Santero et al. BMC Cancer (2021) 21:712 https://doi.org/10.1186/s12885-021-08330-5 RESEARCH Open Access Efficacy of systemic oncological treatments in patients with advanced esophageal or gastric cancers at high risk of dying in the middle and short term: an overview of systematic reviews M. Santero1, J. Pérez-Bracchiglione1,2, R. Acosta-Dighero3, A. G. Meade1, A. Antequera1, A. Auladell-Rispau1, M. J. Quintana1,4, C. Requeijo1, G. Rodríguez-Grijalva1, K. Salas-Gama1, R. Dorantes-Romandia1, J. Salazar1, I. Solà1,4, G. Urrútia1,4 and X. Bonfill Cosp1,4* Abstract Background: Esophageal and gastric cancers are a significant public health problem worldwide, with most patients presenting with advanced-stage disease and, consequently, poor prognosis. Systemic oncological treatments (SOT) have been widely used over more conservative approaches, such as supportive care. Nevertheless, its effectiveness in this scenario is not sufficiently clear. This paper provides an overview of systematic reviews that assessed the effectiveness of SOT compared with the best supportive care (BSC) or placebo in patients with advanced esophageal or gastric cancers in an end-of-life context. Methods: We searched MEDLINE, EMBASE, The Cochrane Library, Epistemonikos, and PROSPERO for eligible systematic reviews (SRs) published from 2008 onwards. The primary outcomes were overall survival (OS), progression-free survival (PFS), functional status, and toxicity. Two authors assessed eligibility and extracted data independently. We evaluated the methodological quality of included SRs using the AMSTAR-2 tool and the overlap of primary studies (corrected covered area, CCA). Also, we performed a de novo meta-analysis with data reported for each primary study when it was possible. We assessed the certainty of evidence using the GRADE approach. Results: We identified 16 SRs (19 included trials) for inclusion within this overview. Most reviews had a critically low methodological quality, and there was a very high overlap of primary studies. It is uncertain whether SOT improves OS and PFS over more conservative approaches due to the very low certainty of evidence. Conclusions: The evidence is very uncertain about the effectiveness of SOT for advanced esophageal or gastric cancers. High-quality SRs and further randomized clinical trials that include a thorough assessment of patient- centered outcomes are needed. * Correspondence: xbonfill@santpau.cat 1 Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), C/ Sant Antoni Maria Claret, 167, Pavelló 18, planta 0, 08025 Barcelona, Spain 4 CIBER Epidemiología y Salud Pública (CIBERESP), Universitat Autònoma Barcelona, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Santero et al. BMC Cancer (2021) 21:712 Page 2 of 18 Trial registration: Open Science Framework, https://doi.org/10.17605/OSF.IO/7CHX6. Keywords: Esophageal Cancer, Gastric Cancer, Antineoplastic agents, Biological therapy, Molecular targeted therapy, Immunotherapy, Review literature as topic, Systematic reviews Background society. Therefore, it is of central importance to evaluate Worldwide, esophageal and gastric cancers are a signifi- the appropriateness of the SOT compared to the existing cant public health problem, with approximately 509,000 alternatives, such as BSC, in terms of effectiveness with and 783,000 deaths in 2018, respectively [1]. Their com- special consideration for the patient’s QoL near death bined mortality for both tumor sites is over 1.2 million, and relief of the significant physical and psychological leading to the second most common cancer death cause symptomatic burden that these patients present. Thus, after lung cancer. While global reports have shown a de- this study aims to make a comprehensive synthesis of crease in gastric cancer mortality rates over the past 20 the available evidence regarding the effectiveness of SOT years, a steady increase in esophageal cancer rates has from systematic reviews (SRs) compared with BSC or been observed mainly in the Western Pacific and Euro- placebo in patients with advanced esophageal or gastric pean regions [2]. Moreover, both cancers are overly ag- cancers in an EOL context. gressive; despite their relatively low incidence, they often have a poor prognosis since the diagnosis is usually late [3, Methods 4]. In a metastatic stage, esophageal and gastric cancers We performed an overview of SRs on patients with ad- have less than 30% survival at 1 year and less than 5% at 5 vanced esophageal or gastric cancers published from years, respectively [5]. Due to the above, many patients are 2008 onwards. The current study is part of a broader in a terminal care period with progressive disease and evidence syntheses project that aims to assess the effect- months or less of expected survival which has been con- iveness of SOT versus BSC for patients with advanced ceptualized by some authors as “end of life” (EOL) [6, 7]. non-intestinal digestive cancer (esophageal, gastric, The use of systemic oncological treatments (SOT) hepatobiliary, and pancreatic cancer). We registered the has been widely investigated for esophageal and gas- protocol detailing the methods in the Open Science tric cancers, and as a consequence, chemotherapy Framework (see protocol in Additional file 1) [16] and (CT), targeted therapy, and immunotherapy are we conducted this overview according to rigorous stan- largely used to try to improve survival and quality of dards aligned to Cochrane Methodology [17] and re- life (QoL) [8, 9]. However, its use in the