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REVIEW ARTICLE
Palliative radiotherapy for gastric cancer: Is there a dose relationship between bleeding response and radiotherapy?
Gustavo Arruda VianiI, Caio Viani ArrudaII, Ana Carolina HamamuraI, Alexandre Ciufi FaustinoI, Anielle Freitas Bendo DanelichenI, Fernando Kojo MatsuuraI,
Corresponding author
fernandokm12@gmail.com

Corresponding author.
, Leonardo Vicente Fay NevesI
I Faculdade de Medicina de Ribeirao Preto (FMRP), Universidade de Sao Paulo, Ribeirao Preto, SP, BR
II Instituto de Biociencias, Universidade Estadual Paulista (UNESP), Botucatu, SP, BR
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Gastric cancer &#40;GC&#41; is one of the most prevalent malignant diseases worldwide&#44; and it results in a significant proportion of cancer-related death &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; Surgical resection is considered the cornerstone of GC treatment and the only treatment with the capacity to lead to long-term survival &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">However&#44; even with total gastrectomy and extending lymphadenectomy&#44; the rate of local recurrence is high&#44; and adjuvant chemotherapy or chemoradiation is administered with the aim of reducing recurrence &#40;<a class="elsevierStyleCrossRefs" href="#bib2">2&#8211;5</a>&#41;&#46; Local recurrence or local progression from an unresectable disease is a challenging clinical situation for several reasons&#46; First&#44; the majority of patients with local recurrence&#47;progression experience pain&#44; bleeding&#44; and gastric outlet obstruction&#44; which results in a reduced quality of life and a diminished clinical performance &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; Second&#44; local failure of GC is difficult to salvage with chemotherapy and other treatments&#44; and consequently&#44; the prognosis of these patients is poor &#40;<a class="elsevierStyleCrossRefs" href="#bib6">6&#8211;8</a>&#41;&#46; Third&#44; approximately 50&#37; of patients with local recurrence have metastatic disease at the same time &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; In this clinical scenario&#44; the oncologist has several treatment options&#44; including palliative gastrectomy&#44; surgical bypass&#44; endoscopic intervention&#44; palliative chemotherapy&#44; or radiotherapy &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#44;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib9">9&#8211;12</a>&#41;&#46; Of these&#44; palliative external beam radiotherapy &#40;EBRT&#41; has some advantages over others&#44; including greater safety and the fact that it is a non-invasive technique with relatively few restraints concerning the eligibility for treatment &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; Besides&#44; EBRT is effective in mitigating symptoms&#44; and&#44; as it acts directly on neoplastic cells&#44; it has a reasonable probability of delaying tumor progression&#46; Consequently&#44; EBRT may be indicated even for patients with poor clinical performance and various grades of bleeding&#46; Previous studies have shown that EBRT controls tumor bleeding at a rate between 50&#37; and 91&#37; &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Although 10 fractions of 300 Gy is one of the most common radiotherapy regimes&#44; several other radiotherapy regimes are used in clinical practice &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Currently&#44; there are doubts about which is the best schedule to palliate local symptoms as well as whether the bleeding response is a good prognostic marker for survival&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Therefore&#44; in this meta-analysis&#44; we evaluated the treatment outcomes of EBRT to palliate bleeding from GC due to local recurrence&#47;progression&#46; Ultimately&#44; we aimed to determine the relationship between bleeding response and the RT schedule&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">METHODS</span><p id="para40" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis &#40;PRISMA&#41; statement and the Meta-analyses Of Observational Studies in Epidemiology &#40;MOOSE&#41; guideline &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; The requirement for approval from the Ethics Committee was waived&#46; Two reviewers performed the research&#44; selected the articles by title and abstract&#44; and then read the full article&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Two investigators conducted a systematic search of PubMed&#44; the Cochrane Central Register of Controlled Trials&#44; and Embase for studies to assess the treatment outcomes of palliative radiotherapy for GC due to local recurrence or progression&#46; We used the following terms &#8220;gastric cancer&#44;&#8221; &#8220;stomach cancer&#8221; and &#8220;radiotherapy&#44;&#8221; &#8220;palliative&#44;&#8221; &#8220;bleeding&#44;&#8221; and other synonyms&#46; The lists containing the articles and