cancers Systematic Review Systemic Oncological Treatments versus Supportive Care for Patients with Advanced Hepatobiliary Cancers: An Overview of Systematic Reviews Javier Bracchiglione 1,2,3,† , Gerardo Rodríguez-Grijalva 1,† , Carolina Requeijo 1, * , Marilina Santero 1 , Josefina Salazar 1 , Karla Salas-Gama 3,4 , Adriana-Gabriela Meade 1 , Alba Antequera 1 , Ariadna Auladell-Rispau 1 , María Jesús Quintana 1,3,5 , Ivan Solà 1,3,5 , Gerard Urrútia 1,3,5 , Roberto Acosta-Dighero 2 and Xavier Bonfill Cosp 1,3,5 1 Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain 2 Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Viña del Mar 46383, Chile 3 CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain 4 Quality, Process and Innovation Direction, Valld’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain 5 Departament de Pediatria, d’Obstetrícia i Ginecologia, i Medicina Preventiva i Salut Pública, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain * Correspondence: crequeijo@santpau.cat † These authors contributed equally to this work. Simple Summary: Hepatobiliary cancers (that include hepatocellular carcinoma, intrahepatic or ex- trahepatic cholangiocarcinoma and gallbladder cancer) are usually treated with systemic oncological treatments (i.e., chemotherapy, immunotherapy and biological or targeted therapies) mainly due to Citation: Bracchiglione, J.; their improvement in survival. However, the trade-off between these therapies and usual practice Rodríguez-Grijalva, G.; Requeijo, C.; supportive care is not clear, and other outcomes beyond survival should be considered in advanced Santero, M.; Salazar, J.; Salas-Gama, stages, such as quality of life or symptom control. The present study is part of a wider project K.; Meade, A.-G.; Antequera, A.; aiming to conduct broad evidence syntheses assessing the effects of systemic oncological treatments Auladell-Rispau, A.; Quintana, M.J.; versus usual practice supportive care for patients with advanced non-intestinal digestive cancers. We et al. Systemic Oncological performed an overview of systematic reviews assessing the effects of systemic oncological treatments Treatments versus Supportive Care versus usual practice supportive care for patients with primary advanced hepatobiliary cancer. We for Patients with Advanced found evidence that for these patients (specifically for advanced hepatocellular carcinoma), systemic Hepatobiliary Cancers: An Overview oncological treatments tend to improve survival at the expense of greater toxicity. Much of systematic of Systematic Reviews. Cancers 2023, reviews included was of low quality and highly overlapped. Nevertheless, the evidence we found 15, 766. https://doi.org/10.3390/ failed to report other important outcomes that could be critical for decision making, including quality cancers15030766 of life or symptom control. Future research assessing these patient-important outcomes is needed. Academic Editors: Anurag K. Singh, Evan Michael Graboyes and Marco Abstract: Background: The trade-off between systemic oncological treatments (SOTs) and UPSC in Cesare Maltoni patients with primary advanced hepatobiliary cancers (HBCs) is not clear in terms of patient-centred Received: 25 November 2022 outcomes beyond survival. This overview aims to assess the effectiveness of SOTs (chemotherapy, Revised: 14 January 2023 immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs. Methods: We Accepted: 18 January 2023 searched for systematic reviews (SRs) in PubMed, EMBASE, the Cochrane Library, Epistemonikos Published: 26 January 2023 and PROSPERO. Two authors assessed eligibility independently and performed data extraction. We estimated the quality of SRs and the overlap of primary studies, performed de novo meta-analyses and assessed the certainty of evidence for each outcome. Results: We included 18 SRs, most of which were of low quality and highly overlapped. For advanced hepatocellular carcinoma, SOTs showed Copyright: © 2023 by the authors. better overall survival (HR = 0.62, 95% CI 0.55–0.77, high certainty for first-line therapy; HR = 0.85, Licensee MDPI, Basel, Switzerland. 95% CI 0.79–0.92, moderate certainty for second-line therapy) with higher toxicity (RR = 1.18, 95% This article is an open access article distributed under the terms and CI 0.87–1.60, very low certainty for first-line therapy; RR = 1.58, 95% CI 1.28–1.96, low certainty conditions of the Creative Commons for second-line therapy). Survival was also better for SOTs in advanced gallbladder cancer. No Attribution (CC BY) license (https:// outcomes beyond survival and toxicity could be meta-analysed. Conclusion: SOTs in advanced HBCs creativecommons.org/licenses/by/ tend to improve survival at the expense of greater toxicity. Future research should inform other 4.0/). patient-important outcomes to guide clinical decision making. Cancers 2023, 15, 766. https://doi.org/10.3390/cancers15030766 https://www.mdpi.com/journal/cancers Cancers 2023, 15, 766 2 of 21 Keywords: liver neoplasms; biliary tract neoplasms; antineoplastic agents; molecular-targeted therapy; biological therapy; immunotherapy; review literature as topic 1. Introduction Primary hepatobiliary cancers (HBCs) are a group of neoplasms related to the liver, bile ducts or gallbladder, and include hepatocellular carcinoma (HCC), intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer [1]. Hepatitis B virus, hepatitis C virus, alcohol abuse, non-alcoholic steatohepatitis and cirrhosis are known risk factors for these neoplasms with high variability among countries [2–5]. Currently, primary liver cancers (i.e., HCC and intrahepatic cholangiocarcinoma) are the sixth most commonly diagnosed cancers worldwide and were the third leading cause of cancer death in 2020, with an age-standardised incidence of 9.5 per 100,000 and a mortality of 8.7 per 100,000 [6,7], while gallbladder cancer has an age-standardised incidence and mortality of 1.2 and 0.8 per 100,000, respectively [6,7]. Based on current trends, it is estimated that liver cancers will have an overall increase of 58.6% in incidence and 60.9% in mortality worldwide by 2040, while gallbladder cancer will increase its incidence and mortality by 68.5% and 71.4%, respectively, in the same period [7]. Approximately 18.0% of liver cancers and 44.0% of gallbladder cancers are diagnosed in a distant stage [8,9]. Patients in these advanced stages have a poor overall prognosis, with a 1-year overall survival of 17.6% for liver cancers and 19.7% for gallbladder cancer and a 3-year overall survival of 5.0% and 3.7%, respectively [8,9]. Systemic oncological treatments (SOTs), such as chemotherapy, immunotherapy and targeted/biological therapies, constitute the widely used therapeutic approaches for pa- tients with primary HBCs in advanced stages [10–13]. However, the reported recommenda- tions are mainly based on survival-related outcomes and do not always consider (at least explicitly) all critical patient-centred outcomes, such as quality of life (QoL) or quality of end-of-life (EoL) care [14]. The EoL period has been conceptualised from a disease-centred perspective (‘a period of irreversible decline before death’) or from a time-based perspective (‘six months or less of life expectancy’) [15], but several authors have shifted these perspec- tives toward a person-centred one, considering the patients’ and their family’s perspectives when making decisions about treatments and overall care [16–19]. Considering this, the use of SOTs during the EoL period, among others, have been considered indicators of aggressive treatment and low-value medical practice [20–23]. Under this perspective, palliative care, usual practice supportive care (UPSC) or best supportive care (BSC), as defined in randomised controlled trials (RCTs), may be a valid therapeutic option for patients with advanced HBCs, not only as a complementary approach but also as a sole therapeutic alternative. Despite not having a consensual definition [24], UPSC can be broadly considered as all the efforts, treatments and techniques that aim to improve QoL and relieve symptoms [25,26]. It has repeatedly been shown to reduce suffering for patients and their families, and to lower public health costs [27–29]. Although SOTs have been reported to improve survival-related outcomes in patients with HBCs, whether this improvement is significant or clinically relevant in the EoL period, compared to UPSC, remains unclear. On the other hand, patients with advanced HBCs could benefit more from receiving palliative management aiming to relieve symptoms, increase their QoL and lower toxicity. In fact, every therapeutic decision should balance the increase in length of survival with maintaining a reasonable QoL, without being jeopardised by the burden of the treatment. In this sense, some authors have suggested a possible overuse of potentially inappropriate cancer care at the EoL, proposing quality indicators to provide healthcare policymakers with information to improve EoL care on a population level [30]. A broad evidence synthesis comparing the effects of SOTs and UPSC on survival- related outcomes, symptom-related outcomes, functional outcomes, toxicity, QoL and Cancers 2023, 15, 766 3 of 21 quality of EoL care could improve shared-decision-making processes between patients and practitioners in clinical practice. This study aims to identify, evaluate and summarise the evidence of all relevant systematic reviews (SRs) examining the benefits and harms of SOTs (chemotherapy, immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs. 2. Materials and Methods The present study is part of a wider project aiming to conduct broad evidence synthe- ses assessing the effects of SOTs versus UPSC for patients with advanced non-intestinal digestive cancers [31–33]. This overview specifically addresses patients with advanced HBCs. We prospectively registered the protocol for this overview [31], adhering to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines [34]. The final version adheres to the Cochrane and the Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines [35,36]. 2.1. Criteria for Considering Reviews for Inclusion We used the PICOS framework (patients, intervention, comparison, outcomes, study type) to guide our eligibility criteria [37]. 2.1.1. Types of Studies We included SRs assessing the clinical impact of SOTs on advanced HBCs, published from 2008 onwards (because one of the first landmark studies for our question was pub- lished this year). We considered an SR to be any type of secondary research published as full text that stated the following: (i) 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) an explicit approach to data analyses and synthesis. We considered eligible SRs conducting pairwise comparisons or network meta-analysis, including RCTs or observational studies. We excluded randomised clinical trials, quasi-experimental studies, observational studies, and descriptive studies. We also excluded clinical practice guidelines and reviews with no systematic methods according to our definition, such as narrative reviews. 2.1.2. Types of Patients We included SRs that considered adults (over 18 years of age) with any primary HBC, classified as advanced or metastatic by the authors of the study (stage IIIb, IIIc and IV for liver cancer, and IIIb and IV for bile duct cancer) at the time of receiving the treatment being evaluated. We excluded participants with lymphatic or stromal cancer, as well as hepatobiliary metastases from other locations. 2.1.3. Types of Interventions and Comparators As interventions, we considered any chemotherapy, immunotherapy or targeted/biological therapy, either given as monotherapy or in combination with other SOTs. We also allowed for inclusion interventions involving chemotherapy or other systemic treatments with concomitant palliative radiotherapy or prior surgery. We excluded reviews considering exclusively primary studies with only surgery or radiotherapy as an experimental interven- tion, or adjuvant or neoadjuvant chemotherapy therapies in the experimental arm. We considered comparators to be any type of support treatment administered for symptomatic or palliative control, comprehending either usual treatment, UPSC or BSC [38]. Studies that did not specifically define the intervention of the control group were also included. Reviews that exclusively considered primary studies including some type of chemotherapy, biological/targeted therapy or immunotherapy in the control group were excluded. We also excluded comparisons with surgical or radiotherapeutic treatments Cancers 2023, 15, 766 4 of 21 with non-palliative intent. For reporting purposes, we generically referred to this group as ‘placebo/UPSC’. 2.1.4. Type of Outcomes As primary outcomes, we considered overall survival (OS) (measured as a dichoto- mous, continuous or time-to-event outcome), functional status (FS) (measured with Karnof- sky or Eastern Cooperative Oncology Group [ECOG] scale) [39], quality of life (measured with any validated scale) and toxicity (measured as overall adverse events grade 3 or higher) [40]. Our secondary outcomes included progression-free survival (PFS), symptoms related to the disease (measured with any validated scale assessing one or more symptoms), admission to hospital or long-term centre or emergency consultations and quality of EoL care, defined as a composite outcome, including admission to the hospital at the EoL (in the last 30 days of life) and palliative care provided during the last year of life and place of death. 