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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 7  |  Page : 206-209

Association between P-Glycoprotein expression and response to chemotherapy in patients with osteosarcoma: A systematic and meta-analysis


Department of Orthopedics, Orthopedics Hospital of Wuhan, Wuhan 430033, China

Date of Web Publication29-Nov-2014

Correspondence Address:
Wu-Sheng Kan
Department of Orthopedics, Orthopedics Hospital of Wuhan, Wuhan 430033
China
Zhi-Gang Zhao
Department of Orthopedics, Orthopedics Hospital of Wuhan, Wuhan 430033
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.145874

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 > Abstract 

Objective: The aim was to investigate the association between p-glycoprotein (Pgp) expression and response to chemotherapy in patients with osteosarcoma.
Materials and Methods: We searched and included the openly published articles evaluated the correlation between Pgp expression and response to chemotherapy. The odds ratio (OR) of response rate for Pgp positive group versus Pgp negative group was aggregated by random or fixed effect model.
Results: Twelve studies were included in our meta-analysis. The mean Pgp positive rate was 0.39 ± 0.10 with its range of (0.14-0.53). The summary response rate was 0.46 ± 0.16 in Pgp positive and 0.57 ± 0.27 in the Pgp negative group, with no statistical difference between two groups (P > 0.05). The pooled OR of response rate for Pgp positive group versus Pgp negative group was 0.75 with its 95% confidence interval of 0.47-1.22, indicating there was no association between Pgp expression and response to chemotherapy in patients with osteosarcoma.
Conclusion: The present evidence indicated that there was no association between p-glycoprotein expression and chemotherapy response in patients with osteosarcoma.

Keywords: Chemotherapy, meta-analysis, osteosarcoma, p-glycoprotein


How to cite this article:
Zhao ZG, Ding F, Liu M, Ma DZ, Zheng CK, Kan WS. Association between P-Glycoprotein expression and response to chemotherapy in patients with osteosarcoma: A systematic and meta-analysis. J Can Res Ther 2014;10, Suppl S3:206-9

How to cite this URL:
Zhao ZG, Ding F, Liu M, Ma DZ, Zheng CK, Kan WS. Association between P-Glycoprotein expression and response to chemotherapy in patients with osteosarcoma: A systematic and meta-analysis. J Can Res Ther [serial online] 2014 [cited 2019 Oct 17];10:206-9. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/206/145874


 > Introduction Top


Osteosarcoma is an aggressive malignant neoplasm arising from primitive transformed cells of mesenchymal origin that exhibits osteoblastic differentiation and produces malignant osteoid. [1] The prognosis of patients with osteosarcoma remains guarded, despite advances in surgical treatment and the availability of new chemotherapeutic agents in recent years. Several prognostic risk factors have been proposed, including tumor size, tumor grade, tumor site, age at diagnosis, and response to chemotherapy. Recently, published articles indicated that the expression of p-glycoprotein (Pgp) was associated with the prognosis and chemotherapy response for patients with osteosarcoma. However, the patients included in the individual study was small and the statistical power for evaluation the association between Pgp expression and response to chemotherapy in patients with osteosarcoma was limited.


 > Materials and methods Top


We identified the relevant studies about the Pgp expression and response to chemotherapy or prognosis in patients with osteosarcoma. The studies were electronic searched in the Medline, EMBASE and Wanfang databases. The search strategy was based on the combinations of osteosarcoma, P-glycoprotein, multidrug resistance protein 1 (MDR1), and multidrug resistance. References of retrieved articles also were screened. The including criteria was the studies that examined the Pgp expression and chemotherapy response or studies providing the Pgp expression status. The language was limited to English and Chinese. The studies reporting the overlapping patients or duplicated studies were excluded of this systematic review and meta-analysis. The general characteristics (first author, year of publication, patients' age of each study, Pgp array method) of the each included studies were extracted by two reviewers independently. The number of Pgp(+) patients, Pgp(−) subjects, the number of chemotherapy response in the Pgp(+) and Pgp(−) group in each study was extracted.

Statistical analysis

The statistical analysis was performed using Stata11.0 and GraphPad Prism 5.0 statistical software. The Pgp expression and chemotherapy response was expressed by dichotomous data. The odds ratio (OR) of response rate for Pgp positive group versus Pgp negative group was calculated for each included study. The heterogeneity for the effect size OR among the eligible studies was evaluated by χ2 test. A fixed effect model was used to pool the OR if no statistical heterogeneity was existed (P > 0.05). Otherwise, random effect mode was used. Double side P < 0.05 was considered as statistically significant.


