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Anticancer Drugs Compared to No Anticancer Drugs in Patients with Advanced Hepatobiliary Cancer: A Mapping Review and Evidence Gap Map
Authors Requeijo C , Bracchiglione J, Meza N, Acosta-Dighero R, Salazar J, Santero M , Meade AG, Quintana MJ , Rodríguez-Grijalva G, Selva A, Solà I , Urrútia G , Bonfill Cosp X
Received 20 July 2023
Accepted for publication 14 October 2023
Published 10 November 2023 Volume 2023:15 Pages 1069—1085
DOI https://doi.org/10.2147/CLEP.S431498
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Vera Ehrenstein
Carolina Requeijo,1,* Javier Bracchiglione,1– 3,* Nicolás Meza,2 Roberto Acosta-Dighero,2 Josefina Salazar,1 Marilina Santero,1 Adriana-G Meade,1 María Jesús Quintana,1,3,4 Gerardo Rodríguez-Grijalva,1 Anna Selva,3,5 Ivan Solà,1,3 Gerard Urrútia,1,3 Xavier Bonfill Cosp1,3,4 On behalf of Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group
1Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; 2Interdisciplinary Centre for Health Studies (CIESAL), Valparaiso University, Viña del Mar, Chile; 3CIBER of Epidemiology and Public Health (CIBERESP), Barcelona, Spain; 4Autonomous University of Barcelona, Barcelona, Spain; 5Clinical Epidemiology and Cancer Screening, Parc Taulí Hospital Universitari, Parc Taulí Research and Innovation Institute Foundation (I3PT-CERCA), Autonomous University of Barcelona, Sabadell, Spain
*These authors contributed equally to this work
Correspondence: Carolina Requeijo, Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), C/ Sant Antoni M. Claret 167. Pavelló 18 planta 0. 08025, Barcelona, Spain, Email [email protected]
Introduction: Despite being commonly recommended, the impact of anticancer drugs (ACDs) on patient-important outcomes beyond survival for advanced hepatobiliary cancers (HBCs) may not have been sufficiently assessed. We aim to identify and map the evidence regarding ACDs versus best supportive care (BSC) for advanced HBCs, considering patient-centered outcomes.
Methods: In this mapping review, we included systematic reviews, randomized controlled trials, quasi-experimental, and observational studies comparing ACDs (chemotherapy, immunotherapy, biological/targeted therapy) versus BSC for advanced HBCs. We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Library, Epistemonikos, PROSPERO and clinicaltrials.gov for eligible studies. Two reviewers performed the screening and data extraction processes. We developed evidence maps for each type of cancer.
Results: We included 87 studies (60 for advanced liver cancer and 27 for gallbladder or bile duct cancers). Most of the evidence favored ACDs for survival outcomes, and BSC for toxicity. We identified several evidence gaps for non-survival outcomes, including quality of life or quality of end-of-life care.
Discussion: Patient-important outcomes beyond survival in advanced HBCs are insufficiently assessed by the available evidence. Future studies need to address these gaps to better inform decision-making processes.
Keywords: liver neoplasms, gallbladder neoplasms, bile duct neoplasms, antineoplastic agents, immunotherapy, biological therapy, palliative care
Introduction
Hepatobiliary cancers (HBCs) —including hepatocellular carcinoma, intra- and extra-hepatic cholangiocarcinoma, and gallbladder cancer— represent more than 5% of all new cancers worldwide, constituting the third cause of death.1,2 A considerable proportion of patients are diagnosed in advanced stages (17.9% for liver and intrahepatic bile duct cancer and 44.3% for gallbladder cancer) with a lack of curative treatment chance and a poor survival rate (one-year survival rate of 17.0% and 19.2%, respectively).1
Anticancer drugs (ACDs), a broad term that considers chemotherapy, targeted/biological therapy, and immunotherapy, are the main recommended treatment for these patients.3–6 Nevertheless, they are associated with important toxicity and impact on quality of life (QoL), which may be in conflict with patient values and preferences and, therefore, may be considered an indicator of poor-quality and aggressive care.6–10 Recommendations for ADCs are usually based on their impact on survival outcomes, with less consideration of other critically important outcomes, such as QoL or quality of end of life (EoL) care.3,4,11 Additionally, some guidelines recognize evidence gaps for particular clinical scenarios, such as second-line treatments for advanced biliary tract tumors.5 A reasonable alternative therapeutic strategy for these patients could be best supportive care (BSC) alone. This broad concept encompasses therapeutic efforts focused on symptom control and improvement in patients’ QoL, including various treatments given by highly personalized multidisciplinary teams to on-demand consultations.12–14 In this clinical scenario, BSC with no ACDs can usually represent a valid alternative option through achieving similar survival results with lower toxicity.15–17
Currently, there is still uncertainty regarding the extent to which primary studies and evidence syntheses are assessing and reporting outcomes beyond survival for the comparison of ACDs versus BSC in patients with advanced HBCs. Characterizing if important outcomes are reported by the relevant body of evidence and identifying outcome-reporting gaps could help improve the awareness and inclusion of critical outcomes in decision-making processes. Therefore, the purpose of this study is to identify, describe, organize, and map the currently available evidence and potential gaps about the efficacy and safety of ACDs compared to BSC for patients with advanced HBCs.