2.1.5. Search Methods and Selection of Studies We performed a first search strategy from inception until December 2019 in the fol- lowing databases: Cochrane Database of Systematic Reviews; MEDLINE/PubMed; EM- BASE/OVID; Epistemonikos; and PROSPERO. We did not use any language or publication status restrictions. Because this overview is part of a wider project, this initial search strategy included other types of non-intestinal digestive cancers [31]. Table S1 provides the detailed search strategy for MEDLINE/PubMed, which was adapted to the other databases. For the purposes of this overview, we updated the electronic search to August 2022, using a similar search strategy but considering only terms related to HBCs. Table S2 provides the detailed search strategy for this update. We also asked experts in the field for potentially relevant studies. Two previously trained review authors (among JB, GRG, CR, MS, JS, KSG, AGM, AA, AAR, RAD, MJQ) performed an independent title and abstract screening of the results obtained from the search. A third review author (among JB, GRG, CR, MJQ) solved any disagreement. Afterwards, two review authors (among JB, GRG, CR, MS, JS, KSG, AGM, AA, AAR, RAD) conducted the full-text screening, with a third author (among JB, GRG, CR, MJQ) solving any disagreement. We used Covidence for the screening process www.covidence.org. 2.2. Data Extraction and Analysis One review author (among JB, GRG, CR, MS, JS, KSG, AGM, AA, AAR, RAD) extracted data from the included SRs, using a previously piloted data extraction sheet. A second reviewer (among JB, GRG, CR, MS, JS, KSG, AGM, AA, AAR, RAD) cross-checked this process. We extracted both synthesised findings and disaggregated data for each included primary study concerning the outcomes of interest, as reported by the respective SR. We extracted data directly from the primary studies only if the SR did not clearly provide it. One author (among JB, GRG) assessed the risk of bias (RoB) for each included SR using the AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) tool [41]. A second author (among JB and GRG) cross-checked this assessment. We also described the RoB assessment of the primary studies made by the authors of each SR. We prioritised the reporting of assessments made using Cochrane RoB tools version 1. If two or more reviews conducted a contradictory assessment of the same primary study, we stated this was an unclear assessment. We built a matrix of evidence for each type of included cancer to assess the possible overlap of primary studies within SRs. In this matrix, the columns represented all the included SRs, and the rows represented the primary studies included in each SR. We considered only the primary studies that provided useful data for our questions. Then, we calculated the overall corrected covered area (CCA), considering a CCA below 5% as slight overlap, >5% and <10% as moderate overlap, >10% and <15% as high overlap and Cancers 2023, 15, 766 5 of 21 >15% as very high overlap [42]. We also described a pairwise overlap assessment, that is, among each possible pair of SRs, considering the same thresholds and using the Graphical Representation of Overlap for OVErviews (GROOVE) tool, as described elsewhere [43]. We described the general characteristics and synthesised results of the included SRs. We also extracted the disaggregated data from each primary study, as reported by each SR. To avoid overestimating the effects by double counting the same study, if the same primary study was included in more than one review, we extracted the data only once. For each comparison, we performed a de novo meta-analysis based on the data of each primary study extracted from the SRs. We analysed dichotomous outcomes with risk ratio (RR), continuous outcomes with the mean difference or standardised mean difference and time-to-event outcomes with hazard ratios (HR). All of these had a 95% confidence interval (CI). Where available, we descriptively presented the results from the network meta-analysis to contrast the findings from pairwise comparisons. We assessed the heterogeneity of the included studies with I2 . We considered an 2 I < 50% as low heterogeneity, >50% and <90% as high and >90% as very high [44]. If heterogeneity was below 90%, we performed a meta-analysis using a random-effects model. If heterogeneity was very high, we only described the results without performing a meta- analysis. We conducted all the analyses according to cancer localisation (liver versus bile duct) with a subgroup analysis according to the line of therapy (first versus second or more) in order to try to explain possible heterogeneity. We assessed the presence of possible publication bias by a visual inspection of a funnel plot for the primary outcomes if there were 10 or more included studies providing data for that specific comparison [45]. We assessed the certainty of the evidence according to GRADE guidance [46,47] for the following outcomes: (i) OS; (ii) symptoms related to the disease; (iii) FS; and (iv) QoL. We classified the certainty of the evidence for each outcome as high, moderate, low or very low. We explicitly stated if a specific outcome had no included studies. In that case, we did not assess the certainty of evidence. We also reported the main findings of the summary of findings (SoF) table in plain language, according to their specific assessment of the certainty of evidence. 3. Results Our initial search strategy yielded a total of 2584 references. After removing duplicates, two reviewers assessed 2099 references by title and abstract, excluding 1894 references. Subsequently, two authors assessed 205 articles by full text, excluding 187 references, and finally including 18 SRs [48–65]. Table S3 provides the list of the excluded studies after full-text assessment, with their reasons. Figure 1 provides the PRISMA flow diagram summarising the screening process. 