EOL context ported our results according to PRISMA (Preferred is still subject to controversy. Some authors have re- Reporting Items for Systematic Reviews and Meta- ported patients experiencing emotional distress, se- Analyses) guidelines [18] (see the completed checklist in verely reduced QoL, a range of diagnosis-specific and Additional file 2). treatment-related problems, and side effects related to these treatments [10, 11]. The overuse of SOT close to death could be an indicator of low-quality medical Search strategy and selection criteria care, defined as the underuse of known effective prac- Figure 1 presents our eligibility criteria. We included tices, or equivocal effectiveness according to the pro- SRs that assessed SOT’s impact in esophageal or gastric vider rather than patient preferences [12]. cancer patients at high risk of dying in the short or More knowledge is needed to improve the ability medium term. We searched for the following outcomes: of the current healthcare system to deliver timely 1) overall survival (OS); 2) progression-free survival and appropriate EOL care. Among patients with (PFS); 3) functional status (FS); 4) toxicity; 5) symptoms esophageal or gastric cancers with poor prognosis, a related to the disease; 6) QoL; 7) admissions to hospital palliative care approach is imperative [13]. In this or long-term center, or emergency consultations; 8) sense, best supportive care (BSC) may include a quality of death (admission to the hospital at the end-of- range of multidisciplinary interventions, such as life; palliative care provided during the last year; place of symptomatic control by radiotherapy, palliative sur- death). We considered the following as primary out- gery, management of antineoplastic-treatment- comes: OS, QoL, FS, and toxicity. related toxicities, analgesia, and psychological or so- We searched in four bibliographic databases: MEDL cial assistance [13–15]. INE (access via PubMed), the Cochrane Database of Sys- It would be very useful to know the precise balance of tematic Reviews, Epistemonikos from inception to Sep- whether these effective treatments compensate for the tember 30th, 2019, and EMBASE (access via Ovid) from adverse effects and costs they have for patients and inception to October 7th, 2019. We did not restrict our Santero et al. BMC Cancer (2021) 21:712 Page 3 of 18 Fig. 1 Eligibility criteria search by language. We provide a detailed search strat- the assessment of the SR with better methodological egy elsewhere [16]. The search strategy for PubMed is quality according to AMSTAR-2 (if the reviews had the described in Additional file 3. Two previously trained re- same quality, we selected the most frequent judgment viewers performed an independent title and abstract from the primary study assessment). Lastly, if a discrep- screening and a full-text screening afterward. A third re- ancy remained, we reported it as “no agreement”. viewer solved any disagreements. We used Covidence for all the screening process [19]. Assessment of overlap of primary studies We built a matrix of evidence to assess the overlap of Data extraction and Risk of Bias Assessment primary studies within SRs. We computed the matrix One reviewer extracted data from the included studies cross-linking the relevant randomized control trials using a previously piloted data extraction sheet, and a (RCTs) in eligible SRs for this overview and calculated second author cross-checked this process. We extracted the corrected covered area (CCA). We considered a from the included SRs both synthesized findings and dis- CCA below 5% as slight overlap, a CCA > 5 and < 10% as aggregated data on reported outcomes of interest for moderate overlap, a CCA > 10 and < 15% as high over- each primary study. One author assessed the methodo- lap, and a CCA > 15% as a very high overlap [21]. logical quality for each SR using the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) tool, Data synthesis and analysis and a second author cross-checked this assessment [20]. We presented a narrative synthesis of the included re- We reported the risk of bias assessment of primary stud- views and summarised the main results on the effective- ies undertaken by the authors of each SR. When two or ness of SOT regarding relevant outcomes. We more SRs had a conflicting risk of bias assessments for a performed a de novo meta-analysis based on primary primary study, we reported the one assessed by the studies data included in eligible SRs when possible for Cochrane tool. If disagreement persisted, we reported each comparison. We analyzed dichotomous outcomes Santero et al. BMC Cancer (2021) 21:712 Page 4 of 18 with an odds ratio (OR), continuous outcomes with the Outcomes reported mean difference or standardized mean difference, and All reviews pre-specified outcome measures and re- time-to-event outcomes with hazard ratios (HR), all of ported OS, PFS, FS, toxicity, and QoL. None of the re- these with a 95% confidence interval (95% CI). We views examined symptoms related to the disease, assessed the heterogeneity of the included studies with admissions, or quality of death. I2 as follows: I2 < 50% as low heterogeneity, I2 > 50 and < 90% as high, and > 90% as very high. When heterogen- Quality assessment of the included systematic reviews eity was below 90%, we performed a meta-analysis in Using the AMSTAR-2 tool, we rated 13 out of 16 SRs RevMan 5.4 using a random-effects model. We reported (81%) as critically low methodological quality (See all the outcomes according