Methods
We conducted a mapping review and evidence gap map,18,19 adhering to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.20 The protocol for this study was prospectively registered and is publicly available in Open Science Framework.21 This study is part of the ASTAC (Appropriateness of Systemic Oncological Treatments for Advanced Cancer study) project, which aims to describe, map, and synthesize the available evidence regarding the efficacy and appropriateness of ACDs for advanced non-intestinal digestive cancers (including hepatobiliary, gastroesophageal, and pancreatic cancer). In this article, we present the results of the mapping review and evidence gap map regarding advanced HBCs.
Eligibility Criteria
We used the PICOT framework (Patients, Intervention, Comparison, Outcomes, Type of study) to guide our eligibility criteria.22
Type of Patients
We considered eligible studies including adult patients (over 18 years), with diagnosis of liver, bile duct, or gallbladder cancer, primary or recurrent, in an advanced stage or described as advanced or metastatic by the study authors at the moment of the intervention. For the purpose of this review, we considered as an advanced stage disease those patients with stage IIIb, IIIc, or IV liver cancer, stage IIIb or IV bile duct cancer, or stage IIIb or IV gallbladder cancer.23 We excluded lymphatic, stromal, and neuroendocrine cancers.
Type of Interventions and Comparators
For the intervention arm, we considered any ACDs, including chemotherapy (either monotherapy or in combination), biological/targeted therapy, or immunotherapy, whether individual or combined, with or without supportive care. We excluded studies that considered only surgery or radiotherapy as intervention, as well as studies that considered chemotherapy only as an adjuvant or neoadjuvant therapy. We have also excluded studies that considered only local therapy such as TACE therapy or similar.
We considered as comparator any supportive treatment, administered with the purpose of symptomatic or palliative control, with no ACDs. This includes either usual treatment, supportive care, or BSC.13 Studies that did not explicitly define the intervention of the control group, or studies with placebo as the control group, were also included. We excluded studies if the control group considered any type of ACD. We also excluded comparisons comprehending an intervention with non-palliative intent, such as surgery or radiotherapy with curative intent.
Type of Outcomes
We considered the following outcomes: Overall survival (OS); progression-free survival (PFS); functional status; toxicity; symptoms related to the disease; quality of life (QoL); admissions to hospital or long-term center, or emergency consultations; and quality of death (EoL care), including admission to hospital at the EoL, palliative care provided during the last year, and place of death. Appendix 1 provides a detailed definition of assessed outcomes.
Type of Studies
We included systematic reviews (SRs), randomized controlled trials (RCTs), quasi-experimental studies, and observational studies assessing the impact of ACDs on advanced or metastatic HBCs (including hepatocellular carcinoma, cholangiocarcinoma, and gallbladder cancer). In the case of SRs, we considered only those published from 2008 onwards, since a previous overview did not preliminarily identify relevant studies before that date.6 We did not apply any publication date or language restrictions to primary studies.
We considered as a SR any type of secondary research that raised: i) an explicit eligibility criteria or research question, ii) a structured search strategy (defined as explicit search terms and data frame, in at least two databases), iii) explicit inclusion criteria and screening methods, iv) an explicit assessment of the quality or risk of bias of each included study, and v) explicit approach to data analysis and synthesis.22,24 RCTs were defined as any experimental primary study with a random allocation of interventions. We considered as a quasi-experimental study design any research with a non-randomized allocation of interventions, such as interrupted time series or before–after studies. We considered as an observational study all case-control, cohort or cross-sectional studies, as long as they were controlled and included, at least, 30 patients. We excluded any descriptive studies, clinical practice guidelines, case reports, and non-systematic reviews (such as narrative reviews).