3.1. Description of Included Reviews The included SRs were published between 2011 and 2022. Most of the SRs were conducted by research groups based in China [50–53,56,58,59], Canada [48,54,55,65] and the USA [49,61,62,64]. Among the included SRs, 11 (61.1%) performed pairwise meta- analyses [48–50,52,55,57,61,63,65] and seven (38.9%) conducted a network meta- analysis [51,56,58,59,62,64]. Table 1 provides an overall description of the included SRs. All the included SRs assessed only RCTs. Most studied patients with advanced HCC [49–57,59–65]. The most studied SOTs were biological/targeted therapies, especially sorafenib. The SRs considered SOTs mainly as a first- or second- line therapy. The authors did not provide an explicit definition for comparators, which included ‘placebo’, ‘UPSC’, ‘BSC’, ‘negative controls’ and ‘standard care’. Two SRs studied patients with advanced gallbladder cancer [48,58], but they included only one unique primary study assessing the effects of chemotherapy versus UPSC. None of the SRs assessed SOTs in patients with advanced cholangiocarcinoma. Cancers 2023, 15, x FOR PEER REVIEW 6 of 22 Cancers 2023, 15, 766 6 of 21 Figure 1. PRISMA flow diagram for the selection of studies. Figure 1. PRISMA flow diagram for the selection of studies. 3.2. Methodological Quality of the Included Reviews 3.1. Description of Included Reviews In most cases, overall quality was classified as critically low [49,52–55,58–60,63–65] or Thelow included SRs weremainly [51,56,57,61,62], published due tobetween a lack of2011 protocoland registration 2022. Mostand of the not SRs were a list of reporting conducted by research the excluded groups studies. based Table in Chinaa [50–53,56,58,59], 2 provides detailed assessment Canada [48,54,55,65] of each and using included review the USA the[49,61,62,64]. AMSTAR-2 tool. Among FiguretheS1included providesSRs, 11 description a brief (61.1%) performed pairwise of each unique me- study primary ta-analyses [48–50,52,55,57,61,63,65] and seven (38.9%) conducted included within the reviews and the RoB assessment, as estimated by the SR authors. a network me- ta-analysis [51,56,58,59,62,64]. 3.3. 1Overlap Table providesAnalysis an overall description of the included SRs. All the included SRs assessed only TheRCTs. Most SRs included studied patients witha advanced comprehended total of 22HCC unique[49–57,59–65]. Theto trials relevant most our scope. studiedFigure SOTs 2were biological/targeted presents an evidence matrix therapies, showing especially sorafenib. all the included The the SRs and SRsrelevant consid-primary ered SOTs mainly studies as aoverview. for our first- or second- line included The SR that therapy. The mostauthors did not studies of the primary providerelevant an ex- for our plicit definition scope was forthat comparators, conducted which includedet‘placebo’, by Solimando ‘UPSC’, al. [60], while ‘BSC’, a total ‘negative of nine con- only SRs included trols’ and ‘standard care’. Two SRs studied patients with advanced gallbladder one [48,57,58,63] or two [49,52,53,56,65] primary studies relevant to our PICO question. cancer [48,58], All butrelevant they included primary only one unique studies primary study were published between assessing 2008 andthe2020. effectsFigure of chem- 3 provides otherapy theversus UPSC. pairwise None of the assessment SRs assessed of overlap amongSOTs SRs in patients using with advanced the GROOVE chol-Overall tool [44]. angiocarcinoma. overlap was very high for the whole matrix (CCA 22.2%, and 29.5% when adjusting by chronological structural missingness) [43,44]. The pairwise analysis of overlap revealed 3.2. Methodological a total of 66Quality nodes of the slight with Included Reviews10 nodes with moderate overlap, five nodes with overlap, high overlap and 72 nodes with In most cases, overall quality was classifiedvery high overlap (including as critically 11 pairs of reviews with 100% low [49,52–55,58–60,63–65] overlap). The SRs or low [51,56,57,61,62], by Abdel-Rahman mainly due to a lack of et protocol al. and Jiang et al. were registration and the not only ones to reporting a assess list of the excluded studies. Table 2 provides a detailed assessment of each included re-between gallbladder cancer [48,58]; therefore, it was expected that no overlap would occur thesethe view using reviews and thetool. AMSTAR-2 rest. Figure S1 provides a brief description of each unique primary study included within the reviews and the RoB assessment, as estimated by the SR authors. Cancers 2023, 15, 766 7 of 21 Table 1. Description of the included SRs. Relevant Included Type of Primary Type of Line of Outcomes CoI of the Databases Search Study ID Country Type of SOT Comparator Meta- Funding Studies 1 /Total Patients 1 Treatment Assessed Review Searched Timeframe Analysis Included Studies MEDLINE, Until Ling-lin 2011 Advanced EMBASE, China 2/4 BIO/TT (Sorafenib) First Placebo OS Pairwise NS NS November [53] HCC Cochrane, 2019 other Zhang 2012 Advanced MEDLINE, January 2005 China 2/6 BIO/TT (Sorafenib) First Placebo OS, toxicity Pairwise Public No CoI [52] HCC EMBASE, WoS to June 2011 MEDLINE, Faruque Advanced Public and Until April Canada 2/72 BIO/TT (Sorafenib) First NS OS, toxicity Pairwise With CoI EMBASE, 2014 [65] HCC private 2012 Cochrane MEDLINE, Finn 2017 Advanced EMBASE, Until February USA 2/14 BIO/TT (Sorafenib) First Placebo OS Pairwise Private With CoI [49] HCC CENTRAL, 2016 Scopus MEDLINE, EMBASE, Abdel-Rahman Advanced CT (Fluorouracil/folinic OS, PFS, CENTRAL, 2018 Canada 1/7 gallbladder acid, or gemc- NS BSC Pairwise No funding No CoI Until June 2017 toxicity WoS, LILACS, [48] cancer itabine/oxaliplatin) clinicaltri- als.gov BIO/TT and IT (Sorafenib, vandetanib, Negative MEDLINE, Guo 2019 Advanced brivanib, tivantinib, control OS, PFS, Until March China 12/31 First, second Network NS No CoI EMBASE, [51] HCC ramucirumab, axitinib, (placebo or no toxicity 2019 CENTRAL codrituzumab, treatment) cabozatinib) MEDLINE, EMBASE, Huang 2019 Advanced Until April China 5/11 BIO/TT (Sorafenib) First, second Placebo/BSC OS, toxicity Pairwise NS No CoI CENTRAL, [50] HCC 2018 WoS, clinicaltri- als.gov BIO/TT and IT (Sorafenib, MEDLINE, Sonbol 2020 Advanced pembrolizumab, EMBASE, Until March USA 8/14 First, second Placebo OS, PFS Network NS With CoI [64] HCC regorafenib, CENTRAL, 2020 cabozantinib, WoS, Scopus ramucirumab, brivanib) MEDLINE, Until Ziogas 2021 Advanced OS, PFS, Greece 1/63 IT (Pembrolizumab) Second Placebo Pairwise NS With CoI Cochrane, clin- November [63] HCC toxicity icaltrials.gov 2020 BIO/TT and IT (Sorafenib, regorafenib, cabozitinib, MEDLINE, Park 2021 Advanced USA 13/24 ramucirumab, apatinib, First, second Placebo OS, PFS Network No funding With CoI EMBASE, Until June 2020 [62] HCC pembrolizumab, Cochrane brivanib, tivantinib, everolimus, axitinib) Cancers 2023, 15, 766 8 of 21 Table 