to a type of SOT (chemo- Table 2). Only the review of Chan et al. 2017 [27] was therapy, immunotherapy, and targeted/biological therap- evaluated as high quality. Common critical flaws were ies). We also conducted a sensitivity analysis, the lack of report of an explicit protocol for conducting considering only studies in which comparison is de- the SR, the lack of information on the sources of fund- scribed explicitly as BSC. ing, and an inadequate assessment of the impact of the risk of bias of primary studies. Assessment of certainty of the evidence We assessed the certainty of the evidence for each pri- Risk of bias from the primary RCTs included in SRs mary outcome according to the Grading of Recommen- Figure 4 summarises the risk of bias of the included pri- dations Assessment, Development, and Evaluation mary studies, as reported by the corresponding SR. Most (GRADE) guidance and performed a Summary of Find- reviews reported the risk of bias using the Cochrane risk ings (SoF) table [22]. We classified the certainty of the of bias tool, while four used the Jadad Scale [23, 25, 30, evidence for each outcome as high, moderate, low, or 31]. Three discrepancies between SR’s assessments very low. We also reported the SoF in plain-language remained as “no agreement.” (Bramhall 2002, Kang summary. 2012, Kang 2017). A single domain (performance bias) of one primary trial (Glimelius 1997) was not reported. Results Our initial searches yielded 2452 results, and 191 were Effectiveness of systemic oncological treatment evaluated as full-text articles following title and abstract Due to the variability among the reviews and the out- screening. According to the eligibility criteria, we in- comes reported, we could combine results only for OS cluded 16 SRs in this overview [15, 23–37]. Figure 2 pre- and PFS (Fig. 5). sents the PRISMA flow diagram. Reasons for exclusion and references to 175 final excluded articles are given in Overall survival Additional file 4. CT for advanced gastric cancer: According to our de Table 1 and Additional file 5 summarise the general novo meta-analysis (Fig. 5.1), CT may improve OS over characteristics of included SRs. Of the included reviews, more conservative approaches (HR 0.44, 95%CI 0.33 to two were Cochrane SRs [15, 29], and four were network 0.58; five studies; low certainty). Wagner 2017 concludes meta-analyses [28, 31, 32, 34]. Included SRs were pub- that CT (first-line) improves survival (6.7 months) in lished between 2014 and 2020, nine were performed in comparison to BSC alone. Adding docetaxel to high-income countries, and seven of them in China. All platinum-fluoropyrimidine-based CT regimens may ex- SRs included meta-analyses except for Harvey 2017 [28]. tend OS (just 1 month) with increased toxicity. It is not Three SRs exclusively addressed patients with gastric clear yet whether the benefit of adding a third drug (do- cancer [23, 25, 30], nine reviews included only patients cetaxel or epirubicin) to a two-drug platinum- with gastric cancer including the gastroesophageal junc- fluoropyrimidine CT combination outweighs its toxicity. tion (GEJ) [26–29, 31–33, 35, 37] and the remaining four Consideration of the profile of side effects and the im- considered both patients with esophageal and GEJ can- pact of these side effects on the person’s QoL, as well as cer [15, 24, 34, 36]. The retrieved SRs included a total of the tumor burden and necessity to obtain a response 19 primary studies relevant to our question (See Add- rapidly is therefore essential in the choice of the regi- itional file 6). men. As a second-line treatment, Iacovelli 2014 reported Figure 3 shows the overlap matrix of included re- that CT was able to decrease the risk of death by 27%. views. The overall CCA was 17.19%, which is consid- In patients with ECOG = 0, a greater benefit was found ered a very high overlap. Eight primary studies were for chemotherapy with a reduction of the risk of death included in two SRs [24, 36], and five in another five by 43%. This analysis reports that active and available SRs [15, 23, 27, 28, 32]. therapies can prolong survival in patients with advanced Santero et al. BMC Cancer (2021) 21:712 Page 5 of 18 Fig. 2 PRISMA flow diagram gastric cancer with a different outcome based on the ini- analysis performed by Zhao 2018 concluded that apati- tial patient’s performance status. nib, regorafenib, and rilotumumab improved patient OS. CT for advanced esophageal cancer: According to our de Biological therapy for gastric cancer (including GEJ): Ac- novo meta-analysis (Fig. 5.2), it is very uncertain whether cording to our de novo meta-analysis (Fig. 5.4), biological CT improves OS over more conservative approaches (HR therapy probably improves OS over more conservative ap- 0.77, 95% CI 0.63 to 0.94; two studies; very low certainty). proaches (HR 0.64, 95% CI 0.51 to 0.8; five studies; mod- Based on Janmaat’s 2017 analysis, CT can be considered erate certainty). Liu 2018 concluded that vascular standard care for esophageal cancer. Nevertheless, the main endothelial growth factor receptor (VEGFR) drugs were analysis included CT or targeted therapy agent(s) plus con- effective targeted therapy in advanced or metastatic gastric trol intervention versus control intervention alone. cancer, and their toxicity is within a controllable range. Immunotherapy for gastric cancer (including GEJ): Ac- VEGFR antibody drugs were more effective than VEGFR cording to our de novo meta-analysis (Fig. 5.3), it is very tyrosine kinase inhibitor drugs