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CLINICAL SCIENCE
Serum alkaline phosphatase predicts survival outcomes in patients with skeletal metastatic nasopharyngeal carcinoma
Ying Jin, Mei-Qin Yuan, Jun-Qing Chen, Yi-Ping Zhang
Corresponding author
zhang_yp999@sina.cn

corresponding author
Zhejiang Cancer Hospital, Department of Medical Oncology, Hangzhou, China
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival curves are shown for the total sample of 416 patients according to the pre-treatment &#40;and post-treatment&#41; S-ALP level&#46; <span class="elsevierStyleBold">A&#41;</span> PFS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> OS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">C&#41;</span> PFS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">D&#41;</span> OS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">E&#41;</span> PFS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">F&#41;</span> OS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Nasopharyngeal carcinoma &#40;NPC&#41; is a leading form of cancer in several well-defined populations&#44; such as the natives of southern China&#44; Southeast Asia&#44; the Arctic&#44; the Middle East&#44; and North Africa &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; With advances in radiotherapy techniques&#44; the regional control rate of NPC has increased remarkably &#40;<a class="elsevierStyleCrossRef" href="#bib1">3</a>&#41;&#46; In recent years&#44; the combination of targeted medicine with intensity-modulated radiotherapy has also brought promising results for locoregionally advanced NPC &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#44;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#46; The majority of deaths occur not because of the tumor in the primary site but rather because of distant metastasis&#46; Different reports have shown that approximately 17&#37; to 54&#37; of patients with NPC failed treatments due to distant metastases and that approximately one-third of patients presented disseminated disease at the primary diagnosis &#40;<a class="elsevierStyleCrossRef" href="#bib4">6</a>&#41;&#46; Bone is one of the preferred target sites for cancer metastasis&#46; NPC has a propensity to spread to bone&#44; and most of the patients who present with bone metastasis have an increased risk of skeletal-related events &#40;SREs&#41;&#44; including receiving radiotherapy for bone pain&#44; pathological fracture&#44; spinal cord compression and hypercalcemia&#44; all of which result in reduced quality of life and an increased risk of death &#40;<a class="elsevierStyleCrossRef" href="#bib5">7</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Once bony metastasis has been diagnosed&#44; the current standard treatment modality for these patients essentially involves cisplatin-based palliative chemotherapy with or without local radiation therapy according to the symptoms of bone pain &#40;<a class="elsevierStyleCrossRef" href="#bib6">8</a>&#41;&#46; Determining the early response to treatment is essential to the subsequent management in disseminated NPC patients&#46; In the past&#44; the tumor evaluation criteria developed by the WHO defined bone tumor response by the change of lesion size in skeletal scintigraphy and plain radiography&#46; However&#44; because the change in osteodestructive lesion size is always slow&#44; this method is not useful in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#bib7">9</a>&#41;&#46; Currently&#44; the most scientific and widely used tumor response criteria in the clinical setting are the Response Evaluation Criteria in Solid Tumors &#40;RECIST&#41;&#44; but in this system&#44; bone metastasis is classified as &#8216;non-measurable&#8217; and a &#8216;non-target lesion&#8217; &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46; As a result&#44; a readily available biomarker that may enhance the ability to predict the short-term treatment response and long-term survival outcome of NPC patients with bone metastasis is urgently needed&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Serum alkaline phosphatase &#40;S-ALP&#41; has been extensively used to screen patients for bone metastasis because it is a simple and inexpensive routine hospital test that is easily available and yields quick results&#46; The prognostic role of S-ALP has been explored in various types of malignancies with bony metastatic disease&#46; Both the baseline S-ALP and changes in S-ALP have been reported as prognostic factors for treatment effect and survival such as in bony metastatic prostate cancer &#40;<a class="elsevierStyleCrossRef" href="#bib8">11</a>&#41;&#44; bony metastatic breast cancer &#40;<a class="elsevierStyleCrossRef" href="#bib9">12</a>&#41;&#44; and clear cell chondrosarcoma of the bone &#40;<a class="elsevierStyleCrossRef" href="#bib10">13</a>&#41;&#46; In our previous study &#40;<a class="elsevierStyleCrossRef" href="#bib11">14</a>&#41;&#44; we showed that elevated pretreatment S-ALP was an independently negative prognosticator for disseminated NPC&#46; However&#44; to the best of our knowledge&#44; there is no previous research that has explored the clinical application of S-ALP changes in patients with skeletal metastatic NPC receiving palliative chemotherapy&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">The aim of this retrospective study was to investigate the prognostic value of S-ALP as a tumor marker in patients with bony metastatic NPC treated with systemic chemotherapy&#46; Pre-treatment and post-treatment S-ALP levels were measured&#46; The correlations of the S-ALP levels to the treatment response evaluation and survival outcome were analyzed&#46;</p><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">Patients and methods</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Inclusion criteria and enrollment</span><p id="para50" class="elsevierStylePara elsevierViewall">The charts of 1&#44;380 patients with