1. Cont. Relevant Included Type of Primary Type of Line of Outcomes CoI of the Databases Search Study ID Country Type of SOT Comparator Meta- Funding Studies 1 /Total Patients 1 Treatment Assessed Review Searched Timeframe Analysis Included Studies BIO/TT (Regorafenib, MEDLINE, Chen 2021 Advanced OS, PFS, Until April China 4/4 cabozantinib, Second Placebo Network No funding No CoI EMBASE, [59] HCC toxicity 2019 ramucirumab) Cochrane BIO/TT and IT (Regorafenib, cabozantinib, brivanib, OS, PFS, MEDLINE, January 2000 Meyers 2021 Advanced Second or Canada 12/49 tivantinib, Placebo/BSC toxicity, QoL, Pairwise No funding With CoI EMBASE, to January [54] HCC more pembrolizumab, symptoms Cochrane 2020 everolimus, ADI-peg 20, S-1, RO5137382/GC33) BIO/TT and IT (Sorafenib, tivantinib, S-1, regorafenib, Haber 2021 Advanced MEDLINE, June 2002 to USA 13/49 ramucirumab, First, second Placebo OS, PFS Pairwise Public With CoI [61] HCC Cochrane, WoS December 2020 ADI-PEG20, everolimus, cabozantinib, brivanib, pembrolizumab) Advanced MEDLINE, Jiang 2021 CT (FUFA, or gemc- OS, PFS, Until August China 1/24 gallbladder NS BSC Network Public NS EMBASE, [58] itabine/oxaliplatin) toxicity 2020 cancer Cochrane MEDLINE, Jácome 2021 Advanced OS, PFS, Until February Brazil 1/3 IT (Pembrolizumab) Second Standard care Pairwise NS With CoI CENTRAL, [57] HCC toxicity 2020 WoS, LILACS MEDLINE, EMBASE, Liu 2021 Advanced OS, PFS, CENTRAL, Until August China 2/15 BIO/TT (Sorafenib) First Placebo Network Public No CoI [56] HCC toxicity Cochrane, 2021 WoS, Scopus, other BIO/TT and IT (Tivantinib, S-1, regorafenib, MEDLINE, Solimando Advanced ramucirumab, WoS, Scopus, Until 2022 Italy 14/14 Second Placebo OS, PFS Network Public No CoI HCC ADI-PEG20, everolimus, clinicaltri- December 2020 [60] cabozantinib, brivanib, als.gov pembrolizumab, axitinib, codrituzumab) BIO/TT and IT (Sorafenib, tivantinib, regorafenib, MEDLINE, January 1990 Griffiths 2022 Advanced ramucirumab, First, second or Canada 13/30 Placebo Toxicity Pairwise NS With CoI EMBASE, to December [55] HCC everolimus, more CENTRAL 2021 cabozantinib, brivanib, pembrolizumab, axitinib) 1We considered only relevant primary studies, defined as those that provided data for any comparison and outcome considered by this overview. BIO/TT: biological/targeted therapies; CoI: conflict of interest; CT: chemotherapy; IT: immunotherapy; NS: not specified; OS: overall survival; PFS: progression-free survival; QoL: quality of life; WoS: Web of Science 3.2. Methodological quality of the included reviews. Cancers 2023, 15, 766 9 of 21 Table 2. Quality assessment of the included reviews according to AMSTAR-2. Overall Quality of Study ID Q1 Q2 1 Q3 Q4 1 Q5 Q6 Q7 1 Q8 Q9 1 Q10 Q11 1 Q12 Q13 1 Q14 Q15 1 Q16 the Review Ling-lin 2011 Y N Y PY Y Y N PY Y N Y N N N N N Critically low [53] Zhang 2012 Y N Y PY Y N N Y Y N Y N N Y Y Y Critically low [52] Faruque N N Y PY Y Y N Y Y Y Y Y Y Y Y Y Critically low 2014 [65] Finn 2017 Y PY N Y Y N N Y Y N Y N N Y Y Y Critically low [49] Abdel- Rahman 2018 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N High [48] Guo 2019 Y Y Y Y Y Y N Y Y N NA Y Y Y Y Y Low [51] Huang 2019 Y PY N Y Y Y Y Y Y N Y Y Y Y Y N Moderate [50] Sonbol 2020 Y N N PY N Y N PY Y N Y Y Y Y N Y Critically low [64] Ziogas 2021 Y N N Y Y Y N PY N N NA NA N Y NA Y Critically low [63] Park 2021 Y Y Y PY PY N N PY Y N Y Y Y N Y Y Low [62] Chen 2021 Y N Y PY N Y N PY Y N Y Y Y Y Y Y Critically low [59] Meyers 2021 Y N Y PY N N N PY Y N NA NA N N NA Y Critically low [54] Haber 2021 Y N Y PY Y Y Y PY PY N NA NA Y Y NA Y Low [61] Jiang 2021 Y N Y PY N Y N Y Y N NA NA Y Y NA Y Critically low [58] Jácome 2021 Y PY Y PY Y Y N N Y N NA NA Y Y NA N Low [57] Liu 2021 Y PY Y PY Y Y N PY Y N Y Y Y Y Y Y Low [56] Cancers 2023, 15, 766 10 of 21 Table 2. Cont. Overall Quality of Study ID Q1 Q2 1 Q3 Q4 1 Q5 Q6 Q7 1 Q8 Q9 1 Q10 Q11 1 Q12 Q13 1 Q14 Q15 1 Q16 the Review Solimando 2022 Y N Y PY N Y N PY Y N Y Y Y Y Y N Critically low [60] Griffiths 2022 Y N Y Y Y Y N PY Y N Y Y Y N N Y Critically low [55] 1 Considered critical for AMSTAR-2 assessment; N: No; NA: Not applicable*; PY: Partial Yes; Y: Yes; Q1: Did the research questions and inclusion criteria for the review include the components of PICO? Q2: 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? Q3: Did the review authors explain their selection of the study designs for inclusion in the review? Q4: Did the review authors use a comprehensive literature search strategy? Q5: Did the review authors perform study selection in duplicate? Q6: Did the review authors perform data extraction in duplicate? Q7: Did the review authors provide a list of excluded studies and justify the exclusions? Q8: Did the review authors describe the included studies in adequate detail? Q9: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? Q10: Did the review authors report on the sources of funding for the studies included in the review? Q11: If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? Q12: 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? Q13: Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? Q14: Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? Q15: 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? Q16: Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? * We assessed some of the answers related to meta-analysis as NA if the review had no meta-analysis, had only one included study relevant for our question or if the conducted meta-analyses were not related to the scope of this overview. justing by chronological structural missingness) [43,44]. The pairwise analysis of overlap revealed a total of 66 nodes with slight overlap, 10 nodes with moderate overlap, five nodes with high overlap and 72 nodes with very high overlap (including 11 pairs of re- views with 100% overlap). The SRs by Abdel-Rahman et al. and Jiang et al. were the only Cancers 2023, 15, 766 ones to assess gallbladder cancer [48,58]; therefore, it was expected that no overlap would 11 of 21 occur between these reviews and the rest Figure 2. Figure 2. Matrix Matrixofofevidence. evidence.AllAllthe theincluded included SRs SRs areare listed listed in the in the columns. columns. All relevant All the the relevant pri- primary mary studies studies (i.e., reporting (i.e., those those reporting at leastatone least one outcome outcome of interest of interest for thefor the studied studied interventions) interventions) are are listed listed in the in the ‘1’ rows. rows. ‘1’ represents represents a a primary primary study study included included in a in a specific specific SR. SR. ‘X’ ‘X’ represents represents chrono- chronological Cancers 2023, 15, x FOR PEER REVIEW logical structural missingness, that is, a primary study that cannot possibly be included 12 in aofSR, 22 structural missingness, that is, a primary study that cannot possibly be included in a SR, given that given that its publication date was more recent than the search date of the SR. its publication date was more recent than the search date of the SR. Figure 3. ‘Graphical representation of overlap’ (GROOVE) assessment for each possible pair of of SRs. SRs. of CCA, For purposes of pairwise analysis of CCA, we we did did not not consider consider structural structural missingness. missingness. 