in terms of the OS of gas- uncertain whether immunotherapy improves OS over tric cancer patients with little toxicity. more conservative approaches (HR 0.70, 95% CI 0.52 to Targeted therapy for esophageal (including GEJ): Ac- 0.93; two studies; very low certainty). A network meta- cording to Dutton et al. (2014), gefitinib (2nd-line) did Table 1 General characteristics of included systematic reviews Author, Country Time Search strategy/ Database RCTs RCTs (n) P I C O Funding Conflicts AMSTAR year frame (n) included of assessment in our interest. overview. Iacovelli USA From Cochrane Central Register of Controlled 5 5 Gastric CT, Biological, BSC / Functional No None CRITICALLY 2014 [23] January Trials, MEDLINE, PubMed. cancer or targeted Supportive status, OS LOW 2004 to therapy care Santero et al. BMC Cancer February 2014 TerVeer Netherlands Up to Cochrane Central Register of Controlled 28 8 Esophageal, CT, Biological, BSC / OS, PFS, No Yes CRITICALLY 2016 [24] January Trials, EMBASE, MEDLINE. gastric, and or targeted Placebo Toxicity LOW 2016 GEJ cancer therapy Wang China Up to Cochrane Library, EMBASE, PubMed 10 3 Gastric Biological or Placebo OS Public None LOW (2021) 21:712 2016 [25] December cancer targeted 31, 2015 therapy Chan a Australia Up to Cochrane Central Register of Controlled 15 4 Gastric and Biological or Placebo OS, PFS, No Yes CRITICALLY 2017 [26] December Trials, EMBASE, PubMed. GEJ cancer targeted Toxicity, LOW 2014 therapy QoL Chan b China Up to 2016 CINAHL, Cochrane Central Register of 5 5 Gastric and CT, Biological, BSC / OS, PFS, No None HIGH 2017 [27] Controlled Trials, EMBASE, MEDLINE GEJ cancer or targeted Placebo Toxicity therapy Harvey UK Between PubMed, Scopus. 5 5 Gastric and CT BSC OS NR NR CRITICALLY 2017 [28] 1990 and GEJ cancer LOW 2015 Janmaat Netherlands Up to 13 Cochrane Central Register of Controlled 41 5 Esophageal CT, Biological, BSC / OS Public None HIGH 2017 [15] May 2015 Trials, Clinicaltrials.gov, EMBASE, Google and GEJ or targeted Placebo / Scholar, MEDLINE, PubMed, Web of Science, cancer therapy Non- WHO International Clinical Trials Registry specified Platform (ICTRP) Wagner Switzerland Up to June Cochrane Central Register of Controlled 64 3 Gastric and CT BSC OS Public Yes HIGH 2017 [29] 2016 Trials, MEDLINE, Hand searched reference GEJ cancer lists from studies, abstracts, conference. Wang China Up to Embase, Medline, the Cochrane Central 9 2 Gastric Biological or Placebo Toxicity NR None MODERATE 2017 [30] December Register of Controlled Trials, Cochrane cancer targeted 2015 Database of Systematic Reviews, EMBASE, therapy MEDLINE Xie 2017 China Between Cochrane Library and Scopus, EMBASE, 23 2 Gastric and CT, Biological, Placebo OS NR None CRITICALLY [31] January 1st, GEJ cancer or targeted LOW 2000 and therapy October 1st, 2016 Zhu Canada Up to June American Society of Clinical Oncology 8 5 Gastric and CT, Biological, BSC / OS Private Yes CRITICALLY 2017 [32] 2014 abstracts, Cochrane Central Register of GEJ cancer or targeted Placebo LOW Controlled Trials, EMBASE, MEDLINE. therapy Liu 2018 China Up to Cochrane Central Register of Controlled 8 4 Gastric and Biological or Placebo OS, PFS, Public / None LOW Page 6 of 18 Table 1 General characteristics of included systematic reviews (Continued) Author, Country Time Search strategy/ Database RCTs RCTs (n) P I C O Funding Conflicts AMSTAR year frame (n) included of assessment in our interest. overview. [33] March 15, Trials, Clinicaltrials.gov, EMBASE, EU Clinical GEJ cancer targeted Toxicity Private 2017 Trials Register, Japan Pharmaceutical therapy Information Center, PubMed. Santero et al. BMC Cancer Zhao China Between Cochrane Library, EMBASE, PubMed. 16 6 Esophageal, Biological or Placebo OS, PFS, Public None CRITICALLY 2018 [34] 2002 and gastric and targeted Toxicity LOW 2017 GEJ therapy Chen China Up to PubMed 9 2 Gastric and Immunotherapy BSC / OS, PFS, Public None CRITICALLY 2019 [35] September GEJ cancer Placebo Toxicity LOW 2018 (2021) 21:712 van Netherlands Up to April Cochrane Central Register of Controlled 43 8 Esophageal, CT, Biological, BSC / QoL Public Yes CRITICALLY Kleef 2018 Trials, EMBASE, MEDLINE. gastric and or targeted Placebo LOW 2019 [36] GEJ therapy Wallis Canada Up to EMBASE, MEDLINE, PubMed, Scopus. 23 1 Gastric and Immunotherapy Placebo OS Private Yes CRITICALLY 2019 [37] October 2, GEJ cancer LOW 2018 GEJ gastroesophageal junction, P patients, I intervention, C comparator, O outcomes, CT chemotherapy, BSC best supportive care, OS overall survival, PFS progression-free survival, QoL quality of life, NR not reported Page 7 of 18 Santero et al. BMC Cancer (2021) 21:712 Page 8 of 18 Fig. 3 Overlap matrix not improve OS over more conservative approaches (HR significant survival benefit was identified at study com- 0.90, 95% CI 0.74 to 1.09). Dutton et al. 2014 investi- pletion in the predefined subgroup of 123 patients who gated gefitinib in participants with progression after CT had received prior CT (P = 0.045, HR 1.53 (1.00–2.34)). and excluded participants receiving cytotoxic CT, im- This benefit increased with 2 years of additional follow- munotherapy, hormonal therapy, or radiotherapy to the up (P = 0.006, HR 1.68, 95% CI 1.16 to 2.44). site of measurable or evaluable disease within the 4 CT for esophageal and gastric cancers (including GEJ): weeks before inclusion. According to Ford et al. (2014), docetaxel as second-line Biological therapy for gastric cancer: According to therapy improved OS over BSC (HR 0.67, 95% CI 0.49 Ohtsu