metastatic NPC admitted to Zhejiang Cancer Hospital between January 2000 and December 2011 were reviewed&#46; The following inclusion criteria were applied&#58; &#40;i&#41; patients with histological confirmation of NPC&#59; &#40;ii&#41; patients with radiological confirmation of bone metastatic lesion&#40;s&#41;&#59; &#40;iii&#41; patients with a good performance status &#40;Karnofsky Performance Scores &#8805;80&#41;&#59; &#40;iv&#41; patients with the appropriate renal&#44; cardiac and liver function to tolerate chemotherapy&#59; &#40;v&#41; patients with complete pre-treatment and post-treatment S-ALP records&#59; and &#40;vi&#41; patients with complete follow-up data&#46; The following exclusion criteria were applied&#58; &#40;i&#41; patients with other types of malignancy&#59; &#40;ii&#41; patients aged &#60;18 years&#59; and &#40;iii&#41; patients who were pregnant at the time of diagnosis&#46; Finally&#44; we were able to retrieve the data for 416 patients&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Definition</span><p id="para60" class="elsevierStylePara elsevierViewall">Metastasis at the time of presentation was defined as patients who presented with distant metastasis when first diagnosed with NPC&#46; This feature was analyzed as a separate category from the patients who presented with localized disease but then developed metastases at a later date&#46; The SREs were classified as fractures&#44; spinal cord compression&#44; radiation to bone&#44; surgery on bone and hypercalcemia&#46; Progression-free survival &#40;PFS&#41; was defined as the time from the first diagnosis of metastasis to disease progression &#40;newly occurring metastatic lesion&#44; recurrence or the expansion of the primary lesion&#41;&#46; Overall survival &#40;OS&#41; was defined as the time from the first diagnosis of metastasis to the time of death&#46; Patients whose deaths were not caused by cancer progression were excluded from the study&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">S-ALP was estimated using the optimized standard method recommended by the German Society of Clinical Chemistry &#40;<a class="elsevierStyleCrossRef" href="#bib12">15</a>&#41;&#46; S-ALP levels lower than 110 IU&#47;L were considered normal because this value corresponds to the extreme range that can be found in a normal population using the method described above&#46; S-ALP &#62;110 IU&#47;L was considered a sign of pathology&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Evaluation protocol</span><p id="para80" class="elsevierStylePara elsevierViewall">The short-term treatment efficacy in patients with measurable lesions was evaluated by measuring the response every 2 treatment cycles during treatment and then every 3 months until death&#46; The response of the tumor to therapy was evaluated based on computed tomography &#40;CT&#41; or magnetic resonance imaging &#40;MRI&#41; scans&#46; The short-term efficacy&#44; based on the RECIST&#44; was assessed as CR&#44; PR&#44; SD and PD&#59; CR and PR were regarded as responses to treatment&#46; The long-term efficacy was evaluated according to the PFS and OS&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Statistical analysis</span><p id="para90" class="elsevierStylePara elsevierViewall">Statistical analysis was performed using the SPSS 17&#46;0 package&#46; Correlations between the S-ALP levels and several variables were assessed using the product moment correlation coefficient &#40;<span class="elsevierStyleItalic">r</span>&#41;&#46; The relationship between short-term treatment efficacy and S-ALP was analyzed using the chi-square test&#46; Survival was analyzed using the Kaplan&#8211;Meier method and then compared using the log-rank test&#46; Univariate and multivariate analyses were performed using the Cox proportion hazards model&#46; <span class="elsevierStyleItalic">P</span>-values for differences between proportions were calculated using Fisher&#39;s exact test &#40;two-tailed&#41;&#46; Statistical significance was defined as <span class="elsevierStyleItalic">P&#60;</span>0&#46;05&#46;</p></span></span></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">RESULTS</span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Descriptive characteristics</span><p id="para100" class="elsevierStylePara elsevierViewall">These features are shown in <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#46; All patients were of Chinese ethnicity with a male predominance &#40;85&#46;1&#37;&#41;&#46; The mean age at diagnosis of metastatic NPC was 44&#46;9 years &#40;ranging from 18 to 70 years&#41;&#46; Approximately one-third of the patients had distant metastasis at presentation&#44; and 63&#46;7&#37; of the patients had vertebral metastases&#46; Two hundred and thirty-one &#40;55&#46;5&#37;&#41; patients had more than one metastatic site&#44; and more than half of the patients had visceral metastasis &#40;lung or liver&#41;&#46; Among the 416 patients&#44; the incidence rate of SREs was 39&#46;9&#37;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para110" class="elsevierStylePara elsevierViewall">Two hundred and thirteen &#40;50&#46;0&#37;&#41; patients showed an increased pretreatment S-ALP&#46; Sex and age&#44; as well as metastases at the time of presentation&#44; did not influence the pretreatment S-ALP levels&#46; The presence of an elevated S-ALP level &#40;&#62;110 IU&#47;L&#41; was significantly correlated with the involvement of more than one metastatic site &#40;P&#8202;&#989;&#8202;0&#46;001&#44; r&#8202;&#989;&#8202;0&#46;167&#41; and specific liver metastasis &#40;P&#60;0&#46;001&#44; r&#8202;&#989;&#8202;0&#46;218&#41;&#44; as well as the presence of SREs &#40;P&#8202;&#989;&#8202;0&#46;016&#44; r&#8202;&#989;&#8202;0&#46;118&#41;&#46; The levels of S-ALP did not correlate with the presence of lung effusion and vertebral effusion&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Treatment</span><p id="para120" class="elsevierStylePara