J Cancer Res Clin Oncol (2014) 140:1205–1210 DOI 10.1007/s00432-014-1644-0

Original Article – Clinical Oncology

Prognostic significance of serum lactate dehydrogenase level in osteosarcoma: a meta‑analysis Jian Chen · Meng‑xiong Sun · Ying‑qi Hua · Zheng‑dong Cai 

Received: 7 March 2014 / Accepted: 9 March 2014 / Published online: 31 March 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract  Background A number of studies have investigated the role of serum lactate dehydrogenase (LDH) level in patients with osteosarcoma but have yielded inconsistent and inconclusive results. Thus, we conducted a meta-analysis to assess its prognostic value more precisely. Methods  Systematic computerized searches of PubMed, Embase and Web of Science databases were performed. The pooled hazard ratio (HR) with 95 % confidence intervals (95 % CI) of overall survival was used to assess the prognostic role of serum LDH level. Results Ten studies published between 1997 and 2013 with a total of 943 osteosarcoma patients were included. Overall, the pooled HR for all ten eligible studies evaluating high LDH level on overall survival was 1.92(95 % CI 1.53–2.40). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Funnel plots and Egger’s tests revealed there was some possibility of publication bias risk in the meta-analysis. Conclusion This meta-analysis shows that high serum LDH level is obviously associated with lower overall survival rate in patients with osteosarcoma, and it is an effective biomarker of prognosis. J. Chen · M. Sun · Y. Hua (*) · Z. Cai (*)  Department of Orthopaedics, Shanghai First People’s Hospital, Nanjing Medical University, Shanghai 200072, China e-mail: [email protected] Z. Cai e-mail: [email protected] J. Chen e-mail: [email protected] M. Sun e-mail: [email protected]

Keywords LDH · Osteosarcoma · Prognosis · Metaanalysis

Introduction Osteosarcoma is the most common primary malignant tumor of bone in children and adolescents (Stiller et al. 2006). Prior to the use of chemotherapy, 80–90 % of patients with osteosarcoma developed metastatic disease despite achieving local tumor control and died of their disease (Dahlin and Unni 1977). Administration of neoadjuvant and adjuvant chemotherapy has improved cure rates up to 60–70 % (Ritter and Bielack 2010). But the prognosis is still unsatisfactory for lung metastasis or chemotherapy resistance. Therefore, there is a need for markers to identify which patients with osteosarcoma have poor prognosis at the time of diagnosis so that novel treatments can be initiated earlier in an effort to improve their prognosis. Lactate dehydrogenase (LDH) is involved in the interconversion of lactate and pyruvate, providing NAD+ for continued glycolysis in active muscle and is needed for long-chain fatty acid oxidation in liver peroxisomes (McClelland et al. 2003). LDH is known to reflect the tumor burden (Walenta and Mueller-Klieser 2004) and has demonstrated prognostic significance in several tumors, including pancreatic cancer (Tas et al. 2001), lung cancer (Albain et al. 1990), orectal cancer (Kemeny and Braun 1983), prostate cancer (Smaletz et al. 2002) and hematologic malignancies (Garcia et al. 1993), as well as in other bone tumors such as Ewing’s tumors (Bacci et al. 1999). Many retrospective studies have evaluated whether serum LDH level may be a prognostic factor for survival

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in patients with osteosarcoma. However, the results of the studies are inconclusive. Some studies have suggested a poorer outcome for patients with high LDH, whereas others do not. It is unknown whether differences in these investigations have been mostly due to their limited sample size or genuine heterogeneity. Thus, we conducted a meta-analysis of all available studies relating serum LDH with the prognosis of patients with osteosarcoma.

Materials and methods Search strategy PubMed, Embase and Web of Science databases were searched using combinations of the following terms: osteosarcoma (or sarcomas of the bones, osteogenic sarcoma) and lactate dehydrogenase (or LDH) and outcome (or surviv*, prognos*, predict*). An upper date limit of January 1, 2014, was applied. Only studies published in English were included, and no unpublished reports were considered. Studies eligible for inclusion in this meta-analysis met the following criteria: (1) prospective or retrospective cohort study. (2) Tumors were histologically confirmed as osteosarcoma. (3) Studies examining the relation between serum LDH level and clinical outcome. (4) The studies provided sufficient information to estimate the hazard ratio (HR) and 95 % confidence interval (95 % CI) of overall survival (OS). When the same authors reported two or more publications on possibly the same patient populations, only the most recent or complete study was included into this meta-analysis.