et al. (2013), everolimus 10 mg/d (2nd-line) did to 0.92). not improve OS over placebo (HR 0.90, 95% CI 0.74 to 1.09). Progression-free survival Targeted therapy for gastric cancer (including GEJ): Biological therapy for gastric cancers (including GEJ): Ac- According to Bramhalll 2002 there was a modest differ- cording to our de novo meta-analysis (Fig. 5.5), bio- ence in survival in the intention-to-treat population in logical therapy (2nd and 3rd line) improved PFS over favor of marimastat (P = 0.07 log-rank test, HR 1.23, more conservative approaches (HR 0.34, 95% CI 0.25 to 95% CI confidence interval 0.98 to 1.55). This survival benefit 0.45; I2 71%; five studies). Liu 2018 concluded that was maintained over a further 2 years of follow-up (P = VEGFR drugs were effective targeted therapy in ad- 0.024, HR 1.27, 95% CI 1.03 to 1.57). The median sur- vanced or metastatic gastric cancer, and their toxicity is vival was 138 days for placebo and 160 days for marima- within a controllable range. VEGFR antibody drugs were stat, with a two-year survival of 3 and 9% respectively. A more effective than VEGFR tyrosine kinase inhibitor Table 2 AMSTAR-2 Systematic Reviews Iacovelli TerVeer Wang Chan Chan Harvey Janmaat Wagner Wang Xie 2017 Zhu Liu 2018 Zhao 2018 Chen 2019 van Kleef Wallis 2014 [23] 2016 [24] 2016 [25] 2017a [26] 2017b [27] 2017 [28] 2017 [15] 2017 [29] 2017 [30] [31] 2017 [33] [34] [35] 2019 [36] 2019 [37] [32] 1. Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes No Yes Yes Yes 2. No No No No Yes No Yes Yes Yes No No Yes No No No No 3. Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes No No No No 4. Partial Yes Yes Yes Yes Yes Partial Yes Yes Yes Yes Partial Yes No Partial Yes Partial Yes Partial Yes Partial Yes Partial Yes Santero et al. BMC Cancer 5. Yes Yes Yes Yes Yes No Yes Yes No No Yes Yes Yes Yes Yes Yes 6. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes 7. No No Yes No Yes No Yes Yes Yes No Yes No No No No No 8. Yes Partial Yes Yes Partial Yes Yes Partial Yes Yes Yes Yes No Yes Partial Yes No Partial Yes Partial Yes Partial Yes 9a. Partial Yes Yes Yes Yes Yes Partial Yes Yes Yes Partial Yes No Yes Yes Yes Yes Yes Yes (2021) 21:712 9b. Includes Includes Includes Includes Includes Includes Includes Includes Includes Includes Yes Includes Includes No Includes Includes only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs only RCTs 10. No No No No No No No No No No No No No No No Yes 11a. Yes Yes Yes Yes Yes No meta- Yes Yes Yes No Yes Yes Yes Yes Yes No analysis conducted 11b. Yes No meta- No meta- No meta- No meta- Yes No meta- No meta- No meta- No meta- Yes No meta- No meta- No meta- No meta- No meta- analysis analysis analysis analysis analysis analysis analysis analysis analysis analysis analysis analysis analysis conducted conducted conducted conducted conducted conducted conducted conducted conducted conducted conducted conducted conducted 12. No No Yes Yes Yes No Yes Yes Yes Yes Yes Yes No No No Yes 13. No No Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No Yes 14. No Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No 15. Yes No Yes Yes Yes No Yes Yes Yes No Yes Yes Yes Yes No No 16. No Yes Yes Yes Yes No Yes Yes No Yes Yes No Yes Yes Yes Yes QUALITY CRITICAL CRITICALLY CRITICALLY CRITICALLY HIGH CRITICALLY LOW LOW CRITICALLY CRITICALLY CRITIC CRITICALLY CRITICALLY CRITICALLY CRITICALLY CRITICALLY OF THE LY LOW LOW LOW LOW LOW LOW LOW ALLY LOW LOW LOW LOW LOW REVIEW LOW Number of 6 5 2 3 0 6 1 1 2 8 2 3 5 5 6 6 critical flaws Number of 4 3 1 3 1 6 1 1 3 6 1 3 6 5 6 3 non-critical flaws 1. Did the research questions and inclusion criteria for the review include the components of PICO? 2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? 3. Did the review authors explain their selection of the study designs for inclusion in the review? 4. Did the review authors use a comprehensive literature search strategy? 5. Did the review authors perform study selection in duplicate? 6. Did the review authors perform data extraction in duplicate? 7. Did the review authors provide a list of excluded studies and justify the exclusions? 8. Did the review authors describe the included studies in adequate detail? 9a. RCT: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? 9b. NSRI: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? 10. Did the review authors report on the sources of funding for the studies included in the review? 11a. RCT: If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? 11b. NSRI: If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? 12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? 13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? 15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? 