Received: 2 December 2022 Accepted: 30 May 2023 DOI: 10.1111/jebm.12539 REVIEW Comparative analysis of systemic oncological treatments and best supportive care for advanced gastresophageal cancer: A comprehensive scoping review and evidence map Santero Marilina1 Meade Adriana1 Selva Anna1,2 Acosta-Dighero Roberto3 Meza Nicolás4 Quintana Maria Jesús1,5,6 Bracchiglione Javier1,4 Requeijo Carolina1 Salazar Josefina1 Rodríguez Grijalva Gerardo1 Solà Ivan1,5 Urrútia Gerard1,5 Bonfill Cosp Xavier1,5,6 Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group1 1 Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Abstract Barcelona, Spain Objective: To identify, describe, and organize the available evidence regarding sys- 2 Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari. Institut temic oncological treatments compared to best supportive care (BSC) for advanced d’Investigació i Innovació Parc Taulí gastresophageal cancer. (I3PT_CERCA). Univesitat Autònoma de Barcelona., Sabadell, Spain Methods: We conducted a thorough search across MEDLINE (PubMed), EMbase 3 Faculty of Medicine, Department of Physical (Ovid), The Cochrane Library, Epistemonikos, PROSPERO, and Clinicaltrials.gov. Therapy, University of Chile, Santiago, Chile Our inclusion criteria encompassed systematic reviews, randomized controlled tri- 4 Interdisciplinary Centre for Health Studies als, quasi-experimental and observational studies involving patients with advanced (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile esophageal or gastric cancer receiving chemotherapy, immunotherapy or biologi- 5 CIBER Epidemiología y Salud Pública cal/targeted therapy compared to BSC. The outcomes included survival, quality of life, (CIBERESP), CIBER, Barcelona, Spain functional status, toxicity, and quality of end-of-life care. 6 Department of Paediatrics, Obstetrics and Results: We included and mapped 72 studies, comprising SRs, experimental and obser- Gynaecology and Preventive Medicine and Public Health, Universitat Autònoma de vational designs, 12 on esophageal cancer, 51 on gastric cancer, and 10 both locations. Barcelona, Barcelona, Spain Most compared schemes including chemotherapy (47 studies), but did not report ther- Correspondence apeutic lines. Moreover, BSC as a control arm was poorly defined, including integral Anna Selva, Clinical Epidemiology and Cancer support and placebo. Data favor the use of systemic oncological treatments in survival Screening, Parc Taulí Hospital Universitari, Sabadell, Parc Taulí, 1, 08208 Sabadell, Spain. outcomes and BSC in toxicity. Data for outcomes including quality of life, functional Email: annaolid@gmail.com; aselva@tauli.cat status, and quality of end-of-life care were limited. We found sundry evidence gaps Funding information specifically in assessing new treatments such as immunotherapy and important out- Instituto de Salud Carlos III, Grant/Award comes such as functional status, symptoms control, hospital admissions, and the quality Numbers: PI18/00034, FI19/00335; European Regional Development Fund of end-life care for all the treatments. Conclusions: There are important evidence gaps regarding new for patients with advanced gastresophageal cancer and the effect of systemic oncological treatments on Santero Marilina and Meade Adriana contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2023 The Authors. Journal of Evidence-Based Medicine published by Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd. 216 wileyonlinelibrary.com/journal/jebm J Evid Based Med. 2023;16:216–236. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. 217 important patient-centered outcomes beyond survival. Future research should clearly describe the population included, specifying previous treatments and considering therapeutic, and consider all patient-centered outcomes. Otherwise, it will be complex to apply research results into practice. KEYWORDS drug therapy, esophageal neoplasms, immunotherapy, molecular targeted therapy, review, stom- ach neoplasms 1 INTRODUCTION types and sources of evidence to inform practice, policymaking, and research.”19 In this context, we conducted a scoping review to Esophageal and gastric cancers are significant public health problems identify, describe, and organize the available evidence about the worldwide. Their combined mortality has exceeded 1.2 million in 2020, efficacy of SOTs compared to BSC for patients with advanced GEC, and they have become the second most common cause of cancer- with the purpose to identify evidence gaps that require further related deaths after lung cancer.1 Both types of cancers are often research. diagnosed in advanced stages, due to their aggressive nature, typically have a poor prognosis.2,3 In a metastatic stage, gastresophageal can- cers (GEC) have less than 30% survival at one year and less than 5% at 2 METHODS 5 years.4 For patients in advanced stages, systemic oncological treatments 2.1 Protocol and registration (SOTs) including chemotherapy (CT), targeted/biological therapy, and immunotherapy are currently the classical therapeutic approaches, Our review was conducted in accordance with the guidance provided and their use has increased as more potentially effective drugs have by the JBI Scoping Review Methodology Group.20–22 The reporting been developed. Nevertheless, they are also associated with notable of the review followed the Preferred Reporting Items for Systematic toxicity that may impact patient’s quality of life (QoL), and what entails Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA- their prescription could be an indicator, in some cases, of poor-quality ScR) guideline, as well as the methodology proposed by Global Evi- and aggressiveness of care.5,6 Best supportive care (BSC), in contrast, dence Mapping Initiative23,24 (PRISMA_ScR checklist is available in is focused on symptom control and improvement in patients’ QoL, Supplementary Material 1). Methods for determining the scope of a including a variety of treatments given by highly personalized multidis- content area25–27 consist of the following: (1) establish the boundaries ciplinary teams to on-demand consultations.7–9 It is widely accepted and context of the subject area in question; (2) search and selection that BSC has a role as a complementary treatment, but it is uncer- of relevant studies; and (3) report on the performance and charac- tain if it could be a reasonable alternative when the disease is more teristics of the study. The protocol for this study was prospectively advanced.10 registered and is openly accessible on Open Science Framework.28 Our previous study recently found that the methodological qual- This study is part of a broader project (ASTAC-Study) that aims ity of guidelines for advanced GEC was heterogeneous, and many of to describe and assess the available evidence on the efficacy and the recommendations were still not based on systematic reviews (SR) appropriateness of SOT in advanced nonintestinal digestive cancers but on individual primary studies, sometimes with nonexperimental (including advanced hepatobiliary, gastresophageal, and pancreatic designs.11 Despite the number of recommendations on advanced GEC cancer). Here, we report the results of the scoping review and evidence treatment,12,13 very few clinical guidelines considered other important mapping on advanced GEC. outcomes beyond survival.14–17 For instance, QoL, functional status, hospital admissions, symptom control, and quality of end-life care were all outcomes that should be considered into treatment discussions with 2.2 Eligibility criteria patients. Besides guidelines, it was crucial to analyze the whole body of We used the PCC framework (Population, Concept, and Context) available evidence identifying possible knowledge gaps to better to guide our review question and eligibility criteria.20 According guide future research and ultimately translate into better patient to this framework, our review question was: “What research has care. Scoping review was a useful tool in the ever-increasing arsenal been conducted to assess the efficacy of SOTs compared to BSC of evidence synthesis approaches.18 It might be conducted to “map for patients with advanced GEC considering patient-centered out- the literature on a particular topic or research area and provide comes?” Supplementary Material 2 presents inclusion and exclusion an opportunity to identify key concepts; gaps in the research; and criteria. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 218 MARILINA ET AL. 2.2.1 Population included in our analysis. In the case of QEx studies, we incorporated experimental studies with an inadequate process of randomization or Adult patients (over 18 years), with esophageal or gastric cancers, specific study designs utilizing a nonrandomized allocation of inter- including gastresophageal junction (GEJ), either primary or recurrent, ventions, such as interrupted time series or before-after studies. OBS either adenocarcinoma or squamous cell carcinoma, in stages IIIb, IIIc, encompassed case-control and cohort studies. We included OBS as or IV,29 or described as advanced or metastatic stage by study authors long as they were controlled and consisted of a minimum of 30 at the moment of the intervention. We excluded lymphatic, stromal, patients. and neuroendocrine cancers. We excluded studies with no control group, clinical practice guide- lines, case reports, nonsystematic reviews (such as narrative reviews), and qualitative studies. 