Cancer and neoplasms
Anticancer drugs vs no anticancer drugs for advanced HBCs
Nov
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.
References
1. Surveillance Research Program, National Cancer Institute. SEER*Explorer: an interactive website for SEER cancer statistics [Internet]. In: Surveillance Research Program, National Cancer Institute [Internet]. [cited November 10, 2021]. Available from: https://seer.cancer.gov/explorer/. Accessed November 01, 2023.
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249. doi:10.3322/caac.21660
3. Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol. 2020;38:4317–4345. doi:10.1200/JCO.20.02672
4. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv238–iv255. doi:10.1093/annonc/mdy308
5. Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v28–v37. doi:10.1093/annonc/mdw324
6. Bracchiglione J, Rodríguez-Grijalva G, Requeijo C, et al. Systemic oncological treatments versus supportive care for patients with advanced Hepatobiliary Cancers: an overview of systematic reviews. Cancers. 2023;15(3):766. doi:10.3390/cancers15030766
7. Corrie PG. Cytotoxic chemotherapy: clinical aspects. Medicine. 2011;39:717–722. doi:10.1016/j.mpmed.2011.09.012
8. Earle CC, Landrum MB, Souza JM, Neville BA, Weeks JC, Ayanian JZ. Aggressiveness of cancer care near the end of life: is it a quality-of-care issue? J Clin Oncol. 2008;26:3860–3866. doi:10.1200/JCO.2007.15.8253
9. Mack JW, Weeks JC, Wright AA, Block SD, Prigerson HG. End-of-life discussions, goal attainment, and distress at the end of life: predictors and outcomes of receipt of care consistent with preferences. J Clin Oncol. 2010;28:1203–1208. doi:10.1200/JCO.2009.25.4672
10. Wasp GT, Knutzen KE, Murray GF, et al. Systemic therapy decision making in advanced cancer: a qualitative analysis of patient-oncologist encounters. JCO Oncol Pract. 2022;18(8):e1357–66.
11. Vogel A, Bridgewater J, Edeline J, et al. Biliary tract cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:127–140. doi:10.1016/j.annonc.2022.10.506
12. Hui D, De La Cruz M, Mori M, et al. Concepts and definitions for “supportive care,” “best supportive care,” “palliative care,” and “hospice care” in the published literature, dictionaries, and textbooks. Support Care Cancer. 2013;21:659–685. doi:10.1007/s00520-012-1564-y
13. Zafar SY, Currow DC, Cherny N, Strasser F, Fowler R, Abernethy AP. Consensus-based standards for best supportive care in clinical trials in advanced cancer. Lancet Oncol. 2012;13:e77–82. doi:10.1016/S1470-2045(11)70215-7
14. Nipp RD, Currow DC, Cherny NI, Strasser F, Abernethy AP, Zafar SY. Best supportive care in clinical trials: review of the inconsistency in control arm design. Br J Cancer. 2015;113:6–11. doi:10.1038/bjc.2015.192
15. Demols A, Borbath I, Van den Eynde M, et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, Phase II trial. Ann Oncol. 2020;31:1169–1177. doi:10.1016/j.annonc.2020.05.018
16. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63. doi:10.1056/NEJMoa1717002
17. Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a Phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34. doi:10.1016/S1470-2045(08)70285-7
18. Bragge P, Clavisi O, Turner T, Tavender E, Collie A, Gruen RL. The global evidence mapping initiative: scoping research in broad topic areas. BMC Med Res Methodol. 2011;11:92. doi:10.1186/1471-2288-11-92
19. Campbell F, Tricco AC, Munn Z, et al. Mapping reviews, scoping reviews, and evidence and gap maps (EGMs): the same but different- The “Big Picture” review family. Syst Rev. 2023;12:45. doi:10.1186/s13643-023-02178-5
20. Tricco AC, Lillie E, Zarin W, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): checklist and Explanation. Ann Intern Med. 2018;169:467–473.
21. Pérez-Bracchiglione J, Salazar J, Santero M, et al. Efficacy of systemic oncological treatments in patients with advanced, non-intestinal digestive cancer at high risk of dying in the middle and short term: evidence synthesis. Open Sci Framework. 2022. doi:10.17605/OSF.IO/7CHX6
22. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014;14:579. doi:10.1186/s12913-014-0579-0
23. Institute NC, National Cancer Institute. AJCC Cancer Staging Manual 8th Edition. Definitions; 2020. doi:10.32388/b30ldk.