Search Methods for Identification of Studies
We performed electronic searches in MEDLINE (access via PubMed), EMBASE (access via OVID), the Cochrane Database of Systematic Reviews, CENTRAL, and Epistemonikos from inception until December 2019. We designed search strings adapted to the requirements of each database that combined controlled vocabulary and search terms related to the main concepts of our clinical question. Appendix 2 provides the search strategy for PubMed. As this study is part of a wider project (ASTAC-study), the search strategy included terms for gastro-esophageal and pancreatic cancer, besides hepatobiliary cancer. Since the COVID-19 pandemics delayed the conduction of this study, we later updated the searches in MEDLINE/PubMed until August 2022.
We also searched in PROSPERO and clinicaltrials.gov to identify protocols of potentially eligible studies, asked experts in the field for relevant studies, and conducted a citation search strategy, both backward (checking reference list of the included studies) and forward (identifying studies that cited included studies, using Google Scholar)
Selection of Studies
Two reviewers independently screened titles and abstracts of the retrieved search results. A third reviewer resolved disagreements. Afterward, two reviewers independently conducted the full-text screening, also with a third author solving any disagreement. For all this process we used Covidence.25
Data Extraction
Two reviewers independently extracted data from the included studies, using a previously piloted data extraction sheet. A third reviewer solved discrepancies. For each included study, we extracted the following data: year of publication, country, study design, total number of studies included regarding our question (for SRs), total number of patients included (for primary studies), interventions (broadly classified as chemotherapy, biological/targeted therapy, and/or immunotherapy), comparators (BSC, placebo, or non-specified), outcomes reported, and direction of effect, defined according to its statistical significance as “favors intervention”, “favors comparison”, or “no differences”.
Data Synthesis and Analysis
We described study results in a tabular view, classifying each included study by cancer location, type of intervention, methodological design, reported outcomes, and direction of the effect. We used the R package “evimappr”26 to produce the bubble plots for the evidence gap maps. We present a display that includes the interventions (chemotherapy, biological/targeted therapy, immunotherapy) in the rows, and the outcomes in the columns. The grids were populated with the corresponding studies at each intersection, classified by study design (SR, RCT, quasi-experimental study, or observational study). We identified evidence gaps as those spaces on the grid that did not contain studies. Due to space limits, if a column (or outcome) did not contain any study for any intervention, it was not plotted within the bubble plot.
Results
Our initial search strategy yielded a total of 76,338 records. After removing duplicates, we screened a total of 57,042 references, of which 54,060 were excluded by title and abstract screening. Of the 2982 references included after this initial stage, we could not retrieve 108 reports; therefore, we assessed 2982 full-text studies for eligibility, and we excluded 2676 reports. Finally, we included a total of 198 studies for all cancer locations (hepatobiliary, gastroesophageal, and pancreatic), 87 of which were related to hepatobiliary cancer. One additional study was identified through citation search. Figure 1 summarizes the screening process. Appendix 3 provides the list of the included studies and their publication threads, with references.
 |
Figure 1 PRISMA flowchart. *Five studies provided data and were included in more than one review. Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons. |
Liver Cancer
Sixty studies assessed patients with advanced liver cancer, including 17 SRs,27–43 27 RCTs,16,17,44–68 two RCT protocols69,70 and 14 observational studies.71–84 Table 1 provides the characteristics of the included studies.
 |
Table 1 Characteristics of the Included Studies Providing Data for Advanced Liver Cancer |
Of the 17 SRs included, nine compared biological/targeted therapies to placebo (n=3) or to a not clearly specified comparator (n=6); seven compared biological/targeted and immunotherapy to placebo (n=3), BSC (n=2), placebo or no treatment (n=1) or standard care (n=1); and only one compared immunotherapy to placebo.
Among the 27 RCTs, 22 compared biological/targeted therapies to either placebo (n=18), BSC (n=3) or placebo plus BSC (n=1); three compared chemotherapy to placebo (n=1), BSC (n=1), or to a not clearly specified comparator (n=1); and only two compared immunotherapy to placebo plus BSC. Almost half of the RCTs (n=13) did not specify the lines of therapy. Sorafenib was the most evaluated treatment (n=6).