2.2.2 Concept We did not apply any language or publication date restrictions except for SRs, for which we included only those published from 2008 We included studies that compared SOTs with BSC. For SOT, we onward. considered any CT (either monotherapy or in combination), biologi- cal/targeted therapy (BIO/TT), or immunotherapy, whether individual or combined, with or without supportive care. We excluded studies 2.3 Search methods for identification of studies that solely examined surgical or radiotherapy intervention, as well as studies that considered CT solely as adjuvant or neoadjuvant We conducted thorough electronic searches across multiple databases therapy. to ensure a comprehensive coverage of the relevant literature. The fol- For BSC, we included any supportive treatment aimed at symp- lowing five databases were included MEDLINE (accessed via PubMed), tomatic or palliative control. This encompassed both usual treatment EMbase (accessed via OVID), the Cochrane Database of Systematic approaches and BSC.8 Studies that did not explicitly define the control Reviews (CENTRAL), and Epistemonikos. from inception until April, groupt’s intervention or studies where the control group received a 2022 (date of search). To tailor our search strings to the specific placebo were also included. Exclusions were made for studies in which requirements of each database, we combined controlled vocabulary the control group received any form of CT, biological/targeted therapy, and relevant search terms related to the key concepts of our clinical or immunotherapy. Additionally, interventions with nonpalliative question. The search strategy for MEDLINE (PubMed) can be accessed intent, such as curative surgery or radiotherapy, were excluded. in the Open Science Framework repository (https://osf.io/c6vxp). Supplementary Material 3 presents other patient-centered out- Search strings were common for the whole ASTAC-Study and included comes considered in addition to survival. Overall survival (OS), QoL, different cancer locations: gastresophageal, pancreatic, and hepatobil- functional status, and toxicity were considered as primary outcomes, iary cancer. which were visually mapped. In addition to the database search, we also explored PROSPERO and Clinicaltrials.gov to identify any protocols of potentially eligible stud- ies. To further ensure inclusivity, we reached out to experts in the field 2.2.3 Context to inquire about any relevant studies. It is worth mentioning that we did not employ any other strategies specifically targeting the retrieval We considered studies in any clinical setting. of grey literature. 2.2.4 Type of studies 2.4 Selection of studies We included primary research—randomized controlled trials (RCTs), Initially, two reviewers independently evaluated the titles and quasi-experimental studies (QEx), and observational studies (OBS)— abstracts of the search results, ensuring a comprehensive screening. and SRs according to the recommendations of JBI Scoping Review In instances where discrepancies occurred, a third reviewer was Methodology Group.30 We defined an SR as any form of secondary consulted to resolve any disagreements and ensure consensus. Subse- research that met the following criteria: (I) explicit eligibility cri- quently, two reviewers independently conducted a detailed full-text teria or research question; (II) structured search strategy involving screening of the selected articles, rigorously assessing their eligibility explicit search terms and data framework in at least two databases; for inclusion in the study. Any discrepancies that arose during this (III) clearly defined screening methods; (IV) explicit assessment of stage were resolved through consultation with a third author, ensuring methodological quality or risk of bias of each included study; and a thorough and unbiased evaluation of the articles. To facilitate this (V) explicit approach to data analysis and synthesis.31,32 For RCTs, systematic process and enhance efficiency, we utilized Covidence,33 we considered any experimental primary study that employed a ran- a web-based software platform that streamlines the production of dom allocation of interventions. Study protocols of RCTs were also evidence synthesis. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. 219 2.5 Data extraction protocols.97-100 Eleven studies focused on esophageal cancer, 51 on gastric cancer and 10 addressed both locations. Table 1 summarizes Data extraction was carried out by two reviewers independently using the characteristics of the included studies. Out of the total studies, a pre-tested data extraction sheet in Google Forms. The extraction 56 (77.8%) were published in the past 10 years and were published sheet was carefully piloted prior to use. For each included study, the in English. The published studies were distributed among 23 different following information was extracted: year of publication, country, countries worldwide. China had the highest number of publications,15 study design, conflict of interest, number of studies included answer- followed by Japan,10 South Korea,8 and the Netherlands.6 The rest of ing our review question (for SRs), number of patients included (for the countries had fewer than 5 published studies. primary studies), interventions assessed (CT, BIO/TT, immunotherapy), Among the 11 studies on advanced esophageal comparators (BSC, placebo, or nonspecified), outcomes reported, cancer,40,51,59,67,72,76,79,85,89,90,94 only three were RCT51,59,67 including and direction of effect classified as “favors intervention,” “favors between 20 and 156 participants. All studies assessed the effect of comparison,” or “no differences.” CT. Most of the schemes included 5-Fluorouracil (7 studies), Cisplatin (5 studies), Docetaxel (3 studies), and/or Doxorubicin (1 study). Most studies did not report the line of therapy (7 out of 11), and among 2.6 Data synthesis and analysis those who did, two included SOT as first-line therapy and two second or further therapy lines. One study assessed BIO/TT, considering We conducted a descriptive analysis, reporting frequency counts Gefitinib and Ramucirumab as second, third, or more lines.40 No study and proportions of studies, populations, interventions, and outcomes assessed the effect of immunotherapy compared to BSC in advanced assessed. The results were presented both narratively and in a tabu- esophageal cancer. lar form, enabling the classification of studies based on cancer type, Among the 51 studies including patients with advanced intervention type, methodological design, and the direction of the gastric cancer,35-37,39,43,55-58,78,80-84,98,101-103 only 15 were effect. RCT55–58,60–66,69–71,103 including between 40 and 656 partici- To visually represent evidence, we utilized the evimappr library,34 pants, and 31 studied the effect of CT. Most of the schemes included an R package specifically designed for creating evidence maps. For 5-Fluorouracil (15 studies), Irinotecan (9 studies), Docetaxel (7 studies), each cancer type, we generated bubble plots as evidence maps. and Leucovorin (7 studies). Many CT studies did not report the line of These maps were structured as a grids, with rows representing therapy (12 out of 31), and among those who did, nine included SOT as the different type of SOT and columns representing the outcomes first-line therapy and 13-s or further therapy lines. Nineteen studies assessed, including survival, QoL, functional status, and toxicity. assessed BIO/TT considering Apatinib (13 studies), Ramucirumab (8 Within each intersection of the grid, corresponding studies were studies), and Everolimus (7 studies) mostly as second or more line populated and classified on their study design (SR, RCT, QEx, OBS). We of therapy (16 out of 19). Five studies assessed immunotherapy, identified an evidence gap if an intersection had no primary studies considering Ipilimumab, and Nivolumab as second, third, or more lines included. of therapy. Among the 10 studies including patients with both esophageal and gastric cancer,42,45,46,52,53,68,77,99,100,104 only three were RCT52,53,68 3 RESULTS including between 45 and 449 participants, and nine studied the effect of CT. Most of the schemes included Doxorubicin and/or Irinote- 3.1 Searching articles can. Patients in their first, second, third, or more lines of therapy were considered, but three studies did not report this information. Following the removal of duplicates, our comprehensive search yielded Three studies assessed BIO/TT, considering Apatinib, Everolimus, Gefi- a total of 50,601 records encompassing various cancer locations, tinib, Ramucirumab, Regorafenib, and Marimastat as first, second, third, including gastresophageal, pancreatic, and hepatobiliary cancers. Sub- or more lines of therapy. One study assessed immunotherapy with sequent screening of titles and abstracts led to the exclusion of 47,667 Nivolumab but did not report the lines of therapy. references. Among the remaining 2934 references, we were not able Conflicts of interest (COI) were not reported in 29 (40.3%) studies. to retrieve 106 reports. consequently, we conducted a full-text review Of the 43 studies that included COI disclosures, 16 had at least one of 2828 articles, ultimately including a total of 185 studies that cov- author reporting COI with industry. ered all cancer locations, of which 72 were related to advanced GEC (Figure 1). 