24. Krnic Martinic M, Pieper D, Glatt A, Puljak L. Definition of a systematic review used in overviews of systematic reviews, meta-epidemiological studies and textbooks. BMC Med Res Methodol. 2019;19:203.
25. Veritas Health Innovation, Melbourne, Australia. Covidence systematic review software. Available from: www.covidence.org. Accessed November 01, 2023.
26. Haddaway N. Evimappr. In: Evimappr [Internet]; 2020. Available from: https://github.com/nealhaddaway/evimappr. Accessed November 01, 2023.
27. Chen J, Wang J, Xie F. Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: a network meta-analysis. Medicine. 2021;100:e27013. doi:10.1097/MD.0000000000027013
28. Ding W, Tan Y, Qian Y, et al. First-line targ veted therapies of advanced hepatocellular carcinoma: a Bayesian network analysis of randomized controlled trials. PLoS One. 2020;15:e0229492. doi:10.1371/journal.pone.0229492
29. Faruque LI, Lin M, Battistella M, et al. Systematic review of the risk of adverse outcomes associated with vascular endothelial growth factor inhibitors for the treatment of cancer. PLoS One. 2014;9:e101145. doi:10.1371/journal.pone.0101145
30. Finn RS, Zhu AX, Farah W, et al. Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: a systematic review and meta-analysis. Hepatology. 2018;67:422–435. doi:10.1002/hep.29486
31. Griffiths CD, Zhang B, Tywonek K, Meyers BM, Serrano PE. Toxicity profiles of systemic therapies for advanced hepatocellular carcinoma: a systematic review and meta-analysis. JAMA Netw Open. 2022;5:e2222721. doi:10.1001/jamanetworkopen.2022.22721
32. Guo T, Liu P, Yang J, et al. Evaluation of targeted agents for advanced and unresectable hepatocellular carcinoma: a network meta-analysis. J Cancer. 2019;10:4671–4678. doi:10.7150/jca.32828
33. Haber PK, Puigvehí M, Castet F, et al. Evidence-based management of Hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology. 2021;161:879–898. doi:10.1053/j.gastro.2021.06.008
34. Huang Y, Cheng X, Sun P, Li T, Song Z, Zheng Q. Supplementary sorafenib therapies for Hepatocellular Carcinoma-A systematic review and meta-analysis: supplementary sorafenib for liver cancer. J Clin Gastroenterol. 2019;53:486–494. doi:10.1097/MCG.0000000000001175
35. Jácome AA, Castro ACG, Vasconcelos JPS, et al. Efficacy and safety associated with immune checkpoint inhibitors in unresectable Hepatocellular carcinoma: a meta-analysis. JAMA Netw Open. 2021;4:e2136128. doi:10.1001/jamanetworkopen.2021.36128
36. Ling-lin Z, Li M, Jin-hui T, Ke-hu Y. Sorafenib for advanced hepatocellular carcinoma: a systematic review. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2011;33:51–57. doi:10.3881/j.issn.1000-503X.2011.01.011
37. Liu W, Quan B, Lu S, et al. First-line systemic treatment strategies for unresectable Hepatocellular Carcinoma: a systematic review and network meta-analysis of randomized clinical trials. Front Oncol. 2021;11:771045. doi:10.3389/fonc.2021.771045
38. Meyers BM, Knox JJ, Cosby R, et al. Non-surgical management of advanced hepatocellular carcinoma: a systematic review by Cancer Care Ontario. Can Liver J. 2021;4:257–274. doi:10.3138/canlivj-2020-0039
39. Niu M, Hong D, T-C M, et al. Short-term and long-term efficacy of 7 targeted therapies for the treatment of advanced hepatocellular carcinoma: a network meta-analysis: efficacy of 7 targeted therapies for AHCC. Medicine. 2016;95:e5591. doi:10.1097/MD.0000000000005591
40. Park R, Lopes da Silva L, Nissaisorakarn V, et al. Comparison of efficacy of systemic therapies in advanced Hepatocellular Carcinoma: updated systematic review and frequentist network meta-analysis of randomized controlled trials. J Hepatocell Carcinoma. 2021;8:145–154. doi:10.2147/JHC.S268305
41. Solimando AG, Susca N, Argentiero A, et al. Second-line treatments for advanced Hepatocellular carcinoma: a systematic review and Bayesian network meta-analysis. Clin Exp Med. 2022;22:65–74. doi:10.1007/s10238-021-00727-7
42. Sonbol MB, Riaz IB, Naqvi SAA, et al. Systemic therapy and sequencing options in advanced Hepatocellular carcinoma: a systematic review and network meta-analysis. JAMA Oncol. 2020;6:e204930. doi:10.1001/jamaoncol.2020.4930
