|Year : 2018 | Volume
| Issue : 9 | Page : 468-472
Does serum alkaline phosphatase level really indicate the prognosis in patients with osteosarcoma? A meta-analysis
Rui Gu, Yifu Sun
Department of Orthopaedics, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province 130033, China
|Date of Web Publication||29-Jun-2018|
Department of Orthopaedics, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province 130033
Source of Support: None, Conflict of Interest: None
Objective: Osteosarcoma is the most common malignant bone tumor that occurs in children and adolescents. Various studies have investigated the role of serum alkaline phosphatase (ALP) level in patients with osteosarcoma but report conflicting findings. Thus, a meta-analysis to assess its prognostic value more precisely is conducted.
Materials and Methods: Pooled hazard ratio (HR) with 95% confidence intervals (CIs) of overall survival (OS) was used to assess the prognostic role of serum ALP level. Eleven studies published between 1993 and 2013 with a total of 1336 osteosarcoma patients were included.
Results: Overall, the pooled HR for all 11 eligible studies evaluating high ALP level on OS was 1.60 (95% CI: 1.38–1.86). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Begg's (0.553) and Egger's (0.382) test also did not suggest evidence for publication bias.
Conclusion: This meta-analysis suggests that high serum ALP level is obviously associated with lower OS rate in patients with osteosarcoma, and it is an effective biomarker of prognosis.
Keywords: Alkaline phosphatase, meta-analysis, osteosarcoma, prognosis
|How to cite this article:|
Gu R, Sun Y. Does serum alkaline phosphatase level really indicate the prognosis in patients with osteosarcoma? A meta-analysis. J Can Res Ther 2018;14, Suppl S2:468-72
|How to cite this URL:|
Gu R, Sun Y. Does serum alkaline phosphatase level really indicate the prognosis in patients with osteosarcoma? A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Sep 15];14:468-72. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/468/177217
| > Introduction|| |
Osteosarcoma is the most common malignant bone tumor that occurs in children and adolescents. It comprises about 20% of all primary bone cancers and is characterized by frequent metastasis and resistance to chemotherapy. Before the use of effective chemotherapy, the outcome for patients with osteosarcoma was poor, with 2-year overall survival (OS) rates of 15–20% following surgical resection or radiotherapy. With the administration of neoadjuvant chemotherapy in recent years, the long-term survival rate has been improved to 70–80%. However, the prognosis is still unsatisfactory because of 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.
Alkaline phosphatase (ALP) is a glycoprotein that has its source in bones, liver, kidney, or placenta. Serum ALP level can be easily demonstrated and is one of the markers of bone formation and reflect global skeletal activity. ALP increases if there is active bone formation occurring, as ALP is a byproduct of osteoblast activity. Osteosarcoma is characterized by the production of osteoid tissue or immature bone, so the serum ALP level is high in osteosarcoma patients. There are many studies assessing the prognostic role of serum ALP level in patients with osteosarcoma, and no consistent outcomes are reported. Some studies have suggested a poorer outcome for patients with high ALP,, 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 to provide a comprehensive assessment of the prognostic role of serum ALP level in osteosarcoma.
| > Materials and Methods|| |
We performed a systematic search in PubMed, Embase, and Web of Science databases for eligible publications. The following search terms were used in the meta-analysis: Osteosarcoma (or sarcomas of the bones, osteogenic sarcoma) and ALP (alkaline phospatase or AKP), and outcome (or surviv*, prognos*, predict*). An upper date limit of June 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) Tumors were histologically confirmed as osteosarcoma. (2) Studies examining the relation between serum ALP level and clinical outcome. (3) The studies provided sufficient information to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) of 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.
Two reviewers extracted the data from eligible articles independently. The indispensable information extracted from all primary researches included first author, publication year, country of patients, age and sex of patients, number of cases, and follow-up time. When studies involve time-to-event data, the most appropriate statistics to use are the log HR (log HR) and its variance; however, these are not always explicitly stated in each study. Thus, the log HR and standard error of each study were obtained through the following methods: (1) Directly extracting the unadjusted HR and 95% CI from each article; (2) estimating the HR using the log-rank test, P values, total events, high level, and control group figures; (3) estimating the HR using data from Kaplan–Meier survival curves read by the Engauge Digitizer software (GNU, Boston, USA), as well as the minimal and maximal follow-up times.
Two independent reviewers were assessed the quality of each study using the Newcastle Ottawa Quality Assessment Scale (NOQAS). These scales were used to allocate a maximum of nine points for quality of selection, comparability, exposure, and outcome of study participants.