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Quality assessment The quality of each study was assessed using the Newcastle Ottawa Quality Assessment Scale (NOQAS) by two independent reviewers (Slim et al. 2003). These scales were used to allocate a maximum of nine points for quality of selection, comparability, exposure and outcome of study participants. Statistical analysis We measured the impact of high serum LDH level on survival by HR between the two survival distributions. HRs and 95 % CIs were used to combine as the effective value. Heterogeneity test with inconsistency index (Ι2) statistic and Q statistic was performed. The random effects model was used for the analysis, when an obvious heterogeneity was observed among the included studies (I2 > 50 %). The fixedeffects model was used, while there was no significant heterogeneity between the included studies (I2 ≤ 50 %) (Mantel and Haenszel 1959). By convention, an observed HR > 1 implies worse survival for the group with high LDH level. The impact of LDH on survival was considered to be statistically significant if the 95 % CI did not overlap with 1. To validate the credibility of outcomes in this meta-analysis, sensitivity analysis was performed by sequential omission of individual studies. Visually assessing the symmetry of Begg’s funnel plots and Egger’s test was used to assess the possibility of publication bias (Egger et al. 1997). The software STATA version 12 (StataCorp LP, College Station, TX, USA) was used for statistical analysis. A two-tailed p value 350 >300 >213 >440 NR >225 NR NR

II–IV II NR II–IV IV II NR II NR

1.90 (1.30–2.78) 1.60 (0.90–2.87) 12.06 (1.66–87.24) 9.38 (1.73–50.74) 1.72 (0.83–3.59) 9.15 (1.53–54.51) 2.21 (1.23–3.97) 2.79 (0.73–10.66) 1.47 (0.82–2.64)

NR NR 42 NR 58.2 47.5 89 96 76

Hagleitner et al. (2011)

Netherlands

85 (NR)

17.8

II

1.15 (0.44–2.99)

67

NA not applicable, HR hazard ratio

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Fig. 2  Forest plot of the metaanalysis of prognostic role of high serum LDH level in patients with osteosarcoma

Fig. 3  Forest plot for the sensitivity analysis in the metaanalysis

Meta-analysis estimates, given named study is omitted Lower CI Limit Estimate Upper CI Limit Ayse 2013 Lucksana 1997 Joerg 2007 Enrique 2009 Wu 2009 Ivana 2004 chou 2009 Aparicio 1999 Stefano 2012 Hagleitner 2011 0.88 0.98

In the recent decade, meta-analyses show the significant association between many biomakers and prognosis in osteosarcoma patients. Vascular endothelial growth factors (Qu et al. 2012), cyclooxygenase-2 (Jiao et al. 2013), matrix metalloproteinase 2 (Wen et al. 2014), Cytovillin (Guo et al. 2013) and so on, are all the proposed prognosis biomarkers for osteosarcoma. LDH is involved in the interconversion of lactate and pyruvate, providing NAD+ for continued glycolysis in active muscle and is needed for long-chain fatty acid oxidation in liver peroxisomes. LDH is widely distributed in cells and would release when cells is attacked by neoplasms. So LDH is known to reflect the tumor burden (Walenta and Mueller-Klieser 2004) and has

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3.06

3.39

demonstrated prognostic significance in several tumors. Therefore, there is an obviously biochemical possibility of serum LDH level being a prognostic marker in patients with osteosarcoma. Serum LDH has been proposed as a prognostic factor in high-grade osteosarcoma in some researches; however, the results are conflicting (Goorin et al. 2003). The findings from our meta-analysis shows that high serum LDH is obviously associated with lower overall survival rate in patients with osteosarcoma, which provides an epidemiological evidence for the prognostic role of serum LDH in osteosarcoma. Several limitations of this meta-analysis are acknowledged. First, All the inclusion researches were limited to

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Fig. 4  Funnel plot of the meta-analysis of the prognostic role of LDH in patients with osteosarcoma

Begg's funnel plot with pseudo 95% confidence limits 4

log[hr]

2

0

-2 0

.5

1

s.e. of: log[hr]

English literatures, so some related published studies in other languages that might meet the inclusion criteria might be missed. Besides, only published studies were included. Probably some relevant unpublished studies that meet the inclusion criteria are missed. Therefore, publication bias may be present. Second, there were only ten documents with a total of 943 osteosarcoma patients in our metaanalysis. The comparatively modest size of the sample can unavoidably increase the risk of bias in this meta-analysis. Thus, more researches with large sample size are needed to further clarify the prognostic significance of serum LDH in the patients with osteosarcoma. Third, another potential source of bias is related to the method of HR and 95 % CI extrapolation. Different methods of extracting HR mentioned before may induce bias. Data for multivariate survival analysis reported in the article were included in the present meta-analysis; if these data were not available, data calculated from survival curves by univariate analysis were included. These results should be confirmed by an adequately designed prospective study. Fourth, the literatures included in our meta-analysis were published from 1997 to 2013. The articles published 5 years ago whose methods were applied to the therapy of osteosarcoma may differ from the nearest published. In conclusion, the meta-analysis shows that high serum LDH is obviously associated with lower overall survival rate in patients with osteosarcoma, and it is an effective biomarker of prognosis. To strengthen our findings, welldesigned prospective studies with better standardized assessment of prognostic markers should help to explore the relation between high serum LDH and survival of osteosarcoma. Conflict of interest The authors declare that they have no conflict of interest.

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Prognostic significance of serum lactate dehydrogenase level in osteosarcoma: a meta-analysis.

A number of studies have investigated the role of serum lactate dehydrogenase (LDH) level in patients with osteosarcoma but have yielded inconsistent ...
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