elsevierViewall">An overwhelming majority &#40;70&#46;9&#37;&#41; of the patients were treated with cisplatin-based doublets&#46; The most frequently used regimens included cisplatin &#40;25 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously on days 1-3 every 21 days&#41; plus 5-fluorouracil &#40;600 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously on days 1-5 every 21 days&#41; and paclitaxel &#40;175 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously over 3 hours on day 1 every 21 days&#41; plus cisplatin &#40;25 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously on days 1-3 every 21 cycles&#41;&#46; One hundred and one &#40;29&#46;1&#37;&#41; patients received a triple-drug combination chemotherapy&#46; The most frequently used regimen was paclitaxel &#40;150 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously over 3 hours on day 1 every 21 days&#41; plus cisplatin &#40;25 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously on days 1-3 every 21 cycles&#41; plus 5-fluorouracil &#40;500 mg&#47;m<span class="elsevierStyleSup">2</span> intravenously on days 1-5 every 21 days&#41;&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">Correlation between S-ALP and treatment response</span><p id="para130" class="elsevierStylePara elsevierViewall">For the 217 patients who had measurable lesions &#40;with lung or liver metastasis&#41;&#44; the overall clinical response rate was 59&#46;0&#37; &#40;CR in 6 patients and PR in 122 patients&#41;&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">The difference between the response &#40;CR and PR&#41; rate of patients with normal baseline S-ALP levels &#40;CR&#8202;&#989;&#8202;5 and PR&#8202;&#989;&#8202;55&#41; and those with elevated baseline S-ALP levels &#40;CR&#8202;&#989;&#8202;1 and PR&#8202;&#989;&#8202;67&#41; was not significant &#40;<span class="elsevierStyleItalic">P</span>&#8202;&#989;&#8202; 0&#46;217&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1A</a>&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><p id="para150" class="elsevierStylePara elsevierViewall">Among the 121 patients with elevated pre-treatment S-ALP levels&#44; a drop in the post-treatment S-ALP to a normal level at any time during the treatment was noted in 72 &#40;59&#46;5&#37;&#41; patients&#46; All 6 patients who achieved CR showed a normal post-treatment S-ALP&#46; Thirty-nine of the PR and 14 of the SD patients showed a sharp drop in S-ALP from an elevated level to a normal level&#46; The response rate was significantly higher in patients with a normal post-treatment S-ALP level &#40;CR&#8202;&#989;&#8202;6 and PR&#8202;&#989;&#8202;94&#41; compared with those with sustained high post-treatment S-ALP levels &#40;CR&#8202;&#989;&#8202;0 and PR&#8202;&#989;&#8202;28&#41; &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1B</a>&#41;&#46;</p></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">Correlation between S-ALP and survival outcome</span><p id="para160" class="elsevierStylePara elsevierViewall">The mean PFS and OS for the total 416 patients were 8&#46;3 &#40;0&#46;5-75&#46;5&#41; and 23&#46;3 &#40;2&#46;0-106&#46;0&#41; months&#44; respectively&#46; The mean PFS and OS in patients with a normal baseline S-ALP level were significantly longer than in those with elevated S-ALP levels &#40;the mean PFS was 10&#46;3 vs&#46; 6&#46;1 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; the mean OS was 28&#46;8 vs&#46; 17&#46;6 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2A and 2B</a>&#41;&#46; The mean PFS and OS in patients with normal post-treatment S-ALP levels were significantly longer than those with elevated S-ALP levels &#40;the mean PFS was 9&#46;7 vs&#46; 4&#46;8 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; the mean OS was 27&#46;5 vs&#46; 13&#46;4 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig2">Figure 2C and 2D</a>&#41;&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia><p id="para170" class="elsevierStylePara elsevierViewall">The 416 patients were divided into four subgroups according to their pre-treatment S-ALP level and post-treatment S-ALP level&#58; 1&#41; elevated pre-treatment S-ALP and elevated post-treatment S-ALP &#40;83 patients&#41;&#59; 2&#41; elevated pre-treatment S-ALP and normal post-treatment S-ALP &#40;120 patients&#41;&#59; 3&#41; normal pre-treatment S-ALP and elevated post-treatment S-ALP &#40;39 patients&#41;&#59; 4&#41; normal pre-treatment S-ALP and normal post-treatment S-ALP &#40;174 patients&#41;&#46; The mean PFS for these four subgroups was 4&#46;4&#44; 7&#46;3&#44; 5&#46;7 and 11&#46;3 months&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; The mean OS was 11&#46;5&#44; 21&#46;8&#44; 17&#46;5 and 31&#46;4 months&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRefs" href="#fig2">Fig&#46; 2E and Fig&#46; 2F</a>&#41;&#46;</p></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">Prognostic factors for survival outcome</span><p id="para180" class="elsevierStylePara elsevierViewall">Factors that were incorporated into the analysis included patient factors &#40;age group&#44; gender&#41;&#44; disease factors &#40;metastasis at presentation&#44; visceral involvement&#44; vertebral involvement&#44; number of involved sites&#44; pre-treatment and post-treatment S-ALP levels&#44; presence of SREs&#41; and treatment factor &#40;number of drugs for chemotherapy&#41;&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">The Cox multivariate analysis identified that only the pre-treatment S-ALP level and post-treatment S-ALP level were independent prognostic factors for PFS &#40;HR&#8202;&#989;&#8202;1&#46;656&#44; P&#60;0&#46;001&#59; HR&#8202;&#989;&#8202;2&#46;226&#44; P&#60;0&#46;001&#41; and for OS &#40;HR&#8202;&#989;&#8202;1&#46;794&#44; P&#60;0&#46;001&#59; HR&#8202;&#989;&#8202;2&#46;657&#44; P&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRefs" href="#tbl2">Tables 2 and 