 > Results Top


Eligible studies and characteristics

We searched the Medline, EMBASE and Wanfang databases to find the relevant studies. Finally, according to the included criteria, 12 articles fulfilled the including criteria and included in this systematic review and meta-analysis. The publication year ranges from 1995 to 2006 and the number of patients included in each study range from 10 to 94. The characteristics of eligible papers were shown in [Table 1].
Table 1: Characteristics of eligible studies


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P-glycoprotein positive rate

We extracted the P-glycoprotein positive patients in each individual paper and calculated the positive rate. The P-glycoprotein positive rate range 14-53% [Figure 1] with and mean positive rate of 39 ± 10%.
Figure 1: The P-glycoprotein positive rate distribution in each include study

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Response rate

We calculated the chemotherapy response rate in the Pgp(+) and Pgp(−) group. The chemotherapy response rate in Pgp(+) group rage from 25% to 68% and in Pgp(−) range from 20% to 89% [Figure 2]. The summary response rate was 0.46 ± 0.16 in Pgp positive and 0.57 ± 0.27 in the Pgp negative group, with no statistical difference between two groups (P > 0.05).
Figure 2: The chemotherapy response rate in the Pgp(+) and Pgp(−) group (the same color indicated the same study)

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Meta-analysis

Heterogeneity test indicated no statistical heterogeneity was found across the included studies (I2 = 29.6, P = 0.18). The OR was pooled by fixed effect model. The pooled OR of response rate for Pgp positive group versus Pgp negative group was 0.75 with its 95% confidence interval (95%CI) of 0.47-1.22, indicating there was no association between Pgp expression and response to chemotherapy in patients with osteosarcoma [Figure 3].
Figure 3: The forest plot of evaluation the association between P-glycoprotein expression and response to chemotherapy in patients with osteosarcoma

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Sensitivity analysis

A sensitivity analysis was performed to evaluate the stability of the results. The pooled OR was calculated by omitting each of the included studies. After omitting the studies, the OR ranges from 0.66 to 0.85 without significant changes [Figure 4]. The sensitivity analysis indicated that the results of this meta-analysis was not sensitive to any one of the include articles. The results of this study were relative stable.
Figure 4: The pooled odds ratio by omitting each of the included studies

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Publication bias

We performed the funnel plot to evaluate the publication bias. The funnel plot showed generally symmetry, which indicated that there was no significant publication bias [Figure 5].
Figure 5: The funnel polt for evaluating the publication bias

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 > Discussion Top


In this systematic review and meta-analysis, we reviewed and included twelve articles. The Pgp positive rate for the 12 studies ranges from 14% to 53% with and mean positive rate of 39 ± 10%. The lowest Pgp positive rate was found in Oda et al. [3] and highest Pgp positive rate in Dai et al. [11] The Pgp positive rate was quite different among the included studies. We suppose that the reason for the quite different Pgp positive was the small number cases recruited in each of the individual studies. The mean subjects number included in the eligible studies was 45.7 ± 27.9 with its range of 10-94. In the previously published studies, the Pgp was proposed as a biomarker for resistance for chemotherapy response. Serra et al. [2] reported that overexpression of the Pgp seemed to be associated with higher relapse rate and the trend toward worse prognosis in patients with osteosarcoma. However, Kumta et al. [8] and his college found that P-glycoprotein expression at the time of diagnosis did not correlate statistically with chemonecrosis. In their study, the authors included 45 osteosarcoma patients, and the Pgp expression was tested in pretreatment biopsies and posttreatment resection specimens. Pgp expression was positive in 16 subjects in whom the response in 4 and resistance in 12 with a response rate of 25.0%. In our systematic review and meta-analysis, we calculated the chemotherapy response rate in the Pgp(+) and Pgp(−) group. The chemotherapy response rate in Pgp(+) group rage from 25% to 68% and in Pgp(−) range from 20% to 89%. The summary response rate was 0.46 ± 0.16 in Pgp positive and 0.57 ± 0.27 in the Pgp negative group, with no statistical difference between two groups (P > 0.05). We further evaluated the association between Pgp expression and response to chemotherapy in patients with osteosarcoma by pooling the OR. The pooled OR of response rate for Pgp positive group versus Pgp negative group was 0.75 with its 95%CI of 0.47-1.22, indicating there was no association between Pgp expression and response to chemotherapy in patients with osteosarcoma.