43. Zhang X, Yang X-R, Huang X-W, et al. Sorafenib in treatment of patients with advanced hepatocellular carcinoma: a systematic review. Hepatobiliary Pancreat Dis Int. 2012;11:458–466. doi:10.1016/S1499-3872(12)60209-4
44. Abdel Wahab MM, Ezz Elarab LR, Ezz Elarab MA. Capecitabine plus cisplatin treatment in patients with advanced hepatocellular carcinoma. Chin-Ger J Clin Oncol. 2010;9:718–723. doi:10.1007/s10330-010-0698-y
45. Abou-Alfa GK, Puig O, Daniele B, et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol. 2016;65:289–295. doi:10.1016/j.jhep.2016.04.004
46. Abou-Alfa GK, Qin S, Ryoo B-Y, et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann Oncol. 2018;29:1402–1408. doi:10.1093/annonc/mdy101
47. Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, Phase 3 trial. Lancet Gastroenterol Hepatol. 2021;6:559–568. doi:10.1016/S2468-1253(21)00109-6
48. Llovet JM, Decaens T, Raoul J-L, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509–3516. doi:10.1200/JCO.2012.47.3009
49. EudraCT Number 2007-007629-32 – Clinical trial results – EU Clinical Trials Register; [cited June 14, 2023]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-007629-32/results. Accessed November 01, 2023.
50. Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57–67. doi:10.1001/jama.2014.7189
51. Hsu C, Yang T-S, Huo T-I, et al. Vandetanib in patients with inoperable hepatocellular carcinoma: a Phase II, randomized, double-blind, placebo-controlled study. J Hepatol. 2012;56:1097–1103. doi:10.1016/j.jhep.2011.12.013
52. Ishikawa T, Ichida T, Sugitani S, et al. Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma. J Gastroenterol Hepatol. 2001;16:452–459. doi:10.1046/j.1440-1746.2001.02352.x
53. Kudo M, Morimoto M, Moriguchi M, et al. A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma. Cancer Sci. 2020;111:3759–3769. doi:10.1111/cas.14582
54. Ji Y-X, Zhang Z-F, Lan K-T, et al. Sorafenib in liver function impaired advanced hepatocellular carcinoma. Chin Med Sci J. 2014;29:7–14. doi:10.1016/S1001-9294(14)60017-1
55. Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist. 2009;14:95–100. doi:10.1634/theoncologist.2008-0185
56. Kang Y-K, Yau T, Park J-W, et al. Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol. 2015;26:2457–2463. doi:10.1093/annonc/mdv388
57. Finn RS, Ryoo B-Y, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced Hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38:193–202. doi:10.1200/JCO.19.01307
58. Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62:479–483. doi:10.1002/1097-0142(19880801)62:33.0.CO;2-L
59. Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19:682–693. doi:10.1016/S1470-2045(18)30146-3
60. Blanc J-F, Khemissa F, Bronowicki J-P, et al. Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis. Hepatol Int. 2021;15:93–104. doi:10.1007/s12072-020-10120-3
61. Zhu AX, Park JO, Ryoo B-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859–870. doi:10.1016/S1470-2045(15)00050-9
62. Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–296. doi:10.1016/S1470-2045(18)30937-9
63. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
64. Rimassa L, Pressiani T, Boni C, et al. A phase II randomized dose escalation trial of sorafenib in patients with advanced hepatocellular carcinoma. Oncologist. 2013;18:379–380. doi:10.1634/theoncologist.2012-0221
65. Kudo M, Moriguchi M, Numata K, et al. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2:407–417. doi:10.1016/S2468-1253(17)30072-9
66. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55–63. doi:10.1016/S1470-2045(12)70490-4
67. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. doi:10.1056/NEJMoa0708857
68. Stemmer SM, Manojlovic NS, Marinca MV, et al. Namodenoson in advanced Hepatocellular carcinoma and Child-Pugh B Cirrhosis: randomized Placebo-Controlled Clinical Trial. Cancers. 2021:13. doi:10.3390/cancers13020187
69. Daniele B, Di Maio M, Gallo C, et al. A randomized phase III trial comparing sorafenib plus best supportive care (BSC) versus BSC alone in Child-Pugh B patients (pts) with advanced hepatocellular carcinoma (HCC): the BOOST study. J Clin Oncol. 2012;30:TPS4151–TPS4151. doi:10.1200/jco.2012.30.15_suppl.tps4151
70. NCT. Sorafenib in liver function impaired advanced Hepatocellular carcinoma; 2013. Available from: https://clinicaltrials.gov/ct2/show/NCT01932385. Accessed November 01, 2023.