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl2"></elsevierMultimedia><elsevierMultimedia ident="tbl3"></elsevierMultimedia></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">Survival analysis for only bone metastasis</span><p id="para200" class="elsevierStylePara elsevierViewall">The mean PFS and OS for the 199 patients with only bony involvement were 9&#46;9 &#40;1&#46;0-75&#46;5&#41; and 24&#46;4 &#40;2&#46;0-106&#46;0&#41; months&#44; respectively&#46; The mean PFS and OS in patients with a normal baseline S-ALP level were significantly longer than those with an elevated S-ALP level &#40;the mean PFS was 12&#46;3 vs&#46; 6&#46;3 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; the median OS was 29&#46;3 vs&#46; 17&#46;5 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3A and 3B</a>&#41;&#46; The mean PFS and OS in patients with a normal post-treatment S-ALP level were significantly longer than in those with an elevated S-ALP level &#40;the mean PFS was 11&#46;6 vs&#46; 4&#46;6 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; the mean OS was 28&#46;6 vs&#46; 12&#46;0 months&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3C and 3D</a>&#41;&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia><p id="para210" class="elsevierStylePara elsevierViewall">The 199 patients were divided into four subgroups according to the pre-treatment S-ALP level and the post-treatment S-ALP level&#58; 1&#41; elevated pre-treatment S-ALP and elevated post-treatment S-ALP &#40;34 patients&#41;&#59; 2&#41; elevated pre-treatment S-ALP and normal post-treatment S-ALP &#40;48 patients&#41;&#59; 3&#41; normal pre-treatment S-ALP and elevated post-treatment S-ALP &#40;16 patients&#41;&#59; 4&#41; normal pre-treatment S-ALP and normal post-treatment S-ALP &#40;101 patients&#41;&#46; The mean PFS for these four subgroups was 4&#46;0&#44; 8&#46;0&#44; 6&#46;1 and 13&#46;3 months&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; The mean OS was 10&#46;3&#44; 22&#46;5&#44; 15&#46;7 and 31&#46;4 months&#44; respectively &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig3">Figure 3E and 3F</a>&#41;&#46;</p></span></span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">DISCUSSION</span><p id="para220" class="elsevierStylePara elsevierViewall">Among the distant metastatic sites from NPC&#44; the skeleton is one of the most common organs found to be involved &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#46; Bone metastasis is a pathological status of bone metabolism in which the normal balance between resorption of old bone and formation of new bone is destroyed &#40;<a class="elsevierStyleCrossRef" href="#bib13">17</a>&#41;&#46; Following up changes in bone metabolism is crucial because it can provide information for treatment evaluation in patients with skeletal metastases&#46; However&#44; bone density changes occur too slowly to allow the clinician to use an acceptable imaging test to monitor the early response to treatment&#46; X-ray has low sensitivity and can only detect lesions when the diameters of the bone metastatic sites are bigger than 1 cm&#46; Bone scans can detect bone lesions earlier than can X-ray&#44; but this method has low specificity and a high false-positive rate&#46; CT is radiative&#44; PET&#47;CT is expensive&#44; and MRI also suffers from limitations&#46; It is therefore unpractical to use the above means to dynamically monitor the changes in bone metabolism&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">In recent years&#44; serum markers of bone formation and resorption processes have held great promise as a new means of obtaining the required information&#46; Effective chemotherapy for patients with skeletal metastatic NPC likely has a favorable effect on serum biomarkers of bone turnover&#44; but this impact is still unknown &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#8211;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; Alkaline phosphatase &#40;ALP&#41; is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules&#44; including nucleotides&#44; proteins&#44; and alkaloids&#46; The process of removing the phosphate group is called dephosphorylation&#46; In humans&#44; almost all tissues throughout the entire body contain this enzyme&#44; but it is particularly concentrated in the bone&#44; liver&#44; bile duct&#44; kidney&#44; and placenta&#46; Although ALP is abundant in tissue cells&#44; blood levels of the enzyme are normally low&#46; However&#44; in some pathological and specific physiological situations&#44; they release more ALP into the bloodstream&#46; Conditions that can cause increased ALP in the serum include pregnancy&#44; bile duct obstruction&#44; kidney disease&#44; hepatocellular carcinoma&#44; and bone metastasis &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib21">21&#8211;24</a>&#41;&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">An elevation of S-ALP is most frequently reported in bone metastasis from certain malignancies&#44; such as lung cancer&#44; breast cancer&#44; and prostate cancer &#40;<a class="elsevierStyleCrossRef" href="#bib19">25-27</a>&#41;&#46; Until now&#44; the clinical application of S-ALP in patients with skeletal metastatic NPC has rarely been mentioned&#46; This is the first time the prognostic role and dynamic changes in the significance of S-ALP in disseminated NPC with bone involvement has been explored&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">The results of this study are consistent with those several of previous studies indicating that the activity of S-ALP is an important prognostic factor for patients with bony malignancies &#40;<a class="elsevierStyleCrossRef" href="#bib20">28</a>&#44;<a class="elsevierStyleCrossRef" href="#bib21">29</a>&#41;&#46; In our report&#44; elevated S-ALP levels were significantly correlated with the presence of liver metastasis and skeletal-related events&#44; as well as the involvement of more than one metastatic site&#46; The median PFS