3.4. Effects of 3.4. Effects of Interventions Interventions The The included included SRs SRsprovided provideddata dataforfor thethe following three following comparisons: three SOTsSOTs comparisons: as first- as line first-line therapy versus placebo/UPSC in advanced HCC; SOTs as second-line therapy or therapy versus placebo/UPSC in advanced HCC; SOTs as second-line therapy or more more versus versus placebo/BSC placebo/BSC inin advanced advanced HCC; HCC; and and chemotherapy chemotherapy versus versus placebo/UPSC placebo/UPSC in in advanced gallbladder cancer. Figure S2 provides the SoF tables for the outcomes of in- terest within each comparison. 3.4.1. Advanced Hepatocellular Carcinoma SOTs as First-Line Therapy versus Placebo/UPSC Figure 3. ‘Graphical representation of overlap’ (GROOVE) assessment for each possible pair of SRs. For purposes of pairwise analysis of CCA, we did not consider structural missingness. 3.4. Effects of Interventions The included SRs provided data for the following three comparisons: SOTs as Cancers 2023, 15, 766 12 of 21 first-line therapy versus placebo/UPSC in advanced HCC; SOTs as second-line therapy or more versus placebo/BSC in advanced HCC; and chemotherapy versus placebo/UPSC in advanced gallbladder cancer. Figure S2 provides the SoF tables for the outcomes of in- advanced terest gallbladder within cancer. Figure S2 provides the SoF tables for the outcomes of interest each comparison. within each comparison. 3.4.1. Advanced Hepatocellular Carcinoma 3.4.1. Advanced Hepatocellular Carcinoma SOTs as First-Line Therapy versus Placebo/UPSC SOTs as First-Line Therapy versus Placebo/UPSC Eleven SRs [49–53,55,56,61,62,64,65], including four unique RCTs [66–69], assessed Eleven SRs [49–53,55,56,61,62,64,65], including four unique RCTs [66–69], assessed the effects of SOTs as first-line therapy versus placebo/UPSC. These trials assessed only the effects of SOTs as first-line therapy versus placebo/UPSC. These trials assessed only biological/targeted therapies. Three trials included sorafenib as the intervention [66–68], biological/targeted therapies. Three trials included sorafenib as the intervention [66–68], and one trial assessed vandetanib as the intervention [69]. However, no data were and one trial assessed vandetanib as the intervention [69]. However, no data were available available to be meta-analysed from this last study. to be meta-analysed from this last study. The The overall overall pooled effect favoured pooled effect favoured the the use use of of sorafenib sorafenib over over placebo/UPSC placebo/UPSC in in terms terms of of OS (HR = 0.62, 95% CI 0.55 to 0.77, high certainty). Sorafenib showed a higher rate OS (HR = 0.62, 95% CI 0.55 to 0.77, high certainty). Sorafenib showed a higher rate of of adverse adverse events events over placebo/UPSC (RR over placebo/UPSC (RR==1.18, 1.18,95% 95%CI CI0.87 0.87toto 1.60, 1.60, very very low low certainty). certainty). Figure Figure 44 provides provides the the forest plots for forest plots OS and for OS and toxicity toxicity for for this this comparison. comparison. There There was was not not enough enough reported reported data to perform data to perform aa meta-analysis meta-analysis forfor the the other other predefined predefined outcomes. outcomes. Cancers 2023, 15, x FOR PEER REVIEW 13 of 22 (a) (b) Figure 4. Figure 4. Forest Forest plots plots for for the the outcomes outcomes ‘overall ‘overall survival’ survival’ (a) (a) and and ‘toxicity’ ‘toxicity’ (b) (b) for for the the comparison comparison of of SOTs versus placebo/UPSC as first-line therapy in patients with advanced HCC. SOTs versus placebo/UPSC as first-line therapy in patients with advanced HCC. None of None of the the primary primary studies studies included included within within the the SRs SRs directly directly analysed analysed aa SOT SOT other other than sorafenib and vandetanib as a first-line treatment versus placebo/UPSC. than sorafenib and vandetanib as a first-line treatment versus placebo/UPSC. However, However, the results the resultsofofthe theindirect indirectcomparisons comparisons made made in in thethe network network meta-analysis meta-analysis by Guo by Guo et al.et[51] al. [51] revealed revealed that that for for patients patients withoutwithout previous previous systemicsystemic treatment, treatment, lenvatiniblenvatinib and apa- and apatinib had tinibhighest the had the highest probability probability of achieving of the achieving best OSthe andbest PFSOS andyear, at one PFS respectively. at one year, respec- Sonbol tively. et Sonbol al. and Parketetal. al.and Park et that concluded al. concluded that theofcombination the combination atezolizumab of and atezolizumab bevacizumab and bevacizumab was was the the best ranked best ranked treatment for bothtreatment OS [62,64]for and bothPFSOS as[62,64] andtherapy first-line PFS as [64]. first-line Sin- therapy [64]. Sintilimab plus bevacizumab showed the best OS tilimab plus bevacizumab showed the best OS and PFS in the network meta-analysis by and PFS in the network meta-analysis Liu by Liu et al. [56], with theetcombination al. [56], withofthe combination atezolizumab of bevacizumab and atezolizumab ranking and bevacizumab second. ranking second. SOTs as Second-Line Therapy or More versus Placebo/UPSC SOTs as Second-Line Therapy or More versus Placebo/UPSC Eleven SRs [50,51,54,55,57,59–64], including 17 unique RCTs [70–86], assessed the Eleven SRs [50,51,54,55,57,59–64], including 17 unique RCTs [70–86], assessed the effects of SOTs as second-line therapy or more versus placebo/UPSC. SOTs studied by effects of SOTs as second-line therapy or more versus placebo/UPSC. SOTs studied by the the primary studies included targeted/biological therapies (ADI-PEG20, apatinib, axitinib, primary studies included targeted/biological therapies (ADI-PEG20, apatinib, axitinib, brivanib, cabozantinib, everolimus, ramucirumab, regorafenib, sorafenib, tivantinib), im- brivanib, cabozantinib, everolimus, ramucirumab, regorafenib, sorafenib, tivantinib), munotherapy (codrituzumab, pembrolizumab) and chemotherapy (S-1). Figure 5 shows immunotherapy (codrituzumab, pembrolizumab) and chemotherapy (S-1). Figure 5 the pooled effects of SOTs versus placebo/UPSC as second-line therapy or more for the out- shows the pooled effects of SOTs versus placebo/UPSC as second-line therapy or more comes OS, PFS and toxicity, disaggregated by subgroups according to the type of treatment. for the outcomes Overall, SOTs showedOS, PFS and toxicity, a beneficial pooleddisaggregated effect in termsby subgroups of OS (HR = according 0.85, 95%toCIthe type 0.79 to of treatment. Overall, SOTs showed a beneficial pooled effect in terms of OS (HR = 0.85, 95% CI 0.79 to 0.92, moderate certainty) and PFS (HR = 0.67, 95% CI 0.55 to 0.80, low certainty). Toxicity was higher in the SOT group (RR = 1.58, 95% CI 1.28 to 1.96, low cer- tainty). There was not enough reported data to perform a meta-analysis for the other predefined outcomes. One SR [54] narratively reported that QoL was similar for the Cancers 2023, 15, 766 13 of 21 0.92, moderate certainty) and PFS (HR = 0.67, 95% CI 0.55 to 0.80, low certainty). Toxicity was higher in the SOT group (RR = 1.58, 95% CI 1.28 to 1.96, low certainty). There was not enough reported data to perform a meta-analysis for the other predefined outcomes. One SR [54] narratively reported that QoL was similar for the comparison of regorafenib Cancers 2023, 15, x FOR PEER REVIEW 14 of 22 versus placebo/UPSC, and that the symptoms or participant functioning was similar when comparing ramucirumab versus placebo/UPSC. (a) (b) (C) Figure Figure5.5.Forest Forestplots for for plots the the outcomes ‘overall outcomes survival’ ‘overall (a), ‘progression-free survival’ survival’ survival’ (a), ‘progression-free (b) and (b) and ‘toxicity’ (c) for the comparison of SOTs versus placebo/UPSC as second-line therapy or more in ‘toxicity’ (c) for the comparison of SOTs versus placebo/UPSC as second-line therapy or more in patients with advanced HCC. patients with advanced HCC. Most network meta-analyses concluded that, as second-line therapy or more, regorafenib had the best OS ranking [51,60,64] and cabozantinib had the best PFS ranking Cancers 2023, 15, 766 14 of 21 Cancers 2023, 15, x FOR PEER REVIEW 15 of 22 Most network meta-analyses concluded that, as second-line therapy or more, rego- rafenib had thetreatments as second-line best OS ranking [51,60,64] [60,62,64]. Guo et and al. cabozantinib had the best found that regorafenib PFS also hadranking as the best second-line treatments [60,62,64]. Guo et al. found that regorafenib also PFS ranking [51]. Chen et al. suggests that regorafenib may have better OS in the sub- had the best PFS ranking group of[51]. Chenwith patients et al.low-level suggestsalpha-fetoprotein that regorafenib may (<400have better ng/mL) OS in the subgroup of [59]. patients with low-level alpha-fetoprotein (<400 ng/mL) [59]. 3.4.2. Advanced Gallbladder Cancer 3.4.2. Advanced Gallbladder Cancer SOTs versus Placebo/UPSC for Advanced Gallbladder Cancer SOTs versus Placebo/UPSC for Advanced Gallbladder Cancer Two SRs assessed the effects of chemotherapy versus placebo/UPSC [48,58], both Two SRs assessed the effects of chemotherapy versus placebo/UPSC [48,58], both including the same primary study conducted in patients with advanced gallbladder including the same primary study conducted in patients with advanced gallbladder can- cancer [87]. This study compared two chemotherapy regimens (FUFA and Gemox) ver- cer [87]. This study compared two chemotherapy regimens (FUFA and Gemox) versus sus UPSC in 81 patients, showing no benefits of chemotherapy over UPSC in terms of OS UPSC in 81 patients, showing no benefits of chemotherapy over UPSC in terms of OS at at oneone year year (RR (RR = 0.89,95% = 0.89, 95%CICI0.74 0.74toto1.07, 1.07,very verylow lowcertainty) certainty)[48]. [48]. Figure Figure 66 provides provides the the forest plot for OS at one year. No data were available for other outcomes forest plot for OS at one year. No data were available for other outcomes or other types or other types of SOTs. of SOTs. Figure 6. Forest plot for the outcome ‘overall survival’ for the comparison of chemotherapy versus placebo/UPSC placebo/UPSCin inpatients patientswith withadvanced advanced gallbladder gallbladder cancer. cancer. 4. Discussion 4. Discussion This overview identified, evaluated and summarised the evidence of 18 SRs examining This overview identified, evaluated and summarised the evidence of 18 SRs exam- the benefits and harms of SOTs versus UPSC in patients with advanced HBCs. Most of ining the benefits and harms of SOTs versus UPSC in patients with advanced HBCs. Most the SRs included patients with advanced HCC, were highly overlapped and had a low of the SRs included patients with advanced HCC, were highly overlapped and had a low or critically low quality as assessed by the AMSTAR-2 tool. Our overview provided or critically low quality as assessed by the AMSTAR-2 tool. Our overview provided key key findings for three main comparisons: (i) in patients with advanced HCC, sorafenib findings for three main comparisons: (i) in patients with advanced HCC, sorafenib im- improves OS as first-line therapy compared to placebo/UPSC, but its effects on toxicity proves OS as first-line therapy compared to placebo/UPSC, but its effects on toxicity are are still unclear; (ii) in patients with advanced HCC, compared to placebo/UPSC, SOT still unclear; (ii) in patients with advanced HCC, compared to placebo/UPSC, SOT as a as a second-line therapy or more probably improves OS and may improve PFS, but with second-line therapy a higher toxicity; andor (iii) more in probably patients with improves OS and advanced may improve gallbladder cancer,PFS, but withto compared a higher toxicity; and placebo/UPSC, (iii) in patients it is uncertain with advanced if chemotherapy gallbladder improves OS. cancer, compared to pla- cebo/UPSC, it is uncertain if chemotherapy improves OS. In our analysis, SOTs showed favourable effects in terms of survival compared with UPSC Ininour analysis, patients with SOTs showed advanced favourable HCC. effects As first-line in terms therapy, of survival three compared RCTs provided with data on UPSC in patients with advanced HCC. As first-line therapy, three sorafenib versus placebo/UPSC, all showing better OS for the active treatment. Assuming RCTs provided data on sorafenib a basal risk versus of death placebo/UPSC, of 843 per 1000 all showing patients better at oneOS fortreatment year, the activewith treatment. sorafenibAssuming would areduce basal risk this of to death 683 per of 1000. 