71. Abdelmaksoud AHK, Abdelaziz AO, Nabeel MM, et al. Hepatic arterial infusion chemotherapy in the treatment of advanced hepatocellular carcinoma with portal vein thrombosis: a case-control study. Clin Radiol. 2021;76:709.e1–709.e6. doi:10.1016/j.crad.2021.03.022
72. Chen C-T, Feng Y-H, Yen C-J, et al. Prognosis and treatment pattern of advanced hepatocellular carcinoma after failure of first-line atezolizumab and bevacizumab treatment. Hepatol Int. 2022;16:1199–1207. doi:10.1007/s12072-022-10392-x
73. Du Y, Yu P, Huang L, Dai G, Cai X. The comparative safety and efficacy of S-1 versus the best supportive care in advanced hepatocellular carcinoma. Int J Clin Exp Med. 2019;12:5412–5418.
74. El Baghdady N, Elwakeel L, Ellithy M, Hussein N, Shahin S, El Naggar AR. Efficacy and safety of sorafenib versus supportive care in Egyptian advanced hepatocellular carcinoma patients. Arch Pharm Sci Ain Shams Univ. 2020;4:224–236. doi:10.21608/aps.2020.45180.1043
75. Hiramine Y, Tamai T, Imamura Y, et al. Efficacy and optimal treatment sequence of Sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma. Kanzo. 2013;54:233–248. doi:10.2957/kanzo.54.233
76. Hiraoka A, Kumada T, Hatanaka T, et al. Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression. Hepatol Res. 2021;51:880–889. doi:10.1111/hepr.13644
77. Hsiao P, Hsieh K-C, Chen Y-S, et al. Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma. Medicine. 2019;98:e16074. doi:10.1097/MD.0000000000016074
78. Jang JW, Bae SH, Choi JY, et al. A combination therapy with transarterial chemo-lipiodolization and systemic chemo-infusion for large extensive hepatocellular carcinoma invading portal vein in comparison with conservative management. Cancer Chemother Pharmacol. 2007;59:9–15. doi:10.1007/s00280-006-0239-0
79. Kang SH, Cho H, Cho EJ, et al. Efficacy of sorafenib for the treatment of post-transplant hepatocellular carcinoma recurrence. J Korean Med Sci. 2018;33:e283. doi:10.3346/jkms.2018.33.e283
80. Lesmana LA, Gani RA, Hasan I, et al. Influence of the sorafenib patients assistance program on treatment compliance and overall survival of unresectable hepatocellular carcinoma patients. Acta Med Indones. 2012;44:228–232.