reviews were checked&#44; and possible related articles were tracked to complement the electronic query&#46; Searches were performed from January 2000 up to March 2019 and were limited to publications in English&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Study selection</span><p id="para60" class="elsevierStylePara elsevierViewall">Only studies evaluating the treatment outcomes of GC were included&#46; Studies that reported bleeding response according to the authors&#39; criteria and retrospective&#44; prospective&#44; non-randomized&#44; and randomized studies were included&#44; whereas case reports were excluded&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Patients</span><p id="para70" class="elsevierStylePara elsevierViewall">We included studies of patients with a diagnosis of GC who were previously treated or not treated&#44; who had local recurrence or progression&#44; and who were currently being treated with palliative radiotherapy because of tumor bleeding&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Intervention</span><p id="para80" class="elsevierStylePara elsevierViewall">We evaluated the efficacy of palliative radiotherapy&#46; To this end&#44; studies using any fractionation of EBRT to palliate tumor bleeding due to local recurrence or progression of GC were included&#46; Any EBRT technique &#91;2D&#44; 3D&#44; intensity-modulated radiotherapy &#40;IMRT&#41;&#44; or volumetric modulated arc therapy &#40;VMAT&#41;&#93; was permitted&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">Outcomes</span><p id="para90" class="elsevierStylePara elsevierViewall">The following outcomes were evaluated&#58; bleeding response according to the authors&#39; definition&#44; survival&#44; time without bleeding&#44; and therapeutic effectiveness&#46; Subgroup analysis was performed to evaluate the BED level and RT technique&#46; The studies were stratified by BED level&#58; BED &#8805;40 Gy 10&#44; BED from 30 to 39 Gy 10&#44; and BED &#60;30 Gy 10&#46; The studies were divided into two groups &#40;2DRT or 3DRT&#41; according to the RT technique&#46; Meta-regression analysis was performed to evaluate the relationship between the BED and bleeding response&#46; The therapeutic effectiveness ratio was considered as the mean of time with no bleeding&#47;the mean of overall survival time x 100&#46; The therapeutic effectiveness ratio was calculated for each study&#44; and the results were stratified by the BED Gy 10 level&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Clinical data</span><p id="para100" class="elsevierStylePara elsevierViewall">Patient data&#44; treatment characteristics&#44; and outcomes were retrieved for all included studies&#46; Data on the following characteristics were retrieved&#58; RT technique&#44; RT schedule&#44; time of follow up&#44; bleeding response&#44; and overall survival&#46; With regard to the study characteristics&#44; the design&#44; sample size&#44; inclusion&#47;exclusion criteria&#44; and follow-up time were assessed&#46; Two reviewers gathered all data for all included studies using a standardized data extraction form&#46; A third reviewer was consulted in the event of disagreement&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Methodological quality assessment</span><p id="para110" class="elsevierStylePara elsevierViewall">The potential for risk of bias in the studies was evaluated by two authors independently using methodological index for non-randomized studies &#40;MINORS&#41;&#44; the index score utilized for methodological evaluation of non-randomized studies&#46; The items were scored 0 points if not reported&#59; 1 point when reported but inadequate&#59; and 2 points when reported and adequate&#46; The maximum MINOR score is 16 points for non-comparative studies&#46; We considered a low risk of bias when a study fulfilled all MINORS criteria and scored &#62;70&#37; on the global scale&#46; We considered a high risk of bias for all other scores&#46; If only abstracts were available&#44; they were automatically considered to be at high risk of bias&#46; A consensus was reached by the two reviewers&#44; and when there was disagreement&#44; a third reviewer&#39;s opinion was the decisive factor&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Data synthesis and analysis</span><p id="para120" class="elsevierStylePara elsevierViewall">The proportion rate and 95&#37; confidence interval &#40;CI&#41; of the events for each evaluated outcome were calculated &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; The I<span class="elsevierStyleSup">2</span> statistic was used to assess statistical heterogeneity&#44; wherein an I<span class="elsevierStyleSup">2</span> value of &#60;25&#37; was defined as presenting a low level of heterogeneity &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#46; The meta-analysis was performed using Open Meta-Analyst&#44; a free open software&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">Subgroup analyses were performed to determine