We measured the impact of high serum ALP 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 (I2) statistics, which described the proportion of the total variation in meta-analysis assessments from 0% to 100%, was used to evaluate the between-study heterogeneity in our meta-analyses. The random effects model was used for the analysis when an obvious heterogeneity was observed among the included studies (I2 > 50%). The fixed-effects model was used while there was no significant heterogeneity between the included studies (I2 ≤ 50%). By convention, an observed HR >1 implies worse survival for the group with high ALP level. The impact of ALP on survival was considered to be statistically significant if the 95% CI did not overlap with 1. Sensitivity analysis was further performed by excluding single study in turns to assess the impact of the individual study on the pooled estimate. To assess the possibility of publication bias, visually assessing the symmetry of Begg's funnel plots and Egger's test were used. The software STATA version 12 (StataCorp LP, College Station, TX, USA) were used for statistical analysis. A two-tailed P < 0.05 was considered statistically significant.
| > Results|| |
Study characteristics and quality assessment
By searching in PubMed, Embase, and Web of Science, 217 studies were initially identified. Two hundred and six reports that did not meet the inclusion criteria were excluded. [Figure 1] shows a flow diagram of the selection process for relative articles. Finally, 11 studies published between 1993 and 2013 with a total of 1336 osteosarcoma patients were included in our meta-analysis.,,,,,,,,,,,,,,, The major characteristics of the 11 eligible publications are reported in [Table 1]. The studies were conducted in eight countries and published between 1993 and 2013. The total number of patients included meta-analysis was 1336, ranging from 32 to 333 patients per study (median 121). All of the studies reported the prognostic value of ALP for survival in patients with osteosarcoma. Five of the 10 studies identified high serum ALP level as an indicator of poor prognosis, and the other six studies showed no statistical impact of high serum ALP level on survival. Quality assessments revealed average NOQAS scores from the two reviewers of 7.5 and 7.6, indicating that all 10 included studies were of moderate quality.
|Figure 1: Flow diagram shows study selection procedure, 11 articles were included in this meta-analysis|
Click here to view
No significant heterogeneity existed across the included studies (I2 = 7.9%, P = 0.369); thus, the fixed-effect model was used. Overall, the pooled HR for all 11 eligible studies evaluating high ALP level on OS was 1.60 (95% CI: 1.38–1.86), suggesting that high ALP level was an indicator of poor prognosis for osteosarcoma patients [Figure 2]. Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR [Figure 3].
|Figure 2: Forest plot of the meta-analysis of prognostic role of high serum alkaline phosphatase level in patients with osteosarcoma|
Click here to view
The assessment of publication bias of literatures was performed by Begg's test and Egger's test. All 11 eligible studies investigating serum ALP level on OS yielded a Begg's test score of P = 0.533 and an Egger's test score of P = 0.382; meanwhile, according to the symmetry of funnel plot [Figure 4], there was no evidence of publication bias in the meta-analysis.
|Figure 4: Funnel plot of the meta-analysis of the prognostic role of alkaline phosphatase in patients with osteosarcoma|
Click here to view
| > Discussion|| |
Osteosarcoma is the most common primary malignant bone tumor of childhood and it is the second highest cause of cancer-related death in these age groups. Though there are many advances in the treatments, the prognos is for these patients is still poor. Identifications of prognostic factors of osteosarcoma can help us get a better understanding on the molecular pathogenesis of osteosarcoma and choose the ideal treatments. In the recent decade, meta-analysis shows the significant association between many biomakers and prognosis in osteosarcoma patients. Vascular endothelial growth factors, serum lactate dehydrogenase, cyclooxygenase-2, cytovillin, and so on  are all the proposed prognosis biomarkers for osteosarcoma.
ALP is a glycoprotein that has its source in bones, liver, kidney, or placenta. Until recently, relatively little was known regarding the biological or mechanistic relevance of increased serum ALP level in osteosarcoma. Serum ALP level can be easily demonstrated and is one of the markers of bone formation and reflect global skeletal activity. Osteosarcoma is characterized by the production of osteoid tissue or immature bone, so the serum ALP level is high in osteosarcoma patients. Until recently, relatively little was known regarding the biological or mechanistic relevance of increased serum ALP concentration in osteosarcoma. Therefore, there is a biochemical possibility of serum ALP level being a prognostic marker in patients with osteosarcoma. A number of studies have investigated the role of serum ALP level in patients with osteosarcoma. However, previously published studies have reported conflicting findings, and the impact of serum ALP level on the survival of patients with osteosarcoma is still unclear. Thus, to derive a more precise estimate of the prognostic role of serum ALP level in patients with osteosarcoma, we systematically reviewed the published studies and carried out a meta-analysis. Overall, the present meta-analysis has combined 11 studies including 1336 patients to yield statistics, indicating a statistically significant role of serum ALP level on OS in osteosarcoma patients. Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR [Figure 3]. Therefore, the meta-analysis suggests that osteosarcoma patients with high serum ALP level have poorer prognosis of OS compared with those with normal serum ALP level. The findings from our data help to get a precise estimate of the prognostic role of serum ALP level in patients with osteosarcoma.