16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? Page 9 of 18 Santero et al. BMC Cancer (2021) 21:712 Page 10 of 18 drugs in terms of the PFS of gastric cancer patients with particularly relevant for patients with a high risk of dying little toxicity. in the short or medium term. These evidence gaps in Biological and targeted therapy for gastric cancer: Ac- reporting essential outcomes for patients could reflect cording to Bramhall et al. (2002), marimastat as second- either lack of primary data availability in the respective line therapy did not improve PFS over placebo (HR 1.32, studies or event or lack of interest by authors of SRs to 95% CI 1.07 to 1.63). analyze this data actively. Biological therapy for gastric cancer: According to Treatment for locally advanced, unresectable esopha- Othsu et al. (2013), everolimus as the second and third geal or gastric cancers remains highly controversial. For line improved PFS over placebo or BSC (HR 0.66, example, the European Society of Medical Oncology 95% CI 0.56 to 0.78). (ESMO) guidelines are not well-defined in this regard Immunotherapy for gastric cancer (including GEJ): Ac- [41]. They recommend systemic treatment (CT) for pa- cording to Kang et al. (2017), nivolumab improved PFS tients with inoperable locally advanced and/or metastatic over placebo (HR 0.60, 95% CI 0.49 to 0.75). (stage IV) disease, based on improved survival and QoL Biological therapy for esophageal cancer (including compared to BSC alone (I, A). However, comorbidities, GEJ): According to Dutton et al. (2014), gefitinib (2nd organ function, and PS must always be taken into con- line) improved PFS over placebo (HR 0.66, 95% CI 0.66 sideration. (II, B). This recommendation is based on to 0.97). small or large RCTs with suspicion of bias (lower meth- Table 3 provides a narrative synthesis as an overview odological quality) or meta-analyses of such trials or tri- of the other outcomes. All the SRs that reported PFS als with demonstrated heterogeneity. As we have stated, showed a better PFS with SOTs than control [15, 24, 26, our overview’s results do not go in the same direction as 27, 33, 34], while most of the SRs reporting adverse those guidelines recommendations due to the low qual- events showed more adverse events than the interven- ity of the evidence to support an active systemic treat- tion groups [24, 26, 27, 29–31, 33, 35]. There is scarce ment in patients with advanced stages with a high risk of data related to QoL, and none of the included SRs re- dying in the short or medium-term. It is important to ported findings for the outcomes FS, symptoms related note that all the mentioned guidelines recommendations to the disease, admissions, or quality of death. Additional for all the different SOT regimens are mainly based on a file 7 provides SoF tables for the primary outcomes. potential OS improvement of a few months and rarely consider patient-centered outcomes. Discussion Although there is evidence suggesting that SOT’s use near This overview provided a comprehensive synthesis of the EOL is not related to its likelihood of providing a benefit the available evidence regarding the effectiveness of SOT [27, 42–44], our analysis could not confirm any significant compared with BSC or placebo administered in patients differences between SOT and BSC for all the outcomes. The with advanced esophageal or gastric cancers. The discussion about changing the focus of treatment to provid- current analyses revealed that it is uncertain whether ing symptomatic and supportive care is complex. Little lit- SOT, such as CT, immunotherapy, biological and tar- erature addresses the magnitude of financial, psychological, geted therapy improve OS and PFS over more conserva- or physical harms of medication overuse in cancer, even tive approaches due to the very low certainty of when it could be substantial [45]. Smith and Hillner have evidence. Most reviews had a critically low methodo- proposed for patients with advanced cancer, changes in logical quality and did not include outcomes considered medical oncologists’ behavior, and changes in their attitudes important in decision-making. and practices that will bend the cancer-cost curve [46]. For patients with advanced esophageal and gastric cancers, we Context can consider the following aspects: a) to limit second-line Over the last two decades, cancer care’s aggressiveness and third-line treatment for metastatic cancer to sequential near the EOL has emerged as a growing concern [38, monotherapies; b) to limit CT to patients with good PS; c) 39]. For instance, the American Society of Clinical On- to limit further CT to clinical trials in the case of patients cology (ASCO) recommends avoiding the use of CT who are not responding to three consecutive regimens. Be- near the EOL due to the absence of evidence supporting sides, regarding changes in attitudes and practice, we agree its clinical value [40]. This is in line with our results, with the author that better integration of palliative care into confirming the limited attention that patient-centered usual oncology care must be discussed. outcomes have received so far. Usually, SRs only meta- One problem to solve is how supportive care and BSC analyze clinical outcomes such as OS or PFS but do not are implemented in RCTs when used as a comparison include others like FS, toxicity, or symptoms related to treatment arm. Reviews of the cancer clinical trial litera- the disease, admissions to the hospital, or palliative care ture found that RCTs poorly define and standardize BSC provided during the last year. All of these outcomes are as a clinical trial control arm [47, 48]. Such studies risk Santero et al. BMC Cancer (2021) 21:712 Page 11 of 18 Fig. 4 Risk of bias Assessment Santero et al. BMC Cancer (2021) 21:712 Page 12 of 18 Fig. 5 Overall survival and progression-free survival for systemic oncological treatment versus supportive treatment in advanced esophageal or gastric cancers systematically over-estimating the net clinical effect of interpret [49]. As we found in our study, especially in the comparator arms. The vast majority of the studies adverse events, it is important to take responsibility for did not meet the WHO guidelines on BSC because pal- the need to strengthen the rigor of PROs in cancer trials liative care therapies