3.3 Outcomes 3.2 Characteristics of the included studies Figures 2 and 3 show an overall summary of the evidence retrieved for Of the 72 included studies, 22 were SRs,35-49 21 were RCTs,50-70 4 esophageal and gastric cancers, classified by type of SOT and reported were QEx studies,71-74 21 were OBS studies,75-96 and 4 were RCT outcomes. Table 2 provides details about the direction of the effect 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 220 MARILINA ET AL. Identification of studies via databases and registers Identification Records identified from: Records removed before screening: Duplicate records removed Databases (n = 69,897) (n = 19,296 ) Records screened Records excluded (n = 50,601) (n = 47,667) Reports sought for retrieval Reports not retrieved (n = 2,934) Screening (n = 106 ) Reports assessed for eligibility Reports excluded(n= 2643): (n = 2,828 ) Duplicate (n = 40 ) Wrong study design (n = 1,246 ) Wrong comparator (n = 824) Wrong intervention (n = 224) Wrong publication type (n = 182) Wrong patient population (n = 92) Wrong outcomes (n = 35) Studies included in all reviews (n = 185) Records excluded(n=113) Included Studies included in review (n = 72 ) FIGURE 1 PRISMA flowchart. reported by each study for all patient-centered outcomes considered Evidence regarding gastric cancer was mostly from RCT assessing in this scoping review. CT. The most reported outcomes were survival-related, especially Evidence regarding esophageal cancer comes mostly from SR time-to-event survival. Most studies showed a trend favoring SOT in assessing CT. The most reported outcomes were those related to terms of survival outcomes (45 studies), although 14 studies on CT and survival, especially in the form of time-to-event survival. Although 19 BIO/TT (5 SRs, 9 RCT, and 1 OBS) did not find differences in survival studies reported survival outcomes in favor of SOT, eight studies (1 between SOT and BSC or placebo. For QoL outcomes (15 studies), SR, 6 RCT and 1 observational study) did not find differences between about half of the studies did not show a significant difference between SOT and BSC or placebo. For QoL outcomes, most studies (11 studies) SOT and BSC or placebo (8 studies) and the other half reported did not show significant differences between SOT and BSC or placebo, favoring results for SOT (7 studies). Regarding toxicity (24 studies), although some (eight studies) reported favoring results for SOT. All most studies (20 studies) found favorable results for BSC or placebo, but one study reporting toxicity (14 studies) found favorable results although three RCTs did not find differences between BIO/TT and BSC for BSC or placebo. There were evidence gaps regarding the effects or placebo, and one RCT found favorable results for immunotherapy. of immunotherapy for all outcomes and the effects of any SOT in There were evidence gaps regarding the effect of immunotherapy for outcomes such as functional status, symptoms, admissions to hospital, all outcomes, and the effect of any SOT in outcomes such as functional or quality of end-life care. status, symptoms, admissions to hospital and quality of end-life care. MARILINA ET AL. TA B L E 1 Characteristics included studies (n = 72). Study Country Na Design Location Intervention Scheme use Line Comparison Outcome Conflicts 76 Adenis 2010 France 284 OBS Esophageal CTX NS/NC NS/NC NS/NC OS NS/NC Alberts 199251 South Africa 20 RCT Esophageal CTX 5-FU, CIS NS/NC NS/NC OS NS/NC Baumgartner 202076 Austria 244 OBS Esophageal; CTX 5-FU, CAPE, CIS, DOC, NS/NC BSC OS Industry Gastric EPI, OXA, Leucovorin Bernards 201377 Netherlands 4797 OBS Gastric CTX NS/NC NS/NC NS/NC OS No 78 Bernards 2016 Netherlands 710 OBS Esophageal CTX NS/NC NS/NC NS/NC OS No Chan 2017_a,b, 36 China 5 of 5 SR Gastric CTX DOC, IRI 2nd, 3rd or BSC, PLB OS No more BIO/TT Apatinib, EVE, RG OS, PFS, Toxicity b, 35 Chan 2017_b, Australia 4 of 15 SR Gastric BIO/TT Apatinib, Ramucirumab, 2nd, 3rd or PLB OS, PFS, QoL Industry RG more Chen 2018102 China 2 of 13 SR Gastric BIO/TT Apatinib 3rd line PLB OS, PFS, Toxicity No b, 37 Chen 2019_a, China 2 of 9 SR Gastric IM Ipilimumab, NIVO 2nd BSC, PLB OS, PFS No b, 80 Chen 2019_b, China 64 OBS Gastric BIO/TT Apatinib 3rd or more BSC OS No Chua 201999 Australia . PT Esophageal; CTX RG 2nd, 3rd or PLB OS, PFS, QoL NS/NC Gastric more Ciardiello 201998 Italy 136 PT Gastric CTX Pamiparib 1st PLB OS, PFS NS/NC 38 Ciliberto 2015 Italy 3 of 22 SR Gastric BIO/TT Apatinib, EVE, 3rd or more BSC, PLB OS, PFS No Ramucirumab Cordero-Garcia Costa Rica 168 OBS Gastric CTX 5-FU, CAPE, CIS, NS/NC NS/NC OS, PFS No 201980 Epirubicin, OXA, PAC, Leucovorin Dutton 2014,b, 52 UK 449 RCT Esophageal; BIO/TT Gefitinib 2nd, 3rd or BSC, PLB OS, PFS, QoL, Industry Gastric more Symptoms, Toxicity EudraCT 2014,b, 100 Italy . PT Esophageal; CTX RG 2nd PLB . NS/NC Gastric (Continues) 221 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 222 TA B L E 1 (Continued) Study Country Na Design Location Intervention Scheme use Line Comparison Outcome Conflicts Ford 201453 UK 168 RCT Esophageal; CTX DOC 2nd, 3rd or BSC OS, QoL, Symptoms, Industry Gastric more Toxicity Fuchs 2014,b, 103 USA 355 RCT Gastric BIO/TT Ramucirumab NS/NC BSC, PLB OS, PFS, QoL, Toxicity Industry Glimelius 199755 Sweden 61 RCT Gastric CTX 5-FU, EPEG, Leucovorin NS/NC BSCkorea OS, QoL NS/NC 81 Hayashi 2019 Japan 681 OBS Gastric CTX 5-FU, IRI, Platin, Taxane, NS/NC BSC OS No Trastuzumab Hwang 201482 South Korea 68 OBS Gastric CTX 5-FU, CIS, DOC, IRI, OXA, NS/NC BSC OS NS/NC PAC, Leucovorin Iacovelli 201439 Italy 5 of 5 SR Gastric CTX DOC, IRI 2nd BSC, PLB OS No IM Ramucirumab BIO/TT EVE Janmaat 2017,b, 40 Netherlands 5 of 11 SR Esophageal CTX 5-FU,CIS, DOC, DOX, CP 1st, 2nd BSC OS, PFS, QoL, Toxicity NS/NC BIO/TT Ramucirumab, Gefitinib 2nd BSC OS, PFS, QoL, Toxicity Jiang 201272 China 99 Q-Exp Esophageal CTX 5-FU, CIS NS/NC NS/NC Admission, FS, OS, NS/NC Toxicity Kang 201256 South Korea 202 RCT Gastric CTX 5-FU, CAPE, CIS, DOC, 2nd, 3rd or BSC OS No Epirubicin, IRI more Kang 2017,b, 70 South Korea 493 RCT Gastric IM NIVO 3rd or more PLB OS, PFS, Toxicity NS/NC Kang 2019,b, 57 South Korea 460 RCT Gastric BIO/TT Apatinib 3rd or more PLB OS, PFS NS/NC Kano 198284 Japan 196 OBS Gastric CTX MITO, FT NS/NC NS/NC OS NS/NC 85 Kawamoto 2018 Japan 70 OBS Esophageal CTX 5-FU, CIS 1st NS/NC Symptoms No Khatri 201958 India 51 RCT Gastric CTX 5-FU, EPEG, Leucovorin NS/NC BSC OS, QoL NS/NC 73 Kozaczka 1990 Poland 100 Q-Exp Gastric CTX 5-FU, CP, MTX, Lederfolin NS/NC NS/NC OS NS/NC b, 41 Kundel 2020, Israel 1 of 5 SR Gastric IM NIVO 3rd or more PLB OS, PFS Industry Lee 201274 South Korea 372 Q-Exp Gastric CTX NS/NC 2nd BSC OS NS/NC Lee 201686 South Korea 1871 OBS Gastric CTX NS/NC NS/NC NS/NC OS No Levard 199859 France 156 RCT Esophageal CTX 5-FU, CIS NS/NC NS/NC OS, Symptoms, NS/NC Toxicity (Continues) MARILINA ET AL. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TA B L E 1 (Continued) MARILINA ET AL. Study Country Na Design Location Intervention Scheme use Line Comparison Outcome Conflicts b, 60 Li 2013, China 141 RCT Gastric BIO/TT Apatinib 3rd or more PLB OS, PFS, QoL No Li 2016,b, 61 China 267 RCT Gastric BIO/TT Apatinib 3rd or more PLB OS, PFS, QoL, Toxicity Industry Lin 200887 China 389 OBS Gastric CTX 5-FU NS/NC NS/NC OS NS/NC b, 129 Liu 2018, China 3 of 8 SR Gastric BIO/TT Apatinib, Ramucirumab, 2nd, 3rd or PLB OS, PFS No RG more Liu 202042 China 4 of 7 SR Esophageal; CTX DOC,IRI NS/NC BSC, PLB OS, PFS, Toxicity No Gastric IM NIVO 88 Moon 2010 Korea 532 OBS Gastric CTX 5-FU, ADM, CAP, DOC, 1st, 2nd, 3rd BSC OS No DOX IRI,OXA,PAC, S1 or more Moriwaki 201489 Japan 111 OBS Esophageal CTX DOC 2nd BSC OS No 75 Murad 1993 Brazil 40 Q-Exp Gastric CTX 5-FU, DOX, Leucovorin, 1st BSC OS NS/NC MTX Nomura 201690 Japan 283 OBS Esophageal CTX 5-FU, DOC, Fluorouracil, 3rd or more BSC OS, PFS, Toxicity No PAC, Platin, Taxane, INDs, IRI, S1 Oba 201343 Japan 1 of 22 SR Gastric CTX 5-FU, EPEG, Leucovorin NS/NC BSC OS No Ohtsu 2013,b, 62 Japan 656 RCT Gastric BIO/TT EVE 2nd, 3rd or PLB OS, PFS, Toxicity Industry more Park 199791 Korea 409 OBS Gastric CTX 5-FU, DOX, MITO 1st NS/NC OS NS/NC 96 Park 2008 South Korea 254 OBS Gastric CTX NS/NC 2nd BSC OS NS/NC 63 Park 2011 South Korea 193 RCT Gastric CTX DOC, IRI 2nd BSC OS NS/NC Pavlakis 2016,b, 64 Australia 147 RCT Gastric BIO/TT RG 2nd, 3rd or PLB OS, PFS, QoL, Industry more Symptoms, Toxicity Pyrhönen 199565 Finland 41 RCT Gastric CTX 5-FU, Epirubicin, MTX, 1st BSC Admission, OS, PFS, NS/NC Leucovorin Toxicity Qi 201444 China 2 of 7 SR Gastric BIO/TT Apatinib, Ramucirumab 2nd PLB OS, PFS No Qin 201471 China 270 RCT Gastric BIO/TT Apatinib NS/NC PLB OS, PFS NS/NC b, 66 Shitara 2018, Japan 507 RCT Gastric CTX Tipiracil, Trifluridine 3rd or more PLB FS, OS, PFS, QoL, Industry Symptoms, Toxicity (Continues) 223 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 224 TA B L E 1 (Continued) Study Country Na Design Location Intervention Scheme use Line Comparison Outcome Conflicts Schmid 199366 South Africa 86 RCT Esophageal CTX 5-FU, Trimetrexate, NS/NC NS/NC OS, Symptoms NS/NC Ifosfamide, Mesna, Leucovorin Sugimoto 201796 Japan 47 OBS Gastric CTX NS/NC 1st BSC OS NS/NC 95 Sugimoto 2019 Japan 141 OBS Gastric CTX NS/NC 1st, 2nd BSC OS No BIO/TT Ramucirumab, 1st Trastuzumab Swinson 201967 UK 45 RCT Esophageal; CTX CAPE, OXA NS/NC BSC OS NS/NC Gastric TerVeer 2016_a45 Netherlands 7 of 29 SR Esophageal; CTX DOC, IRI 2nd, 3rd or BSC OS, PFS, Toxicity Industry Gastric more BIO/TT Apatinib,EVE, OS, PFS, Toxicity Ramucirumab, RG TerVeer 2016_b46 Netherlands 2 of 65 SR Esophageal; CTX Anthracycline, CIS, 1st BSC OS, PFS Industry Gastric Fluoropyrimidine, IRI, OXA, MTX, taxane Thuss-Patience 2011,b, Germany 40 RCT Gastric CTX IRI 2nd BSC OS No 69 Tsavaris 199993 Greece 260 OBS Gastric CTX 5-FU, Carboplatin, NS/NC NS/NC OS NS/NC Epirubicin, MITO van Kleef 2020104 Netherlands 7 of 43 SR Esophageal; CTX 5-FU, DOC, EPEG, 1st, 2nd, 3rd BSC, PLB OS, QoL, Symptoms Industry Gastric Leucovorin or more BIO/TT Apatinib, EVE, Gefitinib, OS, QoL, Symptoms Ramucirumab, RG, Marimastat (Continues) MARILINA ET AL. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. TA B L E 1 (Continued) Study Country Na Design Location Intervention Scheme use Line Comparison Outcome Conflicts 47 Wagner 2017 Switzerland 2 of 64 SR Gastric CTX 5-FU, ADM, Epirubicin, 1st BSC OS Industry MTX Wallis 2019,b, 48 Canada 1 of 23 SR Gastric IM NIVO NS/NC PLB OS Industry 49 Wang 2017 China 3 of 10 SR Gastric BIO/TT Apatinib, EVE, 2nd PLB OS No Ramucirumab Wong 201794 USA 155 OBS Esophageal CTX NS/NC NS/NC NS/NC OS No 130 Xie 2017 China 2 of 23 SR Gastric BIO/TT Bevazicumab, Cetuximab, NS/NC PLB OS, PFS No EVE, Lapatinib, Nimotuzumab, Onartuzumab, Panitumumab, Ramucirumab, Sunitinib, Trastuzumab, Endostar, Matuzumab Xue 2018131 China 2 of 7 SR Gastric BIO/TT Apatinib 3rd or more PLB OS, PFS No Zeng 2014132 China 1 of 8 SR Gastric CTX IRI NS/NC BSC OS NS/NC b, 133 Zhu 2017, Canada 5 of 8 SR Gastric CTX CIS, DOC, IRI, PAC 2nd, 3rd or BSC, PLB OS Industry more BIO/TT EVE, Ramucirumab 5-FU: fluorouracil; ADM: adriamycin; BIO: biological; BSC: best supportive care; CAPE: capecitabine; CIS: cisplatin; CP: cyclophosphamide; CTX: chemotherapy; IM: immunotherapy; NS/NC: not specified/not clear; OBS: observational study; PT: protocol; Q-Exp: quasi-experimental study; RCT: randomized clinical trial; SR: systematic review; TT:target therapy; DOC: docetaxel; DOX: doxorubicin; EPEG: etoposide; EVE: everolimus; FT: tegafur; GEM: gemcitabine; INDs: investigative new drugs, IRI: irinotecan; NIVO: nivolumab; MITO: mitomycin; MTX: methotrexate; OXA: oxapalatin; PAC: paclitaxel; RG: regorafenib; FS: functional status; OS: overall survival; PFS: progression-free survival; QoL: quality of life. a Number of included participants for primary studies and number of included studies relevant to our clinical question/total of included studies for systematic reviews. b Includes the GEJ. 225 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 226 MARILINA ET AL. Evidence gap map of systemic oncological treatments in patients with advanced esophageal cancer Type of study py Observational Study ra he ot un Quasi-experimental study m Im Randomised controlled trial Interventions Systematic Review py ra he ot me Ch t h g e al/ ic ap d er t e t a og y ol Bi r s at al on of v e e- v e e- m 6m it y om st i o n 12 -e m -e m si us ic e y nt nt s lit lif is to s ti to s ti pt x O ct s To ua m O m n O Pf Ad Fu Q Sy Outcomes FIGURE 2 Evidence map of systemic oncological treatment in patients with advanced esophageal cancer. Evidence gap map of systemic oncological treatments in patients with advanced gastric cancer Type of study py Observational Study ra he ot un Quasi-experimental study m Im Randomised controlled trial Interventions Systematic Review py ra he ot me Ch t h g e al/ ic ap d er t e t a og y ol Bi r s at al on of v e e- v e e- m m 3m 6m m m 6m it y om st i o n 12 24 12 24 -e m -e m si us ic e y nt nt s s s lit lif is to s ti to s ti pt x O O ct Pf s s s s To ua m O O Pf Pf m n O Pf Ad Fu Q Sy Outcomes FIGURE 3 Evidence map of systemic oncological treatment in patients with advanced gastric cancer. 4 DISCUSSION including placebo. As a result of this lack of rigor in study designs, results might be biased over or underestimating the potential benefits 4.1 Summary of findings of SOT and BSC leading to flawed conclusions. Most studies reported survival outcomes favoring the use of SOT, This scoping review comprehensively identified the currently available although some did not find differences between SOT and BSC or evidence about the efficacy and safety of SOT compared to BSC for placebo for either advanced gastric and esophageal cancer. Among the patients with advanced GEC. Two evidence maps presented the results few studies that reported other outcomes, most found no differences from 72 studies, including SRs, experimental and observational designs or better results for SOT in terms of QoL, and favorable results for BSC in similar proportions. Regarding population, we identified diverse or placebo regarding toxicity. It was noteworthy that only slightly more inclusion criteria in terms of anatomic location and cancer stages. than a quarter of the included studies reported on QoL, when preserv- Regarding the intervention, most studies did not report therapeutic ing QoL was one of the main objectives when treating patients with lines. So, this heterogeneity in relation to patientt’s prognosis might advanced cancer.105,106 lead to think they were treating advanced cancer for the first time, Aside from survival, QoL, and toxicity outcomes, we found sundry which was probably not true. Moreover, BSC as a control arm was evidence gaps specifically in assessing new treatments such as poorly defined, sometimes including integral support and sometimes immunotherapy and important outcomes such as functional status, 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. 227 symptoms control, hospital admissions and quality of end-life care for to consider patient values and preferences and involve patients in all the treatments. the decision-making process, it was necessary to provide sufficient information on the effects of intervention in all patient-relevant outcomes. This review showed a lack of evidence in many patient- 4.2 Results in context important outcomes, which hindered the correct decision-making process. To our knowledge, this was the first scoping review and evidence Another important finding of this scoping review was that the third mapping assessing SOT versus BSC on patient-centered outcomes part of published studies assessing the effectiveness of SOT versus BSC for advanced GEC. Our research identified the quantity, design, and in advanced GEC did not provide information on the line of treatment characteristics of research conducted in a broad topic area, such as of included patients. As the expected benefit of SOT on survival out- advanced cancer, in contrast to SR, which usually addressed narrowly- comes could be different in patients in their second or more lines of focused research questions.24 However, scoping reviews have been therapy compared to those on their first line,47 it was crucial that study used in the oncology arena to identify the evidence on a particular authors provided detailed information on included participants so their topic and point out new lines of research that need to be developed. results could be useful for the decision-making process. For example, they had been used to identify breast cancer-related On the other hand, this scoping review revealed that 40% of lymphedema treatments, gastrointestinal stromal tumors (GIST) and included studies did not report potential conflicts of interest. The cancer-related fatigue interventions.107–109 reporting of funding and other support was incorporated in 2010 in Interestingly, we found that China, Japan and South Korea, three the CONSORT checklist for reporting RCT120 and had been consid- Asian countries, lead research in this topic area. This apparent interest ered in the PRISMA statement for reporting systematic reviews since could be explained by the fact that more than 75% of esophageal can- 2004.121 All SRs identified in this scoping review were published after cers and deaths in the world occur in Asia,1 and highest incidence of the PRISMA statement was available, and all but two reported conflicts gastric cancer had been reported from some eastern Asian countries of interest. Regarding RCT, most were published from 2011 on, when such as China, Korea and Japan1 ; China for instance was part of the the CONSORT 2010 statement included the disclosure of conflicts of so-called Asian belt of esophageal cancer,110 an area with the highest interest, but six of them still did not report them. Previous studies incidence. had shown that research sponsored by the pharmaceutical industry Our results confirmed that research on advanced GEC had ignored reports better results for the drug being tested than research funded some dimensions of care that had proven important in the last phase by other sources,122-124 but other studies found no differences in posi- of life, such as symptom control, hospital admissions, and quality tive outcomes between industry-funded and nonfunded RCT.125,126 As of death and dying.111 In this sense, the Core Outcome Measures the role of industry in oncology research had expanded over the last in Effectiveness Trials (COMET) initiative, which advocated for the decades,127 adhering to available reporting checklists and informing development of outcome standardization through the development of about sources of funding, conflicts of interest, and industry collabora- Core Outcome Sets (COS), could help to fill the information gap that tion was mandatory for granting transparency and enabling readers to exists for some important outcomes. COS was an agreed minimum assess studies properly.126 set of important outcomes that should be measured and reported in clinical research and those were relevant for either patients or healthcare professionals.111 Although there were COS for esophageal 4.3 Strengths and limitations cancer resection surgery trials,112 gastric cancer surgery trials,113 and a patient-reported core set of general symptoms for cancer treat- Our study had several strengths. As previously stated, it was the first ment trials,114 there was still no specific COS available for research scoping review regarding SOT compared to BSC in advanced GEC. on advanced cancer. Some authors were working on developing a Also, we made an effort to include all potentially patient-centered out- COS for best care of patients at high risk of dying. Although this set comes beyond survival. We undertook a comprehensive search in five would be useful for patients with advanced cancer, it would only databases without any language or date restriction (except for SRst’ cover the end phase of the process through which these patients pass date of publication) to minimize selection bias. The screening process through.115 and data extraction was performed by two independent reviewers to In addition, it was important to consider the clinical decision- minimize errors. We also designed and created a graphical display in making process regarding medical treatment in an end-of-life context. which we used thought-colored bubbles to map available