and OS in patients with a normal pre-treatment S-ALP level were significantly longer than those with an elevated pre-treatment S-ALP level&#46; The same results were observed as a correlation between the post-treatment S-ALP level and survival outcome&#46; Previous reports have also demonstrated that elevated S-ALP levels are present in both primary and metastatic liver tumors &#40;<a class="elsevierStyleCrossRef" href="#bib30">30</a>&#41;&#46; Because the majority of S-ALP consists of isoenzymes derived from liver and bone&#44; it is reasonable that patients with bony metastasis associated with liver involvement have higher S-ALP levels than those with only bone metastasis&#46; The association between increased pretreatment S-ALP activity and skeletal-related events and the involvement of more than one metastatic site also provide a rationale that the negative clinical prognosis associated with elevated pretreatment S-ALP may simply be attributed to a greater initial tumor burden and consequently more advanced tumor stage&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">As described above&#44; practical imaging techniques for evaluating the treatment response of bone metastases in a timely manner are still lacking&#46; Therefore&#44; we have investigated the predictive value of S-ALP and found that it could serve as a marker to reflect the degree of regression or progression during chemotherapy for the 217 patients who also presented with measurable lesions &#40;with lung or liver metastasis&#41;&#46; All 6 patients who achieved CR showed a normal post-treatment S-ALP&#46; Thirty-nine of the PR and 14 of the SD patients showed a sharp drop in S-ALP from an elevated level to a normal level&#46; The response rate was significantly higher in patients with a normal post-treatment S-ALP level compared with those with a sustained high post-treatment S-ALP level&#46; S-ALP levels have been demonstrated to reflect the growth and regression of various malignant neoplasms&#46; Guru Sonpavde et al evaluated the association between changes in the S-ALP within 90 days with OS in men with castration-resistant prostate cancer and bone metastases treated with docetaxel or mitoxantrone in the TAX327 trial&#46; The results showed that the normalization of S-ALP by day 90 predicted better survival and that an increase in S-ALP by day 90 predicted poor survival &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46; Maisano R et al reported that in 103 consecutive patients with metastatic colorectal cancer treated with chemotherapy&#44; only 3 patients in the high alkaline phosphatase group obtained a partial response &#40;9&#46;4&#37;&#41; compared to 3 complete responses and 24 partial responses &#40;41&#46;5&#37;&#41; in the low alkaline phosphatase group &#40;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#41;&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">The Cox proportional hazard regression model revealed that only the pre-treatment S-ALP level and post-treatment S-ALP level were independent prognostic factors for overall survival&#46; Notably&#44; when both the pre-treatment and post-treatment S-ALP were considered during analysis&#44; SREs and vertebral involvement were no longer found to be independent negative factors&#44; as described in our previous research &#40;<a class="elsevierStyleCrossRef" href="#bib5">7</a>&#41;&#46; As we reported previously &#40;<a class="elsevierStyleCrossRef" href="#bib11">14</a>&#41;&#44; one reasonable explanation is that serum tumor markers can reflect the tumor burden more sensitively and precisely than can the specific site of metastases&#46; Additionally&#44; the various sizes and quantities of the lesions may have different prognostic implications&#46; Numerous large lesions may represent a more extensive spread than that of fewer small lesions&#46; These findings provide a rationale for why S-ALP levels have stood out as an independent prognostic factor for survival outcome&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">After confirming the prognostic role of S-ALP&#44; we further separated the patients into four subgroups according to their survival outcomes by analyzing the pre-treatment and post-treatment S-ALP in combination&#46; The results revealed that the combination of pre-treatment and post-treatment S-ALP was able to discriminate patients with good prognosis from those with poor prognosis in bony metastatic NPC with or without visceral involvement&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">There are several limitations in this study&#46; First&#44; because it is a retrospective study&#44; the patients may have had other nonspecific causes of S-ALP elevation&#46; Second&#44; S-ALP is not fractionated to a specific phenotype in the routine test in our center&#44; and therefore&#44; a bone-specific alkaline phosphatase is not available&#46; However&#44; the inclusion criteria of this study required patients with normal renal&#44; cardiac and liver function&#59; hence&#44; it is unlikely that hepatic dysfunction or renal disease is a significant confounding cause of the observed elevations in S-ALP&#46; Another caveat is that the normal ranges of S-ALP differ slightly in different laboratories&#46; We choose a conventionally accepted normal range for ALP of 110 IU&#47;L in this study&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">In conclusion&#44; S-ALP appears to be a useful marker to predict survival and monitor the response to treatment for bony metastatic NPC&#46; Given that the measurement of S-ALP is a simple&#44; readily quantifiable&#44; inexpensive&#44; and established routine diagnostic test that is easily available with quick results&#44; further prospective research on the usefulness of S-ALP determination for the monitoring of bone metastases is certainly worthwhile&#46;</p></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle200">AUTHOR CONTRIBUTIONS</span><p id="para310" class="elsevierStylePara elsevierViewall">Jin Y contributed to the study design and manuscript preparation&#46; Yuan MQ contributed to data acquisition&#46; Chen JQ contributed to the statistical analysis&#46; Zhang YP contributed to the quality control of the data and manuscript review&#46;</p></span></span>"