81. Sanoff HK, Chang Y, Lund JL, O’Neil BH, Dusetzina SB. Sorafenib effectiveness in advanced Hepatocellular carcinoma. Oncologist. 2016;21:1113–1120. doi:10.1634/theoncologist.2015-0478
82. Trevisani F, Brandi G, Garuti F, et al. Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. J Cancer Res Clin Oncol. 2018;144:403–414. doi:10.1007/s00432-017-2556-6
83. Xia J, Gelfond J, Arora SP. Second-line treatment with nivolumab, cabozantinib, regorafenib, or best supportive care in patients with advanced hepatocellular carcinoma: analysis at a Hispanic-majority NCI-designated cancer center. J Gastrointest Oncol. 2021;12:2943–2951. doi:10.21037/jgo-21-414
84. Zhang Y, Huang G, Miao H, et al. Apatinib treatment may improve survival outcomes of patients with hepatitis B virus-related sorafenib-resistant hepatocellular carcinoma. Ther Adv Med Oncol. 2020;12:1758835920937422. doi:10.1177/1758835920937422
85. Abdel-Rahman O, Elsayed Z, Elhalawani H. Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. Cochrane Database Syst Rev. 2018;4:CD011746. doi:10.1002/14651858.CD011746.pub2
86. Jiang Y, Zeng Z, Zeng J, et al. Efficacy and safety of first-line chemotherapies for patients with advanced biliary tract carcinoma: a systematic review and network meta-analysis. Front Oncol. 2021;11:736113. doi:10.3389/fonc.2021.736113
87. Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701. doi:10.1016/S1470-2045(21)00027-9
88. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807. doi:10.1016/S1470-2045(20)30157-1
89. Glimelius B, Hoffman K, Sjödén PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. doi:10.1093/oxfordjournals.annonc.a010676
90. Kataria B, Sharma A, Mishra S, et al. Capecitabine +best supportive care (BSC) or erlotinib +BSC has overall survival (OS) benefit over BSC alone in unresectable/metastatic gall bladder cancer (GBC) patients with ECOG PS-III. Results from a phase II randomised controlled trial (RCT). Ann Oncol. 2019;30:v279. doi:10.1093/annonc/mdz247.052
91. Park DH, Lee SS, Park SE, et al. Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine, S-1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma. Eur J Cancer. 2014;50:1259–1268. doi:10.1016/j.ejca.2014.01.008
92. Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol. 2010;28:4581–4586. doi:10.1200/JCO.2010.29.3605
93. Takada T, Nimura Y, Katoh H, et al. Prospective randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C for non-resectable pancreatic and biliary carcinoma: multicenter randomized trial. Hepato-gastroenterology. 1998;45:2020–2026.
94. Duan H. An open-label controlled clinical trial of apatinib in the treatment of advanced biliary tract cancer; 2017. Report No.: ChiCTR-IIR-17014202. Available from: https://trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR-IIR-17014202. Accessed November 01, 2023.
95. Singh SK, Talwar R, Kannan N, Tyagi AK, Jaiswal P, Kumar A. Chemotherapy compared with best supportive care for metastatic/unresectable gallbladder cancer: a non-randomized prospective cohort study. Indian J Surg Oncol. 2016;7:25–31. doi:10.1007/s13193-015-0443-7
96. Azarfane M, Lièvre A, Senellart H, et al. Predictive factors of chemotherapy initiation after biliary drainage for advanced biliary tract cancer: a retrospective multicenter study. J Gastrointestin Liver Dis. 2021;30:254–258. doi:10.15403/jgld-3120
97. Brunner TB, Schwab D, Meyer T, Sauer R. Chemoradiation may prolong survival of patients with non-bulky unresectable extrahepatic biliary carcinoma. A retrospective analysis. Strahlenther Onkol. 2004;180:751–757. doi:10.1007/s00066-004-1315-1
98. Dierks J, Gaspersz MP, Belkouz A, et al. Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin. Acta Oncol. 2018;57:807–812. doi:10.1080/0284186X.2017.1418532
99. Dover LL, McDonald AM, Derek DA, Wang TN, Oster RA, Jacob R. Impact of definitive chemoradiation therapy on survival in patients with unresectable cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2014;90:S204. doi:10.1016/j.ijrobp.2014.05.759