whether there was a relationship between the BED and bleeding response&#46; A meta-regression analysis was used to evaluate the relationship between the BED and bleeding&#46; The BED was calculated using the following formula&#58;</p><p id="para140" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="eq001"></elsevierMultimedia></p><p id="para150" class="elsevierStylePara elsevierViewall">The alpha&#47;beta ratio used for GC was 10&#44; and the estimated survival of responders and non-responders was compared&#46; A <span class="elsevierStyleItalic">p</span>-value &#60;0&#46;05 was considered statistically significant in all analyses&#46;</p></span></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">RESULTS</span><p id="para160" class="elsevierStylePara elsevierViewall">We identified eleven non-comparative retrospective studies&#44; which included 409 patients treated with EBRT to control bleeding due to local recurrence&#47;progression of GC &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib17">17&#8211;26</a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig1">Figure 1&#40;a&#41;</a>&#46; describes the search strategy and the reasons for the exclusion of some studies&#46; Ten of the studies were retrospective &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib17">17&#8211;25</a>&#41;&#44; and one was prospective &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#59; all were published between 2008 and 2019&#46; Gastroscopy was used to confirm gastric bleeding in all patients&#46; The most frequent histology was gastric adenocarcinoma&#46; Regarding the radiation dose&#44; the RT schedule delivering 30 Gy in ten fractions was the most commonly used&#46; The median BED Gy 10 was 39&#44; ranging from 7&#46;2 to 50 Gy 10&#46; 3DRT was used in six studies&#44; 2D RT in three&#44; and RT delivered using mixed techniques in two&#46; <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a> summarizes the characteristics of the eleven studies&#46; Using the minor score for rating the risk of bias of studies&#44; we stipulated a MINOR score &#60;70&#37; as indicating a high risk of bias&#46; In general&#44; pooling all studies&#44; the mean score was 85&#37; &#40;85&#37;-100&#37;&#41;&#46; Only one study achieved an ideal MINOR score of 100&#37;&#44; and this study was also the only prospective study included in our meta-analysis&#44; as presented in <a class="elsevierStyleCrossRef" href="#fig1">Figure 1&#40;b&#41;</a>&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><elsevierMultimedia ident="tbl1"></elsevierMultimedia><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Survival and bleeding response</span><p id="para170" class="elsevierStylePara elsevierViewall">All studies reported the survival time and bleeding response as outcomes&#46; The eleven studies included a total of 409 patients&#44; and the mean survival reported by all studies was 3&#46;31 months &#40;95&#37;CI 2&#46;73-3&#46;9&#41;&#44; with no heterogeneity &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#46;295 and I<span class="elsevierStyleSup">2</span>&#61;16&#37;&#41; <a class="elsevierStyleCrossRef" href="#fig2">Figure 2&#40;a&#41;</a>&#46; The meta-analysis of all studies reporting the bleeding response rate was 0&#46;77 &#40;95&#37;CI 0&#46;73-0&#46;81&#41;&#44; with no heterogeneity &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#46;7 and I<span class="elsevierStyleSup">2</span>&#61;0&#37;&#41; <a class="elsevierStyleCrossRef" href="#fig2">Figure 2&#40;b&#41;</a>&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Meta-regression and subgroup analyses for bleeding response and survival</span><p id="para180" class="elsevierStylePara elsevierViewall">We performed meta-regression analysis to identify the relationship between BED Gy 10 and bleeding response&#46; A significant relationship was observed between BED Gy 10 and bleeding response &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#44; as shown in <a class="elsevierStyleCrossRef" href="#fig3">Figure 3&#40;a&#41;</a>&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia><p id="para190" class="elsevierStylePara elsevierViewall">Four studies&#44; including 230 patients&#44; reported the difference in survival between bleeding responders and non-responders&#46; Combining the four studies&#44; the mean overall survival difference between bleeding responders and non-responders was significant at 75&#46;8 days &#40;95&#37;CI&#44; 51-99&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41; <a class="elsevierStyleCrossRef" href="#fig3">Figure 3&#40;b&#41;</a>&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">On stratifying the bleeding response according to the BED Gy 10 level&#44; we found a significantly worse response in the subgroup of studies with a BED &#60;30 Gy 10 &#40;0&#46;64&#59; 95&#37;CI&#44; 0&#46;5-0&#46;7&#59; <span class="elsevierStyleItalic">p</span>&#61;0&#46;001&#41;&#44; and no significant difference between a BED level of 30-39 Gy 10 &#40;0&#46;79&#59; 95&#37;CI&#44; 