM pleural effusion, and noted an obvious efficacy, which can effectively reduce effusion, thus relieving symptoms and improving QOL. VEGF is a key medium for the formation of malignant pleural effusion. [2] Hirayama et al. [8] had proven a higher VEGF level in the blood of patients with MPM, and studies also concluded that VEGF in serum of MPM patient was higher than healthy people and other tumor patients, and VEGF concentration was positively associated with microvascular density and poor prognosis. The rise of VEGF leads in the increase of MPM malignancy. The study also noted an overexpression of VEGF in the serum and malignant pleural effusion of MPM patients could be greatly inhibited by anti-VEGF antibody treatment, with 20 (86.96%) pleural effusion being controlled effectively, which indicated the VEGF may be a useful marker for MPM.

The median PFS and OS of the study were 7.0 and 13.5 months, respectively, and the 1-year survival rate was 41.22%. Vogelzang et al. [9] reported a median OS of 12.1 months by pemetrexed plus cisplatin treatment for 448 patients in 2003. And other two clinical studies on the pemetrexed plus carboplatin treatment for MPM concluded a slightly longer median OS by about 14 months [10],[11] due to different patient inclusion criteria. A phase II study [12] found a 5% disease stable, a median PFS of 2.2 months and a median OS of 5.8 months through erlotinib and bevacizumab treatment. A randomized phase II study [13] investigated the efficacy of cisplatin plus gemcitabine with or without bevacizumab combination for 115 chemotherapy-naive MPM patients, and no survival advantage was observed in the bevacizumab group. Similarly, a phase III randomized trial was carried out in France. Preliminary data noted that the 6 months DCR of bevacizumab group was 74%, versus 43% in the control group. Ceresoli et al. [14] made an analysis of pemetrexed treatment after disease progression in 31 patients, and found a response rate of 19%, a DCR of 48%, and the median PFS and OS was 3.8 months and 10.5 months, respectively. This study shows a median OS up to 13.5 months by pemetrexed and bevacizumab intrapleural injection for MPM patients with pleural effusion, which indicates a certain PFS and OS improvement by pemetrexed and bevacizumab. The major toxicities caused by pemetrexed were fatigue, anemia, nausea and vomiting, but with good tolerability. Our previous studies [15] on bevacizumab combination chemotherapy for lung cancer malignant pleural effusion also show an obvious efficacy with no obvious adverse events, which provides some reference for clinical practices.

To sum up, local treatment of bevacizumab and pemetrexed combination is reliable, safe and feasible, and provides a new thought and option for the management of malignant ascites and pleural effusion, is worthy of clinical practice; and VEGF expression can be established as a monitoring predictor of the response of bevacizumab treatment for malignant pleural effusion.

 
 » References Top

1.
Ambrogi V, Mineo TC. Clinical and biologic prognostic factors in malignant pleural mesothelioma. Thorac Cancer 2012;3:289-302.  Back to cited text no. 1
    
2.
Sack U, Hoffmann M, Zhao XJ, Chan KS, Hui DS, Gosse H, et al. Vascular endothelial growth factor in pleural effusions of different origin. Eur Respir J 2005;25:600-4.  Back to cited text no. 2
    
3.
Leung L, Hsin M, Lam KC. Management of malignant pleural effusion: Options and recommended approaches. Thorac Cancer 2013;4:9-13.  Back to cited text no. 3
    
4.
Pichelmayer O, Zielinski C, Raderer M. Response of a nonmalignant pleural effusion to bevacizumab. N Engl J Med 2005;353:740-1.  Back to cited text no. 4
    
5.
Teixeira LR, Vargas FS, Acencio MM, Ribeiro SC, Sales RK, Antonangelo L, et al. Blockage of vascular endothelial growth factor (VEGF) reduces experimental pleurodesis. Lung Cancer 2011;74:392-5.  Back to cited text no. 5
    
6.
Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, et al. TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci U S A 2006;103:10397-402.  Back to cited text no. 6
    
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Musani AI. Treatment options for malignant pleural effusion. Curr Opin Pulm Med 2009;15:380-7.  Back to cited text no. 7
    
8.
Hirayama N, Tabata C, Tabata R, Maeda R, Yasumitsu A, Yamada S, et al. Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma. Respir Med 2011;105:137-42.  Back to cited text no. 8
    
9.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636-44.  Back to cited text no. 9
    
10.
Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006;24:1443-8.  Back to cited text no. 10
    
11.
Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol 2008;19:370-3.  Back to cited text no. 11
    
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Jackman DM, Kindler HL, Yeap BY, Fidias P, Salgia R, Lucca J, et al. Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma. Cancer 2008;113:808-14.  Back to cited text no. 12
    
13.
Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol 2012;30:2509-15.  Back to cited text no. 13
    
14.
Ceresoli GL, Zucali PA, De Vincenzo F, Gianoncelli L, Simonelli M, Lorenzi E, et al. Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma. Lung Cancer 2011;72:73-7.  Back to cited text no. 14
    
15.
Du N, Li X, Li F, Zhao H, Fan Z, Ma J, et al. Intrapleural combination therapy with bevacizumab and cisplatin for non-small cell lung cancer-mediated malignant pleural effusion. Oncol Rep 2013;29:2332-40.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

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