P-glycoprotein also known as MDR1 or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. Pgp is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. [14] It was believed responsible for decreased drug accumulation in multidrug-resistant cells and often mediated the development of resistance to anticancer drugs. However in our systematic review and meta-analysis, we found that there was no association between Pgp expression and response to chemotherapy in patients with osteosarcoma. The results were not in accordance with the known P-glycoprotein function.

There were two important limitations of this systematic review and meta-analysis. First, the patients number included in each study was relative small which mad the statistical power limitation; second, the chemotherapy regimen was different for each study that made the clinical heterogeneity among the included papers. Thus, the conclusion of this study should be further confirmed by multiple center prospective trails.

 
 > References Top

1.
Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment-where do we stand? A state of the art review. Cancer Treat Rev 2014;40:523-32.  Back to cited text no. 1
    
2.
Serra M, Scotlandi K, Manara MC, Maurici D, Benini S, Sarti M, et al. Analysis of P-glycoprotein expression in osteosarcoma. Eur J Cancer 1995;31A:1998-2002.  Back to cited text no. 2
    
3.
Oda Y, Sakamoto A, Shinohara N, Ohga T, Uchiumi T, Kohno K, et al. Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human osteosarcoma. Clin Cancer Res 1998;4:2273-7.  Back to cited text no. 3
    
4.
Kusuzaki K, Hirata M, Takeshita H, Murata H, Hashiguchi S, Ashihara T, et al. Relationship between P-glycoprotein positivity, doxorubicin binding ability and histologic response to chemotherapy in osteosarcomas. Cancer Lett 1999;138:203-8.  Back to cited text no. 4
    
5.
Gorlick R, Liao AC, Antonescu C, Huvos AG, Healey JH, Sowers R, et al. Lack of correlation of functional scintigraphy with (99m) technetium-methoxyisobutylisonitrile with histological necrosis following induction chemotherapy or measures of P-glycoprotein expression in high-grade osteosarcoma. Clin Cancer Res 2001;7:3065-70.  Back to cited text no. 5
    
6.
Baldini N, Scotlandi K, Barbanti-Bròdano G, Manara MC, Maurici D, Bacci G, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med 1995;333:1380-5.  Back to cited text no. 6
    
7.
Hornicek FJ, Gebhardt MC, Wolfe MW, Kharrazi FD, Takeshita H, Parekh SG, et al. P-glycoprotein levels predict poor outcome in patients with osteosarcoma. Clin Orthop Relat Res 2000;11-7.  Back to cited text no. 7
    
8.
Kumta SM, Zhu QS, Lee KM, Griffith J, Chow LT, Leung PC. Clinical significance of P-glycoprotein immunohistochemistry and doxorubicin binding assay in patients with osteosarcoma. Int Orthop 2001;25:279-82.  Back to cited text no. 8
    
9.
Burak Z, Ersoy O, Moretti JL, Erinç R, Ozcan Z, Dirlik A, et al. The role of 99mTc-MIBI scintigraphy in the assessment of MDR1 overexpression in patients with musculoskeletal sarcomas: Comparison with therapy response. Eur J Nucl Med 2001;28:1341-50.  Back to cited text no. 9
    
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Yu XC, Liu XP, Qu ZP, Zhao Y, Ding JY. Expression of P-glycoprotein in osteosarcoma and correlation with the expressions of PCNA P53 nm-23. Orthop J China 2000;7:224-6.  Back to cited text no. 10
    
11.
Dai MN, Wan XZ, Liu ZP, Zong SZ. Relationship between P-glycoprotein, survivin expression and chemotherapy outcome in osteosarcomas. Orthop J China 2006;14:687-9.  Back to cited text no. 11
    
12.
Liu YJ, Li XT, Guo SF, Lin SZ. Expression of P-gp in osteosarcoma and correlation with the expression of LRP bcl-2. Orthop J China 2004;12:85-7.  Back to cited text no. 12
    
13.
Wang TS, Gao QN. Expression and significance of p-gp, GST-ð and Topo II in human osteosarcoma. J Fourth MiI Med Univ 2003;24:919-20.  Back to cited text no. 13
    
14.
Blight MA, Holland IB. Structure and function of haemolysin B, P-glycoprotein and other members of a novel family of membrane translocators. Mol Microbiol 1990;4:873-80.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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