0&#46;7-0&#46;8&#41; and a BED level &#62;40 Gy10 &#40;0&#46;79&#59; 95&#37;CI&#44; 0&#46;7-0&#46;8&#41; <a class="elsevierStyleCrossRef" href="#fig4">Figure 4&#40;a&#41;</a>&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia><p id="para210" class="elsevierStylePara elsevierViewall">In the subgroup analysis for the RT technique&#44; we observed a significant difference in bleeding response between 3DRT 0&#46;79 &#40;95&#37;CI&#44; 0&#46;74-0&#46;84&#41; and 2DRT 0&#46;65 &#40;95&#37;CI&#44; 0&#46;56-0&#46;75&#59; <span class="elsevierStyleItalic">p</span>&#61;0&#46;021&#41; <a class="elsevierStyleCrossRef" href="#fig4">Figure 4&#40;b&#41;</a>&#46;</p></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Time without bleeding and therapeutic effectiveness ratio</span><p id="para220" class="elsevierStylePara elsevierViewall">Ten studies reported the time without bleeding as an outcome&#46; On pooling all studies&#44; the mean time without bleeding was found to be 2&#46;26 months &#40;95&#37;CI&#44; 1&#46;5-2&#46;9&#41; <a class="elsevierStyleCrossRef" href="#fig5">Figure 5&#40;a&#41;</a>&#46; The therapeutic effectiveness ratio was 0&#46;84 &#40;95&#37;CI&#44; 0&#46;78-0&#46;90&#41;&#44; and by stratifying the therapeutic effectiveness ratio by BED level&#44; we observed a significant difference for BED &#60;30 Gy 10 &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41; <a class="elsevierStyleCrossRef" href="#fig5">Figure 5&#40;b&#41;</a>&#46;</p><elsevierMultimedia ident="fig5"></elsevierMultimedia></span></span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">DISCUSSION</span><p id="para230" class="elsevierStylePara elsevierViewall">The present meta-analysis confirms that EBRT is highly effective in stopping bleeding due to local recurrence or progression from GC&#44; with a bleeding response rate of &#62;75&#37; observed by pooling the outcomes of eleven studies&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">The high bleeding response rate with palliative radiotherapy is a significant finding for clinical practice&#44; mainly for elderly and fragile patients &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46; In recent years&#44; new chemotherapy regimens used to palliate patients with advanced&#92;metastatic GC have improved the survival and quality of life of patients &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; However&#44; many patients with local recurrence from GC are unfit to undergo intensive chemotherapy treatment because of their fragile condition or advanced age&#46; Consequently&#44; palliative RT is an excellent treatment option in this clinical situation&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">The quantitative relationship between bleeding response and RT dose is an interesting finding of our study&#46; The meta-regression analysis correlating bleeding response and BED suggests that there is a significant relationship between them and that high BED schedules can result in better bleeding response rates&#46; This information has significant implications in daily clinical practice&#46; Furthermore&#44; this information is novel because a previous systematic review found a lack of dose-response comparing regimens with a BED of &#62;39 Gy 10 <span class="elsevierStyleItalic">versus</span> regimens with BED&#60;39 Gy 10 &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Our data suggest that high BED regimens are capable of producing a better bleeding response and that bleeding responders have improved survival&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">We also investigated the ideal BED to palliate gastric tumor bleeding&#46; To this end&#44; we stratified the studies into three levels according to BED Gy 10&#46; Using this approach&#44; the meta-regression analysis indicated a non-significant difference between BED 30-39 Gy 10 and BED &#8805;40 Gy 10 and a significant difference for BED &#60;30 Gy 10&#46; Notwithstanding&#44; we were unable to establish the ideal cut-off for a better bleeding response&#59; however&#44; our results suggest that a BED &#62;30 Gy 10 should be chosen in clinical practice&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">Although the exact mechanism of hemostasis provoked by irradiation is not fully understood&#44; we hypothesized that RT schedules with a higher BED produce extensive damage in the vascular endothelial cells&#44; inducing embolism of vessels&#44; platelet aggregation&#44; and tissue factor release&#44; and subsequently support a better hemostatic response to RT in studies using schedules with higher BEDs&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">The hemostatic response to RT was a significant prognostic factor for overall survival&#46; The median survival of responders was significantly longer than that of non-responders &#40;47 <span class="elsevierStyleItalic">vs</span> 113&#46;5 days&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;001&#41;&#46; However&#44; the exact relationship between bleeding response