Several limitations of this meta-analysis are acknowledged. First, there were only 11 documents with a total of 1336 osteosarcoma patients in our meta-analysis. The comparatively modest size of the sample can unavoidably increase the risk of bias in this meta-analysis. However, given that osteosarcoma is very not common, the sample size of this investigation is one of the largest to date among studies targeting this malignancy. Second, 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. Third, the literatures included in our meta-analysis were published from 1993 to 2013. The articles published 10 years ago whose methods were applied to the therapy of osteosarcoma may differ from the nearest published. Fourth, as known, normal serum ALP level is higher in infants and children than in adults for bone formation. The cut-off of ALP is also different in studies. The effect of age and various cut-off in different studies could have an influence on the results of this study.
In summary, this meta-analysis suggests that serum ALP has an important impact on OS in patients with osteosarcoma and high serum ALP level is associated with poorer OS. To strengthen our findings, well-designed prospective studies with better standardized assessment of prognostic markers are needed to provide further evidence for the prognostic significance of serum ALP level in patients with osteosarcoma.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Han J, Yong B, Luo C, Tan P, Peng T, Shen J. High serum alkaline phosphatase cooperating with MMP-9 predicts metastasis and poor prognosis in patients with primary osteosarcoma in Southern China. World J Surg Oncol 2012;10:37.
Min D, Lin F, Shen Z, Zheng S, Tan L, Yu W, et al.
Analysis of prognostic factors in 333 Chinese patients with high-grade osteosarcoma treated by multidisciplinary combined therapy. Asia Pac J Clin Oncol 2013;9:71-9.
Pochanugool L, Subhadharaphandou T, Dhanachai M, Hathirat P, Sangthawan D, Pirabul R, et al.
Prognostic factors among 130 patients with osteosarcoma. Clin Orthop Relat Res 1997;345:206-14.
Wu PK, Chen WM, Chen CF, Lee OK, Haung CK, Chen TH. Primary osteogenic sarcoma with pulmonary metastasis: Clinical results and prognostic factors in 91 patients. Jpn J Clin Oncol 2009;39:514-22.
Chou AJ, Kleinerman ES, Krailo MD, Chen Z, Betcher DL, Healey JH, et al.
Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children's Oncology Group. Cancer 2009;115:5339-48.
Aparicio J, Segura A, Montalar J, Garcerá S, Oltra A, Santaballa A, et al.
Long-term results after combined modality treatment for non-metastatic osteosarcoma. Med Oncol 1999;16:255-60.
Ferrari S, Ruggieri P, Cefalo G, Tamburini A, Capanna R, Fagioli F, et al.
Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: An Italian sarcoma group trial ISG/OS-1. J Clin Oncol 2012;30:2112-8.
Wang YH, Han XD, Qiu Y, Xiong J, Yu Y, Wang B, et al.
Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma. J Surg Oncol 2012;105:235-43.
Hagleitner MM, Hoogerbrugge PM, van der Graaf WT, Flucke U, Schreuder HW, te Loo DM. Age as prognostic factor in patients with osteosarcoma. Bone 2011;49:1173-7.
Ger LP, Wang JW, Lin CC, Wang J. Prognostic factors in 43 cases of osteosarcoma. J Formos Med Assoc 1993;92:962-8.
Yalçin B, Gedikoglu G, Kutluk T, Varan A, Akyüz C, Büyükpamukçu M. C-erbB-2 expression and prognostic significance in osteosarcoma. Pediatr Blood Cancer 2008;51:222-7.
Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age: State of the art. Cancer treatment reviews 2006;32:423-36.
Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 2004;9:422-41.
Khoury JF, Ben-Arush MW, Weintraub M, et al
. Alkaline phosphatase level change in patients with osteosarcoma: Its role as a predictive factor of tumor necrosis and clinical outcome. IMAJ 2014;16:26-32.
Ambroszkiewicz J, Gajewska J, Klepacka T, Chelchowska M, Laskowska-Klita T, Wozniak W. Clinical utility of biochemical bone turnover markers in children and adolescents with osteosarcoma. Advances in Medical Sciences 2010;55:266-72.
Chou AJ, Geller DS, Gorlick R. Therapy for osteosarcoma: Where do we go from here? Paediatric Drugs 2008;10:315-27.
Levine AM, Rosenberg SA. Alkaline phosphatase levels in osteosarcoma tissue are related to prognosis. Cancer 1979;44:2291-3.
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17:2815-34.
Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): Development and validation of a new instrument. ANZ Journal of Surgery 2003;73:712-16.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute 1959;22:719-48.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]