100. Ghiassi-Nejad Z, Moshier E, Schwartz M, Buckstein M. Definitive chemoradiation therapy in the treatment of unresectable intrahepatic cholangiocarcinoma: a national cancer data base study. Int J Radiat Oncol Biol Phys. 2016;96:E211–E212. doi:10.1016/j.ijrobp.2016.06.1122
101. Ishii H, Furuse J, Yonemoto N, Nagase M, Yoshino M, Sato T. Chemotherapy in the treatment of advanced gallbladder cancer. Oncology. 2004;66:138–142. doi:10.1159/000077440
102. Ji JH, Kim YS, Park I, et al. Chemotherapy versus best supportive care in advanced biliary tract carcinoma: a multi-institutional propensity score matching analysis. Cancer Res Treat. 2018;50:791–800. doi:10.4143/crt.2017.044
103. Koch C, Franzke C, Bechstein WO, et al. Poor prognosis of advanced cholangiocarcinoma: real-world data from a tertiary referral center. Digestion. 2020;101:458–465. doi:10.1159/000500894
104. Mao W, Deng F, Wang D, Gao L, Shi X. Treatment of advanced gallbladder cancer: a SEER-based study. Cancer Med. 2020;9:141–150. doi:10.1002/cam4.2679
105. Min Jae K, Hwang J-H, Lee J-C, Shin DW, Yang SY. Impact on gemcitabine plus cisplatin in unresectable hilar cholangiocarcinoma patients according to effective bile drainage. Ann Oncol. 2018;29 Suppl 9:ix50. doi:10.1093/annonc/mdy432.010
106. Moik F, Riedl JM, Winder T, et al. Benefit of second-line systemic chemotherapy for advanced biliary tract cancer: a propensity score analysis. Sci Rep. 2019;9:5548. doi:10.1038/s41598-019-42069-1
107. Shin DW, Kim MJ, Lee J-C, et al. Gemcitabine plus cisplatin chemotherapy prolongs the survival in advanced Hilar cholangiocarcinoma: a large multicenter study. Am J Clin Oncol. 2020;43:422–427. doi:10.1097/COC.0000000000000682
108. Singh P, Sharma S, Kapoor R, et al. Best supportive care compared with chemotherapy and radiotherapy for unresectable gallbladder cancer: a tertiary care institute experience. Clin Cancer Investig J. 2014;3:153. doi:10.4103/2278-0513.130214
109. Yonemoto N, Furuse J, Okusaka T, et al. A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer. Jpn J Clin Oncol. 2007;37:843–851. doi:10.1093/jjco/hym116
110. Zaidi A, Chandna N, Narasimhan G, et al. Second-line chemotherapy prolongs survival in real world patients with advanced biliary tract and gallbladder cancers: a multicenter retrospective population-based cohort study. Am J Clin Oncol. 2021;44:93–98. doi:10.1097/COC.0000000000000789
111. Ganz PA. Delivering patient-centered care in the setting of advanced cancer: what does a clinical risk-prediction model have to do with It? JAMA Oncol. 2015;1(4):430–432. doi:10.1001/jamaoncol.2015.0832
112. Balogh EP, Ganz PA, Murphy SB, Nass SJ, Ferrell BR, Stovall E. Patient-centered cancer treatment planning: improving the quality of oncology care. Summary of an Institute of Medicine workshop. Oncologist. 2011;16:1800–1805. doi:10.1634/theoncologist.2011-0252
113. Williamson PR, Altman DG, Bagley H, et al. The COMET Handbook: version 1.0. Trials. 2017;18:280. doi:10.1186/s13063-017-1978-4
114. Prinsen CAC, Vohra S, Rose MR, et al. How to select outcome measurement instruments for outcomes included in a “Core Outcome Set” – a practical guideline. Trials. 2016;17:449. doi:10.1186/s13063-016-1555-2
115. Evans CJ, Benalia H, Preston NJ, et al. The selection and use of outcome measures in palliative and end-of-life care research: the MORECare International Consensus Workshop. J Pain Symptom Manage. 2013;46(6):925–937. doi:10.1016/j.jpainsymman.2013.01.010
116. Ramsey I, Eckert M, Hutchinson AD, Marker J, Corsini N. Core outcome sets in cancer and their approaches to identifying and selecting patient-reported outcome measures: a systematic review. J Patient Rep Outcomes. 2020;4:77. doi:10.1186/s41687-020-00244-3
117. Bouça-Machado R, Rosário M, Alarcão J, Correia-Guedes L, Abreu D, Ferreira JJ. Clinical trials in palliative care: a systematic review of their methodological characteristics and of the quality of their reporting. BMC Palliat Care. 2017;16:10. doi:10.1186/s12904-016-0181-9
118. Zambrano SC, Haugen DF, van der Heide A, et al. Development of an international Core Outcome Set (COS) for best care for the dying person: study protocol. BMC Palliat Care. 2020;19:184. doi:10.1186/s12904-020-00654-6