and survival remains unclear&#46; The natural explanation is that tumor bleeding could provoke malnutrition&#44; immunosuppression&#44; and dehydration&#44; which could limit adequate cancer treatment &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; Another interpretation would be that in patients with a bleeding response&#44; a high BED has an increased local therapeutic effect on the tumor&#44; which may translate into longer survival&#46; In contrast&#44; we were unable to determine whether the improvement in survival is related to a direct effect of bleeding or if the increase in survival in responders is influenced by other factors&#44; such as chemotherapy&#44; performance status&#44; and the existence of metastasis&#46; However&#44; it is undeniable that patients who achieve a bleeding response have better survival than non-responders&#44; independent of a direct effect or a secondary benefit from the hemostatic response&#46; The therapeutic effectiveness ratio&#44; calculated as the mean time without bleeding after RT and the mean overall survival&#44; reinforces this argument&#46; This index gives us an idea of the importance of the bleeding response over survival&#46; Our data show that&#44; in general&#44; if patients achieves a bleeding response&#44; they have an approximately 85&#37; of chance of no further bleeding at a later stage&#46; Besides&#44; the therapeutic effectiveness ratio shows us that RT schedules with a BED &#60;30 Gy 10 should not be recommended&#44; even for patients with poor clinical performance&#44; because of the lower therapeutic effectiveness compared to that of BED &#62;30 Gy 10 regimens &#40;92&#37; <span class="elsevierStyleItalic">vs</span> 53&#37;&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;001&#41;&#46; It is important to note that in the subgroup of studies classified as BED &#60;30 Gy 10 the study conducted by Kawabata et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41; used a lower BED &#40;7&#46;2 Gy10&#41;&#44; with the possibility of a repeated course in cases in which bleeding did not stop&#46; Although this study has used a completely different treatment schema than that used in the other studies&#44; the statistical difference was maintained even when removing it from analysis&#44; which validated the outcome&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">In the literature&#44; mixed RT techniques have been used to palliate local recurrence from GC&#59; among them&#44; the most commonly used techniques are 2DRT and 3DRT&#46; In general&#44; the use of 3DRT allows visualization of the tumor and organs at risk more precisely than that on using 2DRT&#46; Moreover&#44; 3DRT allows us to use multiple fields to deliver a higher radiation dose to the bleeding tumor with better conformality than that on using 2DRT&#44; while also minimizing the higher doses to surrounding organs and tissues&#46; Our analyses detected a significant difference in the rates of bleeding response between the studies using 3DRT and those using 2DRT&#46; Therefore&#44; patients with a high BED schedule would be identified&#44; and the use of 3DRT would improve the chances of success in achieving the bleeding response and&#44; theoretically&#44; better survival as well&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">Because there is a dose-response relationship between the BED schedule and the bleeding response&#44; the tumor burden&#44; presence of metastatic disease&#44; and patient performance status are important clinical data for radiation oncologists with regard to the development of personalized radiotherapy schedules&#46; Thus&#44; a short radiotherapy schedule with a high dose per fraction&#44; that is&#44; BED&#62;30 Gy 10&#44; seems adequate for patients who have metastatic disease with a short life expectancy and require urgent symptom control&#46; In contrast&#44; patients with a good performance status&#44; oligometastatic disease&#44; and who are clinically stable could be treated with a longer radiotherapy course&#44; achieving a BED higher than 30 Gy10&#46;</p><p id="para310" class="elsevierStylePara elsevierViewall">This study provides evidence on the relationship between treatment doses&#44; bleeding response&#44; RT technique&#44; and survival to palliate local recurrence or progression from GC&#46; However&#44; it has some limitations&#46; First&#44; this study is a meta-analysis of retrospective studies that are subject to inherent bias&#46; Second&#44; chemotherapy use&#44; the definition of bleeding response&#44; and treatment techniques were heterogeneous across studies&#46; However&#44; these limitations do not alter any of the outcomes and interpretation derivates of our analysis&#46;</p></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">CONCLUSION</span><p id="para320" class="elsevierStylePara elsevierViewall">The present meta-analysis confirms that palliative RT is highly effective in controlling gastric bleeding due to local recurrence or progression from