evidence in a In this sense, involving patients in the process and considering their reader friendly way. values and preferences was needed to reach truly patient-centered This research, however, was subject to possible limitations. First, a care.116,117 This was especially important in complex scenarios such limitation of scoping reviews (and other knowledge synthesis products) as treating patients with advanced GEC, where benefits and risks was that we could not exclude a potential publication bias. However, were closely balanced. It was known that patient preferences and the we tried to minimize it by searching in public registries (PROSPERO importance and value they give to different outcomes varied across and clinicaltrials.gov) and by asking experts in the field for relevant patients and differed from healthcare professionals.118–120 However, unpublished studies. Second, the pragmatic decision of including SR 228 TA B L E 2 Effect direction reported outcomes of the published studies on systemic oncological treatment in patients with advanced gastresophageal cancer (n = 68). OS PFS time- time- to OS OS OS OS to- PFS PFS PFS PFS Study Design Location Therapy Admission FS event 3m 6m 12 m 24 m event 6m 3m 12 m 24 m Symptoms QoL Toxicity Adenis 201076 OBS Esophageal CTX NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Alberts 199251 RCT Esophageal CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Baumgartner OBS Esophageal; CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 202077 Gastric Bernards 201378 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Bernards 201679 OBS Esophageal CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR a, 36 Chan 2017_a, SR Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Chan 2017_a,a, 36 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR FC a, 35 Chan 2017_b SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR FI NR 102 Chen 2018 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR FC Chen 2019_a,a, 37 SR Gastric IM NR NR FI NR FI FI NR NR NR NS FI NR NR NR NR Chen 2019_b,a, 80 OBS Gastric BIO/TT NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 38 Ciliberto 2015 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR Cordero-Garcia OBS Gastric CTX NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR 201981 Dutton 2014,a, 52 RCT Esophageal BIO/TT NR NR NS NR NR NR NR FI NR NR NR NR FI NS NS 53 Ford 2014 RCT Esophageal; CTX NR NR FI NR NR NR NR NR NR NR NR NR FI NS FC Gastric Ford 201453 RCT Esophageal CTX NR NR NS NR NR NR NR NR NR NR NR NR FI NS FC 53 Ford 2014 RCT Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR FI NS FC Fuchs 2014,a, 103 RCT Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NS NS Glimelius 199755 RCT Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR NR FI NR 82 Hayashi 2019 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Hwang 201483 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 39 Iacovelli 2014 SR Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR (Continues) MARILINA ET AL. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. TA B L E 2 (Continued) OS PFS time- time- to OS OS OS OS to- PFS PFS PFS PFS Study Design Location Therapy Admission FS event 3m 6m 12 m 24 m event 6m 3m 12 m 24 m Symptoms QoL Toxicity 39 Iacovelli 2014 SR Gastric BIO/TT NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 39 Iacovelli 2014 SR Gastric IM NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Janmaat 201740 SR Esophageal; CTX NR NR FI NR NR NR NR NR NR NR NR NR NR FI FC Gastric Janmaat 201740 SR Esophageal CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NS FC Janmaat 201740 SR Esophageal; BIO/TT NR NR FI NR NR NR NR NS NR NR NR NR NR FI FC Gastric Janmaat 201740 SR Esophageal BIO/TT NR NR FI NR NR NR NR NS NR NR NR NR NR FI FC 72 Jiang 2012 Q-Exp Esophageal CTX FC FI NR NR FI FI NR NR NR NR NR NR NR NR FC 56 Kang 2012 RCT Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Kang 2017,a, 70 RCT Gastric IM NR NR FI FI FI FI NR FI NR NR NR NR NR NR FI a, 57 Kang 2019, RCT Gastric BIO/TT NR NR NS NR NR NR NR FI NR NR NR NR NR NR NR Kano 198284 OBS Gastric CTX NR NR NR NR NR NR NR NR NR NR NR FI NR NR NR 85 Kawamoto 2018 OBS Esophageal CTX NR NR NR FI NR NR NR NR NR NR NR NR FI NR NR 58 Khatri 2019 RCT Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR NR FI NR Kozaczka 199073 Q-Exp Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Kundel 2020,a, 41 SR Gastric IM NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR 74 Lee 2012 Q-Exp Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Lee 201686 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 59 Levard 1998 RCT Esophageal CTX NR NR NR NS NR NS NR NR NR NR NR NR NS NR FC Li 2013,a, 59 RCT Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NS NR a, 61 Li 2016, RCT Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NS FC (Continues) 229 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 230 TA B L E 2 (Continued) OS PFS time- time- to OS OS OS OS to- PFS PFS PFS PFS Study Design Location Therapy Admission FS event 3m 6m 12 m 24 m event 6m 3m 12 m 24 m Symptoms QoL Toxicity 87 Lin 2008 OBS Gastric CTX NR NR NR NR NR FI NR NR NR NR NR NR NR NR NR Liu 2018,a, 129 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR Liu 202042 SR Esophageal; CTX NR NR FI NR NR NR NR FI NR NR NR NR NR NR FC Gastric Liu 202042 SR Esophageal; IM NR NR FI NR NR NR NR FI NR NR NR NR NR NR FC Gastric Moon 201088 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 89 Moriwaki 2014 OBS Esophageal CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 75 Murad 1993 Q-Exp Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Nomura 201690 OBS Esophageal CTX NR NR FI NR FI FI NR NR NR NR NR NR NR NR NR Oba 201343 SR Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR a, 62 Ohtsu 2013, RCT Gastric BIO/TT NR NR NS NR FI NR NR NS NR NR NR NR NR NR NS Park 199791 OBS Gastric CTX NR NR NR NR NR FI NR NR NR NR NR NR NR NR NR 97 Park 2008 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Park 201163 RCT Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR a, 63 Pavlakis 2016, RCT Gastric BIO/TT NS NR NS NR NR NR NR FI NR NR NR NR NR NS FC 65 Pyrhönen 1995 RCT Gastric CTX NS NR FI NR NR FI FI FI NR NR NR NR NR NR FC Qi 201465 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR Qin 201471 RCT Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR Shitara 2018,a, 66 RCT Esophageal; CTX NR FI NS NS NR NR NR FI NR NR NR NR NS NS FC Gastric Shitara 2018,a, 66 RCT Gastric CTX NR FI FI NS NR NR NR FI NR NR NR NR NS NS FC Schmid 199367 RCT Esophageal CTX NR NR NS NR NR NR NR NR NR NR NR NR NS NR NR (Continues) MARILINA ET AL. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License TA B L E 2 (Continued) MARILINA ET AL. OS PFS time- time- to OS OS OS OS to- PFS PFS PFS PFS Study Design Location Therapy Admission FS event 3m 6m 12 m 24 m event 6m 3m 12 m 24 m Symptoms QoL Toxicity Sugimoto 201796 OBS Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Sugimoto 201995 OBS Gastric BIO/TT NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Sugimoto 201995 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 68 Swinson 2019 RCT Esophageal; CTX NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Gastric TerVeer 2016_a45 SR Esophageal; CTX NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR Gastric TerVeer 2016_b46 SR Esophageal; BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR FC Gastric TerVeer 2016_b46 SR Esophageal; CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR FC Gastric Thuss-Patience RCT Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 2011,a, 69 Tsavaris 199993 OBS Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 104 van Kleef 2020 SR Esophageal; BIO/TT NR NR NS NR NR NR NR NR NR NR NR NR FI FI NR Gastric van Kleef 2020104 SR Esophageal; CTX NR NR FI NR NR NR NR NR NR NR NR NR FC FI NR Gastric Wagner 201747 SR Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR a, 48 Wallis 2019, SR Gastric IM NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR Wang 201749 SR Gastric BIO/TT NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Wong 201794 OBS Esophageal CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR 130 Xie 2017 SR Gastric BIO/TT NR NR NR NR NR NS NS NR NR NR FI FI NR NR NR Xue 2018131 SR Gastric BIO/TT NR NR FI NR NR NR NR FI NR NR NR NR NR NR NR 132 Zeng 2014 SR Gastric CTX NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR a, 133 Zhu 2017, SR Gastric BIO/TT NR NR NS NR NR NR NR NR NR NR NR NR NR NR NR Zhu 2017,a, 133 SR Gastric CTX NR NR FI NR NR NR NR NR NR NR NR NR NR NR NR FI: favor intervention; FC: favor comparison; NS: no significance difference; NR: not reported. a Includes the GEJ. 231 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 232 MARILINA ET AL. published after 2008 could be seen as a flaw, but as we did not apply CONFLICT OF INTEREST STATEMENT date restrictions for primary studies, we were confident to have The authors declare that they have no competing interests. localized all available evidence that could be included in old SR. Third, because of the study design, we had not assessed the methodological DATA AVAILABILITY STATEMENT quality of included studies and had not analyzed the magnitude of Appendices and the datasets generated and/or analyzed during the effect sizes nor the certainty of the evidence. Nevertheless, it was not current study are available in the Open Science Framework repository the goal of a scoping review, so we suggested the interpretation of the (https://doi.org/10.17605/OSF.IO/7CHX6).28 effect of interventions on different outcomes should be cautious. ORCID Selva Anna https://orcid.org/0000-0002-2754-3158 4.4 Future perspectives Quintana Maria Jesús https://orcid.org/0000-0002-1055-9786 Requeijo Carolina https://orcid.org/0000-0003-3479-4550 The breadth of our scoping review identifies evidence gaps and may guide future research efforts in advanced GEC. The finding of REFERENCES knowledge gaps regarding the effectiveness of SOT on other patient- 1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: centered outcomes beyond survival ones precludes conducting a trust- gLOBOCAN estimates of incidence and mortality worldwide for 36 worthy trade-off between the potential survival benefits of SOT and cancers in 185 countries. CA: Can J Clin. 2021;71(3), 209–249. their potentially negative effects on other important outcomes such as 2. Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol. toxicity, symptoms control, hospital admissions, functional status and 2013;19(34). 3. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gas- quality of end-of-life in patients with advanced GEC. These uncertain- troenterol. 2006;12(3), 354–362. ties claim for the conduction of high-quality research (mainly RCT and 4. SEER*Explorer: An interactive website for SEER cancer statis- SR) comparing SOT with BSC on all other patient-centered outcomes to tics [Internet] [Internet]. Available from: https://seer.cancer.gov/ provide enough evidence to guide clinical guideline recommendations, explorer/ 5. Earle CC, Landrum MB, Souza JM, Neville BA, Weeks JC, Ayanian JZ. facilitate clinical decision-making and provide truly patient-centered Aggressiveness of cancer care near the end of life: is it a quality-of- care. Therefore, our group (ASTAC) plans to conduct de novo high- care issue? J Clin Oncol. 2008;26(23), 3860–3866. quality SRs to update previous ones and include all available RCTs 6. Earle CC, Neville BA, Landrum MB, Ayanian JZ, Block SD, Weeks JC. assessing SOT versus BSC. Trends in the aggressiveness of cancer care near the end of life. J Clin It is essential for future studies to specify previous treatments and Oncol. 2004;22(2), 315–321. 7. Hui D, De La Cruz M, Mori M, et al. Concepts and definitions for “sup- to objectify those patients that do not receive treatment or those in portive care,” “best supportive care,” “palliative care,” and “hospice who failed. Otherwise, it is very difficult to extrapolate the results to care” in the published literature, dictionaries, and textbooks. Support practice. Care Can. 2013;21(3), 659–685. Finally, funding agencies may use our results to access completed 8. Zafar SY, Currow DC, Cherny N, Strasser F, Fowler R, Abernethy AP. Consensus-based standards for best supportive care in clinical trials or ongoing studies in advanced GEC. Also, researchers and experts in in advanced cancer. Lancet Oncol. 2012;13(2), e77–82. the field can use these evidence maps to inform and prioritize their 9. Nipp RD, Currow DC, Cherny NI, Strasser F, Abernethy AP, Zafar SY. own research decisions and study designs to avoid duplicities and fill Best supportive care in clinical trials: review of the inconsistency in knowledge gaps. control arm design. Br J Cancer. 2015;113(1), 6–11. 10. Haun MW, Estel S, Rücker G, et al. Early palliative care for In conclusion, our scoping review identifies the current research adults with advanced cancer. Cochr Datab Syst Rev. 2017;6: in advanced GEC and recognizes important evidence gaps regard- CD011129. ing new interventions such as immunotherapy and the effect of SOTs 11. Santero M, Meade AG, Acosta-Dighero R, et al. European clinical on important patient-centered outcomes needed for decision-making. practice guidelines on the use of chemotherapy for advanced oesophageal and gastric cancers: a critical review using the Future research should clearly describe the population included, spec- AGREE II and the AGREE-REX instruments. Clin Transl Oncol. ifying previous treatments and considering therapeutic lines, and 2022;24(8):1588–1604. consider all patient-centered outcomes. Otherwise, it will be complex 12. Obermannová R, Alsina M, Cervantes A, et al. Oesophageal can- to extrapolate the results into practice. cer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:P992–1004. 13. Lordick F, Carneiro F, Cascinu S, et al. Gastric cancer: ESMO Clinical ACKNOWLEDGMENTS Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. This study is funded through a grant from Instituto de Salud Carlos III 2022;33(10):1005-1020. (PI18/00034) cofinanced by funds from the European Regional Devel- 14. Martín-Richard M, Carmona-Bayonas A, Custodio AB, et al. SEOM opment Fund. Marilina Santero is doctoral candidate for the PhD in clinical guideline for the diagnosis and treatment of gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJA) (2019). Methodology of Biomedical Research and Public Health, Universidad Clin Transl Oncol. 2020;22(2), 236–244. Autònoma de Barcelona, Barcelona, Spain. We thank Pamela Meinardi, 15. Martin-Richard M, Díaz Beveridge R, Arrazubi V, et al. SEOM Clinical Juan Ignacio Irassar, and Carles Pericay for assistance with the edition, Guideline for the diagnosis and treatment of esophageal cancer. Clin and for comments that greatly improved the manuscript. Transl Oncol. 2016;18(12), 1179–1186. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. 233 16. Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clini- 37. Chen C, Zhang F, Zhou N, et al. Efficacy and safety of immune cal Practice Guidelines for diagnosis, treatment and follow-up. Ann checkpoint inhibitors in advanced gastric or gastroesophageal junc- Oncol. 2016;27(5), v38–v49. tion cancer: a systematic review and meta-analysis. Oncoimmunology. 17. Evangelidis N, Tong A, Howell M, et al. International survey to estab- 2019;8(5), e1581547. lish prioritized outcomes for trials in people with coronavirus disease 38. Ciliberto D, Staropoli N, Caglioti F, et al. A systematic review and 2019. Crit Care Med. 2020;48(11), 1612–1621. meta-analysis of randomized trials on the role of targeted therapy 18. Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris in the management of advanced gastric cancer: evidence does not E. Systematic review or scoping review? Guidance for authors when translate? Cancer Biol Ther. 2015;16(8), 1148–1159. choosing between a systematic or scoping review approach. BMC 39. Iacovelli R, Pietrantonio F, Farcomeni A, et al. Chemotherapy or tar- Med Res Methodol. 2018;18(1), 143. geted therapy as second-line treatment of advanced gastric cancer. A 19. Daudt HML, van Mossel C, Scott SJ. Enhancing the scoping study systematic review and meta-analysis of published studies. PLoS One. methodology: a large, inter-professional team’s experience with Ark- 2014;9(9), e108940. sey and O’Malley’s framework. BMC Med Res Methodol. 2013;13(1). 40. Janmaat VT, Steyerberg EW, van der Gaast A, et al. Palliative 20. Peters MDJ, Marnie C, Tricco AC, et al. Updated methodological chemotherapy and targeted therapies for esophageal and gastroe- guidance for the conduct of scoping reviews. JBI Evid Implement. sophageal junction cancer. Cochr Datab Syst Rev. 2017;11:CD004063. 2021;19(1), 3. 41. Kundel Y, Sternschuss M, Moore A, Perl G, Brenner B, Goldvaser 21. Pollock D, Davies EL, Peters MDJ, et al. Undertaking a scoping H. Efficacy of immune-checkpoint inhibitors in metastatic gastric or review: a practical guide for nursing and midwifery students, clin- gastroesophageal junction adenocarcinoma by patient subgroups: icians, researchers, and academics. J Adv Nurs. 2021;77(4), 2102– a systematic review and meta-analysis. Cancer Med. 2020;9(20), 2113. 7613–7625. 22. Khalil H, Peters M, Godfrey CM, McInerney P, Soares CB, Parker D. 42. Liu C, Wang W, Yang J, et al. The efficacy and safety comparison An evidence-based approach to scoping reviews. Worldv Evid-Based of PD-1/PD-L1 antibody, chemotherapy and supportive treatment Nurs. 2016;13(2), 118–123. for pretreated advanced esophagogastric cancer: a network meta- 23. Tricco AC, Lillie E, Zarin W, et al. PRISMA extension for scoping analysis. Ann Palliat Med. 2020;9(4), 1770–1781. reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 43. Group G, Oba K, Paoletti X, et al. Role of chemotherapy for 2018;169(7), 467–473. advanced/recurrent gastric cancer: an individual-patient-data meta- 24. Bragge P, Clavisi O, Turner T, Tavender E, Collie A, Gruen RL. The analysis. Eur J Cancer. 2013;49(7), 1565–1577. global evidence mapping initiative: scoping research in broad topic 44. Qi W-X, Shen Z, Tang L-N, Yao Y. The role of anti-VEGF agents in the areas. BMC Med Res Methodol. 2011;11:92. treatment of advanced gastric cancer: a meta-analysis of randomized 25. Arksey H, O’Malley L. Scoping studies: towards a methodological controlled trials. Tumour Biol. 2014;35(8), 7675–7683. framework. Int J Soc Res Methodol. 2005;8(1), 19–32. 45. Ter Veer E, Haj Mohammad N, van Valkenhoef G, et al. Second- and 26. Bates S, Clapton J, Coren E. Systematic maps to support the evidence third-line systemic therapy in patients with advanced esophagogas- base in social care. Evid Policy. 2007;3(4), 539–551. tric cancer: a systematic review of the literature. Cancer Metastasis 27. Katz DL, Williams A-L, Girard C, et al. The evidence base for com- Rev. 2016;35(3), 439–456. plementary and alternative medicine: methods of Evidence Mapping 46. Ter Veer E, Haj Mohammad N, van Valkenhoef G, et al. The efficacy with application to CAM. Altern Ther Health Med. 2003;9(4), 22–30. and safety of first-line chemotherapy in advanced esophagogas- 28. Pérez JB, Salazar J, Santero M, et al. Efficacy of systemic oncological tric cancer: a network meta-analysis. J Natl Cancer Inst. 2016;108 treatments in patients with advanced, non-intestinal digestive cancer (10). at high risk of dying in the middle and short term: Evidence synthesis 47. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced (ASTAC-study). 2022. https://doi.org/10.17605/OSF.IO/7CHX6 gastric cancer. Cochr Datab Syst Rev. 2017;8:CD004064. 29. National Cancer Institute. AJCC Cancer Staging Manual 8th Edition. 