were not recommended or inte- or studies reports. It is also essential to acknowledge the grated into care. discordances between patient and clinician reports re- Another issue is how studies entitle the patients re- gard the symptoms and severity [50, 51]. It could be use- ported outcomes (PROs). The heterogeneity in the con- ful to follow the Patient-Reported Outcome structs, measures and analytic is very challenging to Terminology Criteria for Adverse Events (PRO-CTAE) Table 3 A narrative synthesis of clinical and patient-centered outcomes SRs Reported outcomes Author, OS RCTs/ PFS RCTs/ FS Toxicity RCTs/ Symptom QoL RCTs/ Admissions QoD year RCTs RCTs RCTs related to RCTs a overview overview overview disease overview Iacovelli ✓ 5/5 NR – NR NR – NR NR – NR NR 2014 [23] Santero et al. BMC Cancer Veer ✓ 8/8 2d-line ramucirumab 5/8 Targeted agents, either in 5/8 NR – 2016 and 2d- or 3d-line monotherapy or combined with [24] everolimus and regoraf- CT showed increased toxicity enib showed limited compared to BSC and CT-alone PFS gain, ranging from 0.3 to 1.6 months (2021) 21:712 Wang ✓ 3/3 NR – NR – NR – 2016 [25] Chan ✓ 4/4 the addition of AAs was 4/4 toxicity > = Grade 3: with OR 139 2/4 significant improvement in QoL 2/4 2017 a associated with (95% CI 117–165) was found with apatinib, in [26] improved PFS: HR 0.68 improving insomnia (p = 0002), (95% CI 0.63–07.4, p < ramucirumab in delaying time to 000001) deterioration of PS > = 2 (p = 0002) and improving functional functioning and nausea (HR < 075), bevacizumab in slowing deterioration in pain (p = 00068), and endostatin in improving global QoL (p < 005) Chan ✓ 4/5 TLT improved PFS (HR 3/5 more toxicities occurred in the TLT 5/5 The QOL data could not be 4/5 2017 b 0.29; 95% CI 0.18–0.45) arms combined in a meta-analysis be- [27] cause only brief descriptions were reported in their final publications Harvey ✓ 4/5 NR – NR – NR – 2017 [28] Janmaat ✓ 5/5 people who receive 2/5 NR – NR – 2017 more CT or targeted [15] therapeutic agents live with less disease progression than people who receive BSC or less therapy Wagner ✓ 3/3 NR – Because of the different ways of 3/3 NR – 2017 reporting, grade I to IV toxicities [29] can be compared only within, but not between studies. Overall, treatment-associated toxicities were higher in the combination of Page 13 of 18 Table 3 A narrative synthesis of clinical and patient-centered outcomes (Continued) SRs Reported outcomes Author, OS RCTs/ PFS RCTs/ FS Toxicity RCTs/ Symptom QoL RCTs/ Admissions QoD year RCTs RCTs RCTs related to RCTs a overview overview overview disease overview CT arms, but this was usually not statistically significant Santero et al. BMC Cancer Wang ✓ 2/2 NR 1/2 the addition of TAs to therapies 2/2 NR – 2017 significantly increased the risk of [30] developing severe AEs (RR: 1.12, 95% CI: 1.02–1.24, P = 0.02), but not for FAEs (RR: 0.97, 95% CI: 0.65–1.45, P = 0.88) NR Compared with other analyzed 2/2 NR (2021) 21:712 Xie 2017 NR – – – [31] treatments, ramucirumab has a higher risk of hematological events during its application. Lapatinib is always combined with severe gastrointestinal events. Trastuzumab is proposed for its high efficacy in improving the survival rate and safety, which is proper for most patients Zhu ✓ 5/5 NR – NR – NR – 2017 [32] Liu 2018 ✓ 4/4 targeting VEGFR drugs 4/4 Fewer AESIs were observed in the 4/4 NR – [33] significantly improved VEGFR-Ab than the VEGFR-TKI PFS [HR 0.50, 95% CI drugs. VEGFR drugs were effective, (0.34, 0.66), P < 0.001] and their toxicity is within a controllable range Zhao ✓ 6/6 apatinib (97.5%) was 6/6 bevacizumab (85.5%) was likely to 5/6 NR – 2018 most likely to improve get the lowest severe AEs, [34] PFS, followed by followed by sunitinib (63%) regorafenib (86.3%) and rilotumumab (65.4%). Chen ✓ 2/2 NR 1/2 The most common grade ≥ 3 2/2 NR – 2019 TRAEs were fatigue, aspartate [35] aminotransferase increased, hepatitis, pneumonitis, colitis, hypopituitarism. The TRAE incidence of anti-PD-1/PD-L1 was less than chemotherapy (TRAE RR = 0.64 p < 0.001; ≥3 TRAE RR = 0.37 p < 0.001). The incidence of ≥3 TRAEs of anti-PD-1/PD-L1 treat- ment was less than that of anti- CTLA-4 (11.7% vs 43.9%) Page 14 of 18 Table 3 A narrative synthesis of clinical and patient-centered outcomes (Continued) SRs Reported outcomes Author, OS RCTs/ PFS RCTs/ FS Toxicity RCTs/ Symptom QoL RCTs/ Admissions QoD year RCTs RCTs RCTs related to RCTs a overview overview overview disease overview van NR – NR – NR – taxanes and targeted agents could 8/8 Kleef provide HRQoL benefit beyond 2019 the first-line compared with BSC Santero et al. BMC Cancer [36] Wallis ✓ 1/4 NR – NR – NR – 2019 [37] AAs Anti-angiogenic agents, BSC best supportive care, AE Adverse events, CT chemotherapy, FAE Fatal adverse events, FS Functional status, OS Overall survival, PFS Progression-free survival, QoD Quality of death, QoL Quality of life, TA Targeted agents, TLT third-line treatment (2021) 21:712 Outcomes in bold are primary outcomes OS has been presented in Fig. 4 (meta-analysis) a RCTs: randomized controlled trials relevant to our question / RCTs overview: total randomized controlled trials included in the SR Page 15 of 18 Santero et al. BMC Cancer (2021) 21:712 Page 16 of 18 tools in case to be necessary and finally to consider all more prone to benefit from intensive systemic treat- the submitted PROs as important supportive data im- ments and avoid the accompanying side effects. proving the validity, reliability, and precision of adverse events