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              "titulo" => "Patients and methods"
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                  "titulo" => "Inclusion criteria and enrollment"
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                  "titulo" => "Statistical analysis"
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          "identificador" => "cesec70"
          "titulo" => "RESULTS"
          "secciones" => array:6 [
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              "titulo" => "Descriptive characteristics"
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            1 => array:2 [
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              "titulo" => "Treatment"
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            2 => array:2 [
              "identificador" => "cesec100"
              "titulo" => "Correlation between S-ALP and treatment response"
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            3 => array:2 [
              "identificador" => "cesec110"
              "titulo" => "Correlation between S-ALP and survival outcome"
            ]
            4 => array:2 [
              "identificador" => "cesec120"
              "titulo" => "Prognostic factors for survival outcome"
            ]
            5 => array:2 [
              "identificador" => "cesec130"
              "titulo" => "Survival analysis for only bone metastasis"
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        3 => array:2 [
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          "titulo" => "DISCUSSION"
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        4 => array:2 [
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          "titulo" => "AUTHOR CONTRIBUTIONS"
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        5 => array:2 [
          "identificador" => "xack639286"
          "titulo" => "Acknowledgments"
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        6 => array:1 [
          "titulo" => "REFERENCES"
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    "fechaRecibido" => "2014-08-20"
    "fechaAceptado" => "2015-01-27"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Nasopharyngeal carcinoma"
            1 => "Palliative chemotherapy"
            2 => "Serum alkaline phosphatase"
            3 => "Skeletal metastasis"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Bone metastasis is frequently associated with nasopharyngeal carcinoma&#46; The diagnosis and follow-up of bone metastatic patients usually relies on skeletal X-ray and bone scintigraphy&#44; which are time-consuming and costly&#46; This study aimed to evaluate whether serum alkaline phosphatase offers clinical value in predicting the clinical response and survival outcome for skeletal metastatic nasopharyngeal carcinoma&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Serum alkaline phosphatase was measured at baseline and then before each cycle of treatment in 416 nasopharyngeal carcinoma patients with bone metastasis&#46; The correlations between the pre-treatment and post-treatment alkaline phosphatase levels and the treatment efficacy were analyzed using the chi-square test&#46; Survival was analyzed using the Kaplan&#8211;Meier method and then compared using the log-rank test&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Patients with elevated pre-treatment alkaline phosphatase &#40;&#62;110 IU&#47;L&#41; had significantly worse progression-free survival &#40;P&#60;0&#46;001&#41; and overall survival &#40;P&#60;0&#46;001&#41; than those with a normal level of this marker &#40;&#8804;110 IU&#47;L&#41;&#46; Patients with elevated post-treatment alkaline phosphatase had worse progression-free survival &#40;P&#60;0&#46;001&#41; and overall survival &#40;P&#60;0&#46;001&#41; compared with those with a normal level&#46; Patients with normal pre-treatment and post-treatment alkaline phosphatase showed the most favorable prognosis&#46; The Cox multivariate analysis revealed that only the pre-treatment and post-treatment alkaline phosphatase levels were independent prognostic factors for progression-free survival &#40;HR&#8202;&#989;&#8202;1&#46;656&#44; P&#60;0&#46;001&#59; HR&#8202;&#989;&#8202;2&#46;226&#44; P&#60;0&#46;001&#41; and for overall survival &#40;HR&#8202;&#989;&#8202;1&#46;794&#44; P&#60;0&#46;001&#59; HR&#8202;&#989;&#8202;2&#46;657&#44; P&#60;0&#46;001&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">Serum alkaline phosphatase appears to be a significant independent prognostic index in patients with skeletal metastatic nasopharyngeal carcinoma&#44; which could reflect the short-term treatment response of palliative chemotherapy and the long-term survival outcomes&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Correlation between the pre-treatment &#40;and post-treatment&#41; S-ALP level with the treatment responses of the 217 patients who had measurable lesions&#46; <span class="elsevierStyleBold">A&#41;</span> Pre-treatment S-ALP level and the treatment response are shown &#40;chi-square test&#44; <span class="elsevierStyleItalic">P</span>&#989;0&#46;217&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> Post-treatment S-ALP level and the treatment response are shown &#40;chi-square test&#44; <span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 902
            "Ancho" => 691
            "Tamanyo" => 65286