48. Wallis CJD, Butaney M, Satkunasivam R, et al. Association of patient Qeios; 2020. sex with efficacy of immune checkpoint inhibitors and overall survival 30. Munn Z, Pollock D, Khalil H, et al. What are scoping reviews? Pro- in advanced cancers: a systematic review and meta-analysis. JAMA viding a formal definition of scoping reviews as a type of evidence Oncol. 2019;5(4), 529–536. synthesis. JBI Evid Synth. 2022;20(4), 950–952. 49. Wang L, Liu Y, Zhou W, Li W. Treatment-related severe and fatal 31. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi adverse events with molecular targeted agents in the treatment S. PICO, PICOS and SPIDER: a comparison study of specificity and of advanced gastric cancer: a meta-analysis. Onco Targets Ther. sensitivity in three search tools for qualitative systematic reviews. 2017;10:2281–2287. BMC Health Serv Res. 2014;14:579. 50. Alberts AS, Burger W, Greeff F, et al. Severe complications of 32. Krnic Martinic M, Pieper D, Glatt A, Puljak L. Definition of a 5-fluorouracil and cisplatin with concomitant radiotherapy in inop- systematic review used in overviews of systematic reviews, meta- erable non-metastatic squamous cell oesophageal cancer after epidemiological studies and textbooks. BMC Med Res Methodol. intubation–early termination of a prospective randomised trial. Eur 2019;19(1), 203. J Cancer. 1992;28A(4-5), 1005–1006. 33. Veritas Health Innovation, Melbourne, Australia. Covidence system- 51. Dutton SJ, Ferry DR, Blazeby JM, et al. Gefitinib for oesophageal atic review software [Internet]. 2020. cancer progressing after chemotherapy (COG): a phase 3, multicen- 34. Haddaway N. Evimappr: an R package for creating bubble plots for tre, double-blind, placebo-controlled randomised trial. Lancet Oncol. evidence maps. 2014;15(8), 894–904. 35. Chan DL, Sjoquist KM, Goldstein D, et al. The effect of anti- 52. Ford HER, Marshall A, Bridgewater JA, et al. Docetaxel versus active angiogenic agents on overall survival in metastatic oesophago-gastric symptom control for refractory oesophagogastric adenocarcinoma cancer: a systematic review and meta-analysis. PLoS One. 2017;12(2), (COUGAR-02): an open-label, phase 3 randomised controlled trial. e0172307. Lancet Oncol. 2014;15(1), 78–86. 36. Chan W-L, Yuen K-K, Siu SW-K, Lam K-O, Kwong DL-W. 53. Muro K, Cho JY, Bodoky G, et al. Age does not influence effi- Third-line systemic treatment versus best supportive care for cacy of ramucirumab in advanced gastric cancer: subgroup analyses advanced/metastatic gastric cancer: a systematic review and of REGARD and RAINBOW. J Gastroenterol Hepatol. 2018;33(4), meta-analysis. Crit Rev Oncol Hematol. 2017;116:68–81. 814–824. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 234 MARILINA ET AL. 54. Glimelius B, Ekström K, Hoffman K, et al. Randomized compari- to, or intolerant of, at least two previous chemotherapy regi- son between chemotherapy plus best supportive care with best mens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, supportive care in advanced gastric cancer. Ann Oncol. 1997;8(2), placebo-controlled, phase 3 trial. Lancet. 2017;390(10111), 2461– 163–168. 2471. 55. Kang JH, Lee SI, Lim DH, et al. Salvage chemotherapy for pretreated 70. Qin S. Phase III study of apatinib in advanced gastric cancer: a gastric cancer: a randomized phase III trial comparing chemotherapy randomized, double-blind, placebo-controlled trial. J Clin Orthod. plus best supportive care with best supportive care alone. J Clin Oncol. 2014;32(15_suppl), 4003. 2012;30(13), 1513–1518. 71. Jiang X-J, Song M-Q, Xin Y-N, Gao Y-Q, Niu Z-Y, Tian Z-B. Endo- 56. Kang YK, Kang WK, Di Bartolomeo M, et al. LBA43 - Randomized scopic stenting and concurrent chemoradiotherapy for advanced phase III ANGEL study of rivoceranib (apatinib) + best supportive esophageal cancer: a case-control study. World J Gastroenterol. care (BSC) vs placebo + BSC in patients with advanced/metastatic 2012;18(12), 1404–1409. gastric cancer who failed ≥2 prior chemotherapy regimens. Ann 72. Kozaczka A, Machalski M. A new chemotherapeutic regimen in the Oncol. 2019;30:v877–v8. treatment of advanced gastric cancer. Neoplasma. 1990;37(1), 77–84. 57. Khatri Samdariya, Kumari. Prospective randomized comparison 73. Lee S, Kang JH, Lim DH, et al. Combined analysis of randomized between 5-fluorouracil, leucovorin and etoposide plus best support- controlled trial (RCT) and patient-preference trial (PPT) evaluating ive care with best supportive care in advanced gastric cancer. Ann second-line chemotherapy (SLC) in advanced gastric cancer (AGC). J Oncol. 2019;30:IV106. Clin Orthod. 2012;30(15_suppl), 4064. 58. Levard H, Pouliquen X, Hay JM, et al. 5-Fluorouracil and cisplatin 74. Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, as palliative treatment of advanced oesophageal squamous cell Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and carcinoma. A multicentre randomised controlled trial. The French methotrexate in advanced gastric cancer. Cancer. 1993;72(1), 37–41. Associations for Surgical Research. Eur J Surg. 1998;164(11), 849– 75. Adenis A, Penel N, Horn S, Dominguez S, Vanhuyse M, Mirabel X. 857. Palliative chemotherapy does not improve survival in metastatic 59. Li J, Qin S, Xu J, et al. Apatinib for chemotherapy-refractory advanced esophageal cancer. Oncology. 2010;79(1-2), 46–54. metastatic gastric cancer: results from a randomized, placebo- 76. Baumgartner R, Taghizadeh H, Jomrich G, Schoppmann SF, Preusser controlled, parallel-arm, phase II trial. J Clin Oncol. 2013;31(26), M, Ilhan-Mutlu A. Utilization and efficacy of palliative chemother- 3219–3225. apy for locally advanced or metastatic gastroesophageal carcinoma. 60. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled Anticancer Res. 2020;40(2), 965–975. phase III trial of apatinib in patients with chemotherapy-refractory 77. Bernards N, Creemers GJ, Nieuwenhuijzen GAP, Bosscha K, Pruijt advanced or metastatic adenocarcinoma of the stomach or gastroe- JFM, Lemmens VEPP. No improvement in median survival for sophageal junction. J Clin Oncol. 2016;34(13), 1448–1454. patients with metastatic gastric cancer despite increased use of 61. Ohtsu A, Ajani JA, Bai Y-X, et al. Everolimus for previously treated chemotherapy. Ann Oncol. 2013;24(12), 3056–3060. advanced gastric cancer: results of the randomized, double-blind, 78. Bernards N, Haj Mohammad N, Creemers GJ, et al. Improvement in phase III GRANITE-1 study. J Clin Oncol. 2013;31(31), 3935–3943. survival for patients with synchronous metastatic esophageal can- 62. Park SH, Lim DH, Park K, et al. A multicenter, randomized phase III cer in the south of the Netherlands from 1994 to 2013. Acta Oncol. trial comparing second-line chemotherapy (SLC) plus best support- 2016;55(9-10), 1161–1167. ive care (BSC) with BSC alone for pretreated advanced gastric cancer 79. Chen J, Wang J, Miao Q. Careful dose modification of apatinib as third (AGC). J Clin Orthod. 2011;29(15_suppl), 4004. or further-line treatment in advanced gastric cancer patients with 63. Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the poor performance status. Medicine. 2019;98(45), e17890. treatment of advanced gastric cancer (INTEGRATE): a multina- 80. Cordero-García E, Ramos-Esquivel A, Alpízar-Alpízar W. Evaluation tional placebo-controlled phase II trial. J Clin Oncol. 2016;34(23), of pharmacological therapies used in Costa Rica in patients with 2728–2735. metastatic gastric cancer: a retrospective study. J Gastrointest Oncol. 64. Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised com- 2019;10(3), 523–528. parison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) 81. Hayashi Y, Nishida T, Tsutsui S, et al. Efficacy of chemotherapy for plus supportive care with supportive care alone in patients with older patients with gastric cancer: a multicenter retrospective cohort non-resectable gastric cancer. Br J Cancer. 1995;71(3), 587–591. study. Int J Clin Oncol. 2019;24(11), 1377–1384. 65. Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo 82. Hwang IG, Choi JH, Park SH, et al. Chemotherapy in advanced in patients with heavily pretreated metastatic gastric cancer (TAGS): gastric cancer patients associated with disseminated intravascular a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet coagulation. Cancer Res Treat. 2014;46(1), 27–32. Oncol. 2018;19(11), 1437–1448. 83. Kano T, Tamada R, Abe Y, et al. Postoperative long-term cancer 66. Schmid EU, Alberts AS, Greeff F, et al. The value of radiother- chemotherapy (PLCC) extends life-span of non-curatively resected apy or chemotherapy after intubation for advanced esophageal patients with stage IV gastric cancer. Jpn J Surg. 1982;12(3), 203–207. carcinoma—a prospective randomized trial. Radiother Oncol. 84. Kawamoto T, Nihei K, Sasai K, Karasawa K. Palliative radiotherapy 1993;28(1), 27–30. and chemoradiotherapy in stage IVA/B esophageal cancer patients 67. Swinson D, Hingorani M, Stokes Z, et al. Best supportive care with dysphagia. Int J Clin Oncol. 2018;23(6), 1076–1083. (BSC) with or without low-dose chemotherapy (chemo) in frail 85. Lee K-W, Lee JH, Kim JW, Kim J-W, Ahn S, Kim JH. Population-based elderly patients with advanced gastroesophageal cancer (aGOAC): outcomes research on treatment patterns and impact of chemother- the uncertain randomization of the GO2 phase III trial. J Clin Orthod. apy in older patients with metastatic gastric cancer. J Cancer Res Clin 2019;37(15_suppl), 4051. Oncol. 2016;142(3), 687–697. 68. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advan- 86. Lin S-Z, Tong H-F, You T, et al. Palliative gastrectomy and chemother- tage for irinotecan versus best supportive care as second-line apy for stage IV gastric cancer. J Cancer Res Clin Oncol. 