GC&#46; Our data suggest a dose-response relationship between bleeding response and BED&#44; and patients with a bleeding response seem to have better survival&#46; Therefore&#44; RT schedules with a high BED should be used in patients with a good performance&#44; oligometastatic disease&#44; and who are clinically stable&#46; Although we did not identify the ideal BED cut-off&#44; our data suggest that BED &#62;30 Gy 10 should be used&#46; Short fractionations with a high dose per fraction&#44; giving a BED &#62;30 Gy 10&#44; should be reserved for patients with a poor clinical performance and in whom bleeding needs to be stopped urgently&#46; Thus&#44; 3DRT should be administered to all patients to maximize the chance of bleeding control and&#44; theoretically&#44; survival&#46;</p></span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">AUTHOR CONTRIBUTIONS</span><p id="para330" class="elsevierStylePara elsevierViewall">Viani GA was the supervisor&#44; responsible for the statistical analyses and manuscript writing&#46; Arruda CV was responsible for the statistical analyses&#46; Hamamura AC&#44; Faustino AC&#44; Danelichen AFB&#44; Matsuura FK and Neves LVF were responsible for the data collection</p></span></span>"
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          "titulo" => "INTRODUCTION"
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          "titulo" => "METHODS"
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              "titulo" => "Clinical data"
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              "titulo" => "Methodological quality assessment"
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          "titulo" => "RESULTS"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "cesec110"
              "titulo" => "Survival and bleeding response"
            ]
            1 => array:2 [
              "identificador" => "cesec120"
              "titulo" => "Meta-regression and subgroup analyses for bleeding response and survival"
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            2 => array:2 [
              "identificador" => "cesec130"
              "titulo" => "Time without bleeding and therapeutic effectiveness ratio"
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        4 => array:2 [
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          "titulo" => "DISCUSSION"
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          "titulo" => "AUTHOR CONTRIBUTIONS"
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          "titulo" => "REFERENCES"
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    "fechaRecibido" => "2019-11-19"
    "fechaAceptado" => "2020-02-27"
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            0 => "Palliative"
            1 => "Radiotherapy"
            2 => "Gastric Cancer"
            3 => "Bleeding"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to evaluate whether there is a relationship between bleeding response and radiotherapy dose to palliate patients with local recurrence or progression of gastric cancer &#40;GC&#41;&#46; To this end&#44; we conducted a systematic review and meta-analysis of observational studies that evaluated the bleeding response in patients with GC with local recurrence or progression&#46; A meta-regression analysis between biological effective dose &#40;BED&#41; and bleeding response was performed&#44; as was subgroup analysis to evaluate the outcome by BED level and radiotherapy &#40;RT&#41; technique&#46; A <span class="elsevierStyleItalic">p</span>-value &#60;0&#46;05 was considered significant&#46;</p><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Ten non-comparative retrospective studies and one prospective study were included&#46; In general&#44; RT was effective at controlling tumor bleeding&#44; and the bleeding response rate was 0&#46;77 &#40;95&#37; confidence interval &#40;CI&#41;&#44; 0&#46;73-0&#46;81&#41;&#46; Meta-regression analysis demonstrated a linear correlation between BED Gy 10 and bleeding response &#40;<span class="elsevierStyleItalic">p</span>&#61;0&#60;0001&#41;&#46; Studies using conformational RT had a significant bleeding response rate compared to those using 2D &#40;0&#46;79&#59; 95&#37;CI&#44; 0&#46;74-0&#46;84 <span class="elsevierStyleItalic">vs</span> 0&#46;65&#59; 95&#37;CI&#44; 0&#46;56-0&#46;75&#59; <span class="elsevierStyleItalic">p</span>&#61;0&#46;021&#41;&#46; In terms of the BED level&#44; a significant difference in BR was identified on comparing BED Gy10 &#8805;40 &#40;0&#46;79&#59; 95&#37;CI&#44; 0&#46;7-0&#46;8&#41;&#44; BED Gy10 30-39 &#40;0&#46;79&#44; 95&#37;CI&#44; 0&#46;71-0&#46;86&#41;&#44; and BED Gy10 &#60;30 &#40;0&#46;64&#59; 95&#37;CI&#44; 0&#46;5-0&#46;7&#59; <span class="elsevierStyleItalic">p</span>&#61;0&#46;0001&#41;&#46; The mean survival time was 3&#46;31 months &#40;95&#37;CI&#44; 2&#46;73-3&#46;9&#41; months&#44; and the responders had a significantly longer survival &#40;longer by 2&#46;5 months&#41; compared to the non-responders &#40;95&#37;CI&#44; 1&#46;7-3&#46;3&#59; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41;&#46;</p><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Palliative RT is effective at controlling bleeding due to local recurrence&#47;progression from GC&#46; Our findings reveal a relationship between BR and BED&#46; BED &#60;30 Gy 10 should not be recommended&#44; and 3DRT should be indicated instead in order to improve the result&#46;</p></span>"