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival curves are shown for the total sample of 416 patients according to the pre-treatment &#40;and post-treatment&#41; S-ALP level&#46; <span class="elsevierStyleBold">A&#41;</span> PFS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> OS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">C&#41;</span> PFS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">D&#41;</span> OS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">E&#41;</span> PFS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">F&#41;</span> OS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig3"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 920
            "Ancho" => 691
            "Tamanyo" => 66197
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival curves are shown for the 199 patients with only bony involvement according to the pre-treatment &#40;and post-treatment&#41; S-ALP level&#46; <span class="elsevierStyleBold">A&#41;</span> PFS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> OS according to the pre-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">C&#41;</span> PFS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">D&#41;</span> OS according to the post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">E&#41;</span> PFS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; <span class="elsevierStyleBold">F&#41;</span> OS according to the combination of pre-treatment and post-treatment S-ALP &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold">No&#46; of cases</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold">Elevated S-ALP</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold">&#37;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold">r-value</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">p</span>-value</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">354&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">171&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">48&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;632&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">51&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;45 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">211&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">109&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">51&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#8722;0&#46;058&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;237&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8805;45 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">205&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">45&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Metastasis at presentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">148&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">49&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;874&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">268&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">130&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">48&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Number of involved sites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>One&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">185&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">39&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;167&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Two or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">231&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">130&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">56&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Liver metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">154&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">63&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;218&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">262&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">106&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">40&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Lung metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">114&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">47&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#8722;0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;721&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">302&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">149&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">49&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Vertebral metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">265&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">51&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;067&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;173&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">44&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Skeletal-related events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Present&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">166&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">56&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;118&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">103&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">41&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Increased S-ALP according to several variables in the 416 patients&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="tfn1" class="elsevierStyleSimplePara elsevierViewall">HR&#58; hazard ratio&#59; 95&#37; CI&#58; 95&#37; confidence interval&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="left" valign="top" scope="col"><span class="elsevierStyleBold">Factors</span></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="top" scope="col"><span class="elsevierStyleBold">Univariate analysis</span></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="top" scope="col"><span class="elsevierStyleBold">Multivariate analysis</span></th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">P-</span>value</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">HR</span> &#40;95&#37; CI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">P-</span>value</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">HR</span> &#40;95&#37; CI&#41;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Sex&#58; Male