2008;134(2), chemotherapy in gastric cancer—a randomised phase III study of 187–192. the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 87. Moon YW, Rha SY, Jeung H-C, et al. Outcomes of multiple salvage 2011;47(15), 2306–2314. chemotherapy for advanced gastric cancer: implications for clinical 69. Kang Y-K, Boku N, Satoh T, et al. Nivolumab in patients with practice and trial design. Cancer Chemother Pharmacol. 2010;66(4), advanced gastric or gastro-oesophageal junction cancer refractory 797–805. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MARILINA ET AL. 235 88. Moriwaki T, Kajiwara T, Matsumoto T, et al. Survival analysis 106. Al-Sakkaf AM, Masia J, Auladell-Rispau A, et al. Evidence mapping of of platinum-refractory patients with advanced esophageal cancer the treatments for breast cancer-related lymphedema. Plast Reconstr treated with docetaxel or best supportive care alone: a retrospective Surg Glob Open. 2022;10(1), e4045. study. Dis Esophagus. 2014;27(8), 737–743. 107. Ballesteros M, Montero N, López-Pousa A, et al. Evidence map- 89. Nomura M, Iwasa S, Tsushima T, et al. Active salvage chemotherapy ping based on systematic reviews of therapeutic interventions for versus best supportive care for patients with recurrent or metastatic gastrointestinal stromal tumors (GIST). BMC Med Res Methodol. squamous cell carcinoma of the esophagus refractory or intolerable 2017;17(1), 135. to fluorouracil, platinum, and taxane. Cancer Chemother Pharmacol. 108. Pearson EJM, Morris ME, di Stefano M, McKinstry CE. Interven- 2016;78(6), 1209–1216. tions for cancer-related fatigue: a scoping review. Eur J Cancer Care. 90. Park JO, Chung HC, Cho JY, et al. Retrospective comparison of infu- 2018;27(1). sional 5-fluorouracil, doxorubicin, and mitomycin-C (modified FAM) 109. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carci- combination chemotherapy versus palliative therapy in treatment of noma. Lancet. 2013;381(9864), 400–412. advanced gastric cancer. Am J Clin Oncol. 1997;20(5), 484–489. 110. Prinsen CAC, Vohra S, Rose MR, et al. How to select outcome mea- 91. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor surement instruments for outcomes included in a “Core Outcome and a novel therapeutic target. Ann Oncol. 2008;19(9), 1523–1529. Set”—a practical guideline. Trials. 2016;17(1), 449. 92. Tsavaris K, Kosmas C, Koufos Ch, et al. Contribution of chemother- 111. Avery KNL, Chalmers KA, Brookes ST, et al. Development of a core apy to the survival of patients with advanced gastric cancer. Journal outcome set for clinical effectiveness trials in esophageal cancer of BUON. 1999;4:151–156. resection surgery. Ann Surg. 2018;267(4), 700–710. 93. Wong AT, Shao M, Rineer J, Osborn V, Schwartz D, Schreiber 112. Alkhaffaf B, Metryka A, Blazeby JM, et al. Core outcome set for sur- D. Treatment and survival outcomes of small cell carcinoma of gical trials in gastric cancer (GASTROS study): international patient the esophagus: an analysis of the National Cancer Data Base. Dis and healthcare professional consensus. Br J Surg. 2021. Online ahead Esophagus. 2017;30(2), 1–5. of print 94. Sugimoto A, Nishida T, Osugi N, et al. Prediction of survival benefit 113. Reeve BB, Mitchell SA, Dueck AC, et al. Recommended patient- when deciding between chemotherapy and best supportive ther- reported core set of symptoms to measure in adult cancer treatment apy in elderly patients with advanced gastric cancer: a retrospective trials. J Natl Cancer Inst. 2014;106(7). cohort study. Mol Clin Oncol. 2019;10(1), 83–91. 114. Zambrano SC, Haugen DF, van der Heide A, et al. Development of 95. Sugimoto A, Nishida T, Takahashi K, et al. Chemotherapy and survival an international Core Outcome Set (COS) for best care for the dying benefit in elderly patients with advanced gastric cancer. J Clin Orthod. person: study protocol. BMC Palliat Care. 2020;19(1), 184. 2017;35(4_suppl), 45. 115. Elwyn G, Frosch D, Thomson R, et al. Shared decision making: 96. Park SR, Hong YS, Park Y, et al. A phase I/II study of S-1 combined a model for clinical practice. J Gen Intern Med. 2012;27(10), with irinotecan and oxaliplatin in patients with metastatic gastric 1361–1367. cancer. J Clin Oncol. 2008;26(15_suppl), 4558. 116. Olthuis G, Leget C, Grypdonck M. Shared decision making needs a 97. Ciardiello F, Bang Y-J, Bendell JC, et al. A phase III, double-blind, ran- care perspective. BMJ. 2012;345:e7419. domized study of pamiparib versus placebo as maintenance therapy 117. Mühlbacher AC, Juhnke C. Patient preferences versus physicians’ in patients with inoperable, locally advanced, or metastatic gastric judgement: does it make a difference in healthcare decision making? cancer (GC) that responded to platinum-based first-line chemother- Appl Health Econ Health Policy. 2013;11(3), 163–180. apy. J Clin Orthod. 2019;37(4_suppl), TPS173–TPS. 118. Zafar SY, Malin JL, Grambow SC, et al. Chemotherapy use and patient 98. Chua YJ, Pavlakis N, Sjoquist KM, et al. Randomised phase 3 study treatment preferences in advanced colorectal cancer: a prospective of regorafenib in refractory advanced gastro-oesophageal cancer cohort study. Cancer. 2013;119(4), 854–862. (AGOC)—INTEGRATE II. Ann Oncol. 2019;30(Supplement_6), vi137. 119. Alonso-Coello P, Montori VM, Díaz MG, et al. Values and prefer- 99. Euctr IT, Regorafenib vs placebo as maintenance therapy in ences for oral antithrombotic therapy in patients with atrial fibrilla- no progression patients after first-line platinum and fluo- tion: physician and patient perspectives. Health Expect. 2015;18(6), ropyrimidines based chemotherapy in HER2 negative locally 2318–2327. advanced/metastatic gastric or gastroesophagel junction cancer. 120. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 state- https://trialsearchwhoint/Trial2aspx?TrialID=EUCTR2014-004395- ment: updated guidelines for reporting parallel group randomised 28-IT. 2019 trials. BMJ. 2010;340:c332. 100. Byoungyong S. Phase 3 study of xelox followed by maintenance 121. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for capecitabine in the advanced gastric cancer. ClinicalTrials.gov: reporting systematic reviews and meta-analyses of studies that eval- NCT02289547 uate healthcare interventions: explanation and elaboration. BMJ. 101. Chen J, Wang J. Efficacy and safety assessment of apatinib in patients 2009;339:b2700. with advanced gastric cancer: a meta-analysis. Onco Targets Ther. 122. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsor- 2018;11:4149–4158. ship and research outcome: systematic review with meta-analysis. 102. Fuchs T, Tomasek J, Yong CJ, et al.. Ramucirumab monotherapy for Intensive Care Med. 2018;44(10), 1603–1612. previously treated advanced gastric or gastro-oesophageal junction 123. Sismondo S. Pharmaceutical company funding and its consequences: adenocarcinoma (REGARD): an international, randomised. Lancet a qualitative systematic review. Contemp Clin Trials. 2008;29(2), 109– 2014;383(9911), P31–39. 113. 103. van Kleef JJ, Ter Veer E, van den Boorn HG, et al. Quality of life during 124. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry palliative systemic therapy for esophagogastric cancer: systematic sponsorship and research outcome and quality: systematic review. review and meta-analysis. J Natl Cancer Inst. 2020;112(1), 12–29. BMJ. 2003;326(7400), 1167–1170. 104. Dorcaratto D, Grande L, Ramón JM, Pera M. Quality of life of patients 125. Djulbegovic B, Kumar A, Miladinovic B, et al. Treatment success with cancer of the oesophagus and stomach. Cir Esp. 2011;89(10), in cancer: industry compared to publicly sponsored randomized 635–644. controlled trials. PLoS One. 2013;8(3), e58711. 105. Vickery CW, Blazeby JM, Conroy T, et al. Development of an EORTC 126. Linker A, Yang A, Roper N, Whitaker E, Korenstein D. Impact of indus- disease-specific quality of life module for use in patients with gastric try collaboration on randomised controlled trials in oncology. Eur J cancer. Eur J Cancer. 2001;37(8), 966–971. Cancer. 2017;72:71–77. 17565391, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jebm.12539 by Readcube (Labtiva Inc.), Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 236 MARILINA ET AL. 127. Booth CM, Cescon DW, Wang L, Tannock IF, Krzyzanowska MK. 132. Zhu X, Ko Y-J, Berry S, Shah K, Lee E, Chan K. A Bayesian network Evolution of the randomized controlled trial in oncology over three meta-analysis on second-line systemic therapy in advanced gastric decades. J Clin Oncol. 2008;26(33), 5458–5464. cancer. Gastric Cancer. 2017;20(4), 646–654. 128. Liu D, Ma X, Xiao D, Jia Y, Wang Y. Efficacy and safety of target- ing VEGFR drugs in treatment for advanced or metastatic gastric cancer: a systemic review and meta-analysis. Oncotarget. 2018;9(8), 8120–8132. SUPPORTING INFORMATION 129. Xie S, Zhang H, Wang X, Ge Q, Hu J. The relative efficacy and Additional supporting information can be found online in the Support- safety of targeted agents used in combination with chemother- apy in treating patients with untreated advanced gastric can- ing Information section at the end of this article. cer: a network meta-analysis. Oncotarget. 2017;8(16), 26959– 26968. 130. Xue J-M, Astère M, Zhong M-X, Lin H, Shen J, Zhu Y-X. Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carci- How to cite this article: Marilina S, Adriana M, Anna S, et al. noma and non-small cell lung cancer: a meta-analysis. Onco Targets Comparative analysis of systemic oncological treatments and Ther. 2018;11:6119–6128. best supportive care for advanced gastresophageal cancer: A 131. Zeng C, Zhou H, Wei Y, Wang L, Xie H, Yao W. Chemotherapy with or without irinotecan in patients with advanced or recurrent gastric comprehensive scoping review and evidence map. J Evid Based cancer: a meta-analysis of randomized controlled trials. Chin Med J. Med. 2023;16:216–236. https://doi.org/10.1111/jebm.12539 2014;127(5), 951–956.