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          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">5&#40;a&#41;&#46; Mean time with no bleeding&#46; 5&#40;b&#41;&#46; Therapeutic effective ratio by BED level&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="TFN01t01" class="elsevierStyleSimplePara elsevierViewall">2DRT&#58; Conventional radiotherapy&#44; 3DRT&#58; Conformational radiotherapy&#44; BED&#58; Biological effective dose&#44; fx&#58; Fractions&#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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Author&#44; year&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">N&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">RT Dose&#47;BED&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Age &#40;median&#41;&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Metastases&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Concurrent chemotherapy&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">RT technique&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kim et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 Gy in 14 fx41 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;73&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;65&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lee et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 Gy in 10 fx39 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;96&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2DRT&#47;3DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hashimoto et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;21&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asakura et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 Gy in 10 fx39 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;96&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;40&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tey et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">115&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 Gy in 10 fx39 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;67&#46;8&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chaw et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 Gy in 1 fx &#40;75&#37;&#41;20 Gy in 5 fx &#40;25&#37;&#41;14&#46;4 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;44&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kondoh et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 Gy in 10 fx39 Gy10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;90&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;33&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kawabata et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 Gy in 3 fx7&#46;2 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NR&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;11&#37;&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2DRT&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lee et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;6 Gy in 20 fx36 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes &#40;16&#46;7&#37;&#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
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                  \t\t\t\t">Yes &#40;83&#37;&#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
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                  \t\t\t\t">2DRT&#47;3DRT&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="\n
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                  \t\t\t\t">Hiramoto et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 Gy in 20 fx48 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">3DRT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Tey et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 Gy in 12 fx46 Gy 10&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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">3DRT&nbsp;\t\t\t\t\t\t\n
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                              """
                            1 => """
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                              """
                            2 => """
                              C DeSantis \n
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                              EM Ward \n
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Article information
ISSN: 18075932
Original language: English
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es en pt

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