or female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;345&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;871 &#40;0&#46;654-1&#46;160&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Age&#58; &#60;45 years or &#8805;45 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;904&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;988 &#40;0&#46;808-1&#46;208&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Metastasis at presentation&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;284 &#40;1&#46;035-1&#46;594&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Liver metastasis&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;122&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;284 &#40;0&#46;936-1&#46;760&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Lung metastasis&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;060&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;336 &#40;0&#46;987-1&#46;808&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Pre-treatment S-ALP level&#58; Normal or elevated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;602 &#40;1&#46;294-1&#46;985&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;656 &#40;1&#46;345-2&#46;040&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Post-treatment S-ALP level&#58; Normal or elevated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">2&#46;254 &#40;1&#46;784-2&#46;848&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">2&#46;226 &#40;1&#46;780-2&#46;783&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Number of drugs for chemotherapy&#58;Two or three&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;047&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;802 &#40;0&#46;645-0&#46;997&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Number of involved sites&#58; 1 or &#8805;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;704&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;928 &#40;0&#46;629-1&#46;367&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Vertebral metastasis&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;984&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;002 &#40;0&#46;816-1&#46;231&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Skeletal-related events&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;899&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;980 &#40;0&#46;723-1&#46;329&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Univariate and multivariate analysis of progression-free survival&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="tfn2" class="elsevierStyleSimplePara elsevierViewall">HR&#58; hazard ratio&#59; 95&#37; CI&#58; 95&#37; confidence interval&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="left" valign="top" scope="col"><span class="elsevierStyleBold">Factors</span></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="top" scope="col"><span class="elsevierStyleBold">Univariate analysis</span></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="top" scope="col"><span class="elsevierStyleBold">Multivariate analysis</span></th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">P-</span>value</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">HR</span> &#40;95&#37; CI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">P-</span>value</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">HR</span>&#40;95&#37; CI&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Sex&#58; Male or female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;845 &#40;0&#46;632-1&#46;130&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Age&#58; &#60;45 years or &#8805;45 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;385&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;094 &#40;0&#46;894-1&#46;338&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Metastasis at presentation&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;523&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;074 &#40;0&#46;862-1&#46;338&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Liver metastasis&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;995&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;001 &#40;0&#46;736-1&#46;361&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Lung metastasis&#58; Present or absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;894&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;980 &#40;0&#46;724-1&#46;325&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Pre-treatment S-ALP level&#58; Normal or elevated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;794 &#40;1&#46;453-2&#46;214&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;794 &#40;1&#46;462-2&#46;201&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Post-treatment S-ALP level&#58; Normal or elevated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">2&#46;777 &#40;2&#46;195-3&#46;514&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">2&#46;657 &#40;2&#46;122-3&#46;327&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Number of drugs for chemotherapy&#58; Two or three&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;881&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">1&#46;017 &#40;0&#46;820-1&#46;261&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">Number of involved sites&#58; 1 or &#8805;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;811&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="top">0&#46;954 &#40;0&#46;645-1&#46;409&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="top">0&#46;069&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="top">&nbsp;\t\t\t\t\t\t\n
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Article information
ISSN: 18075932
Original language: English
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