Finally, among the 14 observational studies included, nine compared biological/targeted therapies to either BSC (n=5) or to a not clearly specified comparator (n=4); one study compared biological/targeted and immunotherapy to BSC; one compared chemotherapy and biological/targeted therapies to no treatment; and three compared chemotherapy to BSC (n=2) or to a not clearly specified comparator (n=1). Half of the studies (n=7) did not specify the lines of therapy.
Figure 2 shows an overall summary of the evidence retrieved, classified by the type of ACD administered and by outcome. This figure only shows those outcomes for which there is no study. Therefore, evidence gaps are not shown here. Figure 3 provides details about the outcomes assessed by each study and the direction of the reported effect.
 |
Figure 2 Evidence map for ACD in advanced liver cancer. The size of each dot represents the number of studies that address the intervention/outcome relationship. The color of each dot represents the methodological design of the study group. |
 |
Figure 3 Summary of the direction of the effect for each study and outcome in patients with advanced liver cancer. Abbreviations: OBS, observational study; RCT, randomized control trial; SR, systematic review; CT, chemotherapy; BIO/TT, biological/target therapy; IT, immunotherapy; OS, Overall Survival. PFS, Progression-free survival; mo, Months; FI, Favors intervention (ACD); ND, No difference; FC, Favors comparison (BSC/placebo); NR, Not reported. |
The most reported outcomes were related to survival (as OS or PFS), mostly favoring intervention, with no studies favoring the comparator. Half of the included studies reported clear data for toxicity, mostly related to ACDs. Very few studies evaluated quality of life and no studies included quality of death as outcome.
Gallbladder and Bile Duct Cancers
Twenty-seven studies assessed patients with advanced gallbladder and bile duct cancers, including two SRs,85,86 eight RCTs,15,87–93 one RCT registration,94 one quasi experimental study95 and 15 observational studies.96–110 Table 2 provides the characteristics of the included studies.
 |
Table 2 Characteristics of the Included Studies on Advanced Gallbladder and Bile Duct Cancers |
Both SRs compared chemotherapy to placebo (n=1) or to a not clearly specified comparator (n=1) as first- or second-line therapies.
Among the eight RCTs, two compared biological/targeted therapies to either placebo (n=1) or placebo plus BSC (n=1), five compared chemotherapy either to BSC (n=3), active symptom control (n=1), or to a not clearly specified comparator (n=1) and one compared chemotherapy and biological/targeted therapies to BSC. More than half of the studies (n=5) did not specify the lines of therapy.
Finally, among the 15 observational studies included, 13 compared chemotherapy to either BSC (n=10) or to a not clearly specified comparator (n=4); and two compared chemotherapy and biological/targeted therapies to BSC (n=1) or no ACDs (n=1). More than half of the studies (n=8) did not specify the lines of therapy.
Figure 4 provides an overall evidence map for ACDs in patients with advanced gallbladder and bile duct cancers, classified by type of administered ACD and by outcome. This figure only shows those outcomes for which there is any study. Therefore, evidence gaps are not shown here. Figure 5 provides a detailed assessment of the direction of the effect for each prespecified outcome within the included studies.
 |
Figure 4 Evidence map for ACD in advanced gallbladder/bile duct cancers. The size of each dot represents the number of studies that address the intervention/outcome relationship. The color of each dot represents the methodological design of the study group. |
 |
Figure 5 Summary of the direction of the effect for each study and outcome in patients with advanced gallbladder and bile duct cancers. Abbreviations: OBS, observational study; RCT, randomized control trial; SR, systematic review; CT, chemotherapy; BIO/TT, biological/target therapy; IT, immunotherapy; OS, Overall Survival; PFS, Progression-free survival; mo, Months; FI, Favors intervention (ACD); ND, No difference; FC, Favors comparison (BSC/placebo); NR, Not reported. |
The most reported outcomes were related to survival (mostly OS followed by PFS), mainly favoring intervention, with no studies favoring comparators. Only four studies reported clear data for toxicity. Very few studies evaluated quality of life and no studies included quality of death as outcome.
Discussion
In this mapping review, we have summarized the body of evidence regarding the effects of ACDs compared to BSC for patients with advanced HBCs in prespecified patient-important outcomes. Most of the studies assessed the effectiveness of biological/targeted therapy in advanced liver cancer, and chemotherapy in advanced gallbladder or bile duct cancers.