report. Conclusions This overview suggests that there is a large uncertainty on the effectiveness of SOT for advanced esophageal or Limitations gastric cancers that could provide a complete under- We are aware that our research may have limitations. standing of benefits and side effects. Broader research, Firstly, the main limitation of this overview arises from including high-quality SRs and further RCTs that con- heterogeneity amongst active treatments assessed. In this sider a thorough assessment of patient-centered out- regard, we assessed the included studies’ heterogeneity comes, is needed to identify improvement targets to and undertook analysis by type of SOT. optimize cancer care value. Secondly, we found that the overlapping RCT distribu- tion may over-represent samples from these primary Abbreviations studies. Nevertheless, we reported this overlap and AMSTAR: A MeaSurement Tool to Assess systematic Reviews; ASCO: American Society of Clinical Oncology; BSC: Best supportive care; quantified it using the mentioned CCA method to help CCA: Corrected covered area; CI: Confidence interval; CT: Chemotherapy; us consider questions that could affect our overview’s EMBASE: Excerpta Medica dataBASE; EOL: End-of-life; ESMO: European Society comprehensiveness and complexity. for Medical Oncology; FS: Functional status; GEJ: Gastro-esophagic junction; GRADE: Grading of Recommendations Assessment, Development, and Finally, the risk of bias assessment of primary studies Evaluation; HR: Hazard ratio; MEDLINE: Medical Literature Analysis and was not performed directly on the original studies but Retrieval System Online; OR: Odds ratio; OS: Overall survival; PFS: Progression- each SR, resulting in an incomplete assessment for some free survival; PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; PROSPERO: International Prospective Register of Systematic studies and potentially hindering the overall assessment. Reviews; PROs: Patients reported outcomes; PRO-CTAE: Patient-Reported We plan to carry out an evidence map and a new SR to Outcome Terminology Criteria for Adverse Events; QoL: Quality of life; address these limitations. RCTs: Randomised controlled trials; SoF: Summary of finding; SRs: Systematic reviews; SOT: Systemic oncological treatment; VEGFR: Vascular endothelial growth factor receptor; WHO: World Health Organization Implications This overview did not identify solid evidence for admin- Supplementary Information The online version contains supplementary material available at https://doi. istering SOT over BSC for patients with advanced org/10.1186/s12885-021-08330-5. esophageal or gastric cancers. Involved doctors and pa- tients should be aware of the limited benefits that inten- Additional file 1. Protocol study. sive SOT can provide when the disease is very advanced. Additional file 2. Complete PRISMA checklist. The PRISMA checklist was The therapeutic decisions for patients with advanced completed in full with the page number of the paper which reports the esophageal or gastric cancers must consider their FS, information that meets the criteria of the checklist. values and preferences, and potential side effects of Additional file 3. Search strategy. treatments. However, to enable patients to make in- Additional file 4. List of excluded reviews and justification for the exclusions. formed choices, they should be provided with balanced Additional file 5. Further characteristics of included systematic reviews. information. Unfortunately, as shown in our overview, Additional file 6. References RCTs. clinical trials and SRs barely report patient-centered Additional file 7. GRADE. outcomes. It is important to note that almost all RCTs for pa- Acknowledgments tients with esophageal or gastric cancers currently focus Marilina Santero is a doctoral candidate for the Ph.D. in Methodology of on treating the disease’s early stages. However, the evi- Biomedical Research and Public Health (Department of Paediatrics, Obstetrics, Gynaecology, and Preventive Medicine), Universidad Autònoma dence collected in this overview shows that it is still ne- de Barcelona, Barcelona, Spain. cessary to evaluate how to treat patients in advanced stages. We claim future clinical trials and reviews to ad- Authors’ contributions dress SOT’s impact in patients with advanced stages at MS, JPB, IS and XBC conceived and designed the overview. KSG, AMA, CR, JS, ARA, GRG, RAD, AGM, JPB, and MS participated in the study selection and high risk of dying in the short or medium term. We do data extraction. MS, RAD, AGM, and JPB contributed to the interpretation of so by considering that before comparing intensive treat- the findings. MS, AGM, and RAD wrote the drafts and prepared the ments, these should demonstrate their advantages over manuscript. GU, JPB, MJQ, and XBC provided supervisory support and reviewed this paper. All authors contributed to their vision of the manuscript more conservative approaches such as BSC, not only on and approved the final version of the review. survival but also on patient-centered outcomes. High- quality SRs with complete reporting of design, method- Authors’ information (1) Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau ology, and analysis of results could perform pre-planned (IIB Sant Pau), Barcelona, Spain (2). Interdisciplinary Centre for Health Studies subgroup analyses to identify those groups of patients (CIESAL), Universidad de Valparaíso, Viña del Mar, Chile (3). Department of Santero et al. 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