Regarding advanced liver cancer, most of the identified evidence reported findings that favored ACDs for survival outcomes and supportive care for toxicity. Nevertheless, less than half of the included studies provided clear comparative data for toxicity. Despite being the third most reported outcome, QoL was explicitly assessed in only nine studies, with most showing no significant differences between groups. Other outcomes were scarcely reported: only two studies reported symptoms, one reported functional status, one reported admission, and none reported outcomes related to quality of death. Despite showing a similar direction of effect in terms of survival outcomes, the mapping of gallbladder and bile duct cancers also revealed a scarce report for other outcomes, with only five studies clearly reporting toxicity, two reporting QoL, one reporting functional status and one reporting symptoms. None of these studies reported data related to hospital admissions or quality of death.
In the context of advanced HBCs, where a poor survival is expected, other outcomes related to patients’ well-being should be considered critical for shared decision-making processes. Primary evidence and its synthesis through SRs are key components for making recommendations (eg, using evidence-to-decision frameworks); therefore, in order to improve quality of care, it is essential for the relevant body of evidence to consider these outcomes. Our results highlight the importance of assessing and reporting outcomes beyond survival-related ones, which are currently not being systematically considered. There are important gaps of evidence in terms of quality of death, admissions to hospital, symptoms, and functional status, and there is still room for improvement in reporting of adverse events.
The delivery of healthcare for patients with advanced cancer should be centered on proven high-value, safe, and effective treatments, ensuring its quality by including the values and preferences of patients and their caregivers.111,112 The consideration of Core Outcome Sets (COS) when undertaking clinical research could close the gap to achieve this objective.113 COS represent a minimum agreed set of outcomes that should be measured and reported in clinical research, which are relevant for key stakeholders, including patients and healthcare professionals.114 The inclusion of Patient Reported Outcome Measures (PROMs) in COS is an area where consensus is still scarce.115 A systematic review showed an important heterogeneity in the selection of PROMs, and the instruments or measures used in cancer populations.116 In this sense, outcome report inconsistency has been elucidated as a cause of the scarce evidence informing clinical guidelines in care at the EoL.117,118 Providing accurate and consistent information about predefined critical outcomes will help to identify both specific clinical questions that have been extensively studied, as well as evidence gaps that need further research. This will help to guide future primary research and evidence syntheses to make better recommendations for the treatment of these patients.
Our study has several strengths. We undertake a comprehensive search strategy on six databases, with additional efforts to identify eligible studies, such as the citation chase process. The screening process was performed by two independent reviewers, as well as the data extraction. We also showed a graphical display of our results. Our evidence map has a broad range of potential end-users including funding agencies, researchers, and clinicians. It complements other review methods for describing existing research, informing future research efforts, and addressing evidence gaps. The main limitation of our study is that the methodological quality of the studies and the magnitude of effect of the findings have not been assessed, as this is outside the scope of a mapping review. Therefore, the effect of the interventions must be interpreted with caution, since our methods do not intend to appraise the internal validity of the findings nor to provide a synthesized estimate. Another possible limitation is publication bias, although we tried to limit this by searching in public study registries.
This evidence mapping shows the current landscape of research for ACDs and BSCs for patients with advanced HBCs. It complements other evidence synthesis methods to better inform research areas that need further attention. We highlight critical evidence gaps regarding non-survival outcomes in both primary studies and evidence syntheses assessing ACDs for patients with advanced HBCs. Future research should explicitly assess and report outcomes that can be critical for decision-making processes, such as toxicity and QoL.
Acknowledgments
Carolina Requeijo is a doctoral candidate for the Ph.D. in Methodology of Biomedical Research and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain.
We would like to thank Yang Song for her help in translating and extracting one of the included reviews, and Juan Carlos Vázquez for his help in the full-text screening process.
Members of ASTAC-Study Research Group: Acosta-Dighero R, Antequera A, Auladell-Rispau A, Bonfill X, Bracchiglione J, Cantero-Fortiz Y, Dorantes R, Hernández ED, Irassar J, Meade AG, Meinardi P, Merchán-Galvis AM, Meza N, Quintana MJ, Requeijo C, Rodríguez-Grijalva G, Salas-Gama K, Salazar J, Santero M, Savall-Esteve O, Selva A, Simancas D, Solà I, Urrútia G.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This study has been funded by Instituto de Salud Carlos III through the project “PI18/00034” (Co-funded by European Regional Development Fund “A way to make Europe”).
Disclosure
The authors declare that they have no competing interests in this work.
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