843 per 1000 patients Because sorafenibat one wasyear, treatment considered thewith sorafenib standard would of care for reduce this to 683 per 1000. Because sorafenib was considered these patients, no research analysed other SOTs head-to-head against placebo/UPSC; the standard of care for these patients, therefore, all the noevidence research for analysed other SOTscomes this comparison head-to-head against from indirect placebo/UPSC; comparisons. As therefore, all the evidence for this comparison comes a second-line therapy or more, cabozantinib, ramucirumab and regorafenib showedfrom indirect comparisons. As aa second-line therapy or benefit statistically significant more, cabozantinib, in OS compared ramucirumab and regorafenib to placebo/UPSC. All othershowed a sta- comparisons tistically were significant benefit non-significant, in OS compared with a tendency to favour SOT,to placebo/UPSC. All other except for ADI-PEG20 andcomparisons everolimus. were Thesenon-significant, with a tendency findings were consistent to favour with those obtainedSOT,byexcept for comparison indirect ADI-PEG20 in and evero- network limus. These findings meta-analyses, were consistent which showed with those that regorafenib obtained by may and cabozantinib indirect be thecomparison best options in network meta-analyses, which showed that regorafenib and cabozantinib in this context. Certainty of evidence for adverse events within all comparisons was low may be the best options in this or very low, butcontext. Certainty SOTs showed of evidence a tendency for adverse to have an overall events within higher all comparisons toxicity than UPSC. was low orsome However, very low,studiesbutreported SOTs showed adverse a tendency events onlyto have for antheoverall higher toxicity experimental arm, whichthan UPSC. limited However, the analysis some studies of these reported adverse events only for the experimental arm, results. which limitedour Overall, thefindings analysisalign of these with results. the recommendations made by the European Society Overall,Oncology for Medical our findings align and (ESMO) withthetheAmerican recommendations Society ofmade by the Clinical European Oncology Soci- (ASCO) ety for Medical Oncology (ESMO) and the American Society of Clinical Oncology (AS- Cancers 2023, 15, 766 15 of 21 guidelines [10,13] for patients with advanced HCC. ESMO recommends, for Barcelona Clinic Liver Cancer (BCLC) C patients, sorafenib as the standard of care as first-line therapy and regorafenib for those who have tolerated sorafenib but progressed, as well as UPSC for BCLC D patients. ASCO recommends atezolizumab-bevacizumab as first-line therapy (or sorafenib or lenvatinib in case of contraindications), and sorafenib, lenvatinib, cabozantinib, regorafenib or ramucirumab as second-line therapy. However, these recommendations do not include other patient-important outcomes, which is consistent with the identified gaps within the SRs. Only one of the included SRs explicitly stated quality of life and symptoms as outcomes, and none of the SRs assessed FS, hospital admissions or quality of EoL care as outcomes. This reporting of findings—centred around survival and toxicity—is consistent with classical recommendations made by expert panels about what endpoints to measure in clinical trials of HCC [88]. In this scenario where the risk–benefit balance is narrow, it is truly important to consider shared-decision-making processes and the values and preferences of patients. More recently, the inclusion of QoL and patient-reported outcomes has been recognised as an unmet need in clinical trials designed specifically for HCC [89], and core outcome sets for cancer, in general, have incorporated several outcomes beyond survival and toxicity, such as symptoms, QoL, overall health status, quality of care and economic outcomes [90,91]. A recent ESMO guideline also recommends monitoring patient- reported outcome measures for patients with cancer in an end-of-life context, focusing on symptom control and functional impairment [92]. Therefore, it is expected that future, high-quality RCTs and SRs will incorporate these outcomes [93,94] to ultimately enhance shared-decision-making processes. Strengths and Limitations Overviews are inherently prone to miss recent primary studies not yet included in SRs. However, we consider that it is likely that we incorporated all bodies of evidence regarding HCC because, with the search update, we found recently published SRs. On the other hand, we found only two SRs for biliary duct cancers and none for cholangiocarcinoma, so it is possible we may have omitted relevant primary studies for these patients, or that there are no other primary studies conducted for this comparison; therefore, our results regarding this population should be interpreted carefully. The screening and data extraction processes were performed by two reviewers, but these stages may have been conducted by different pairs of reviewers. Because we conducted regular meetings throughout the conduction of this overview to standardise the criteria, and because all the reviewers were experienced, we think this issue should not have introduced an important bias in the selection of the studies and data extraction. Another limitation of our study was that the efficacy of each line of treatment could not be differentiated when two or more lines were administered. Although we conducted separate analyses by cancer location and type of treatment, some heterogeneity may persist in each intervention arm. There are different SOT schemes within each broad category of active treatments, and control arms include several different (usually poorly described) interventions. Nevertheless, we planned our methods to help clinicians and patients to have a broad overview of the available options, and not to necessarily provide information about specific treatments schemes. Furthermore, our study also has a meta-epidemiological role by identifying evidence gaps, highlighting and justifying the importance of conducting further research in certain areas (such as the generation of a systematic review regarding the effects of the addition of SOTs to UPSC for patients with advanced biliary tract cancer). Otherwise, regarding the strengths in this overview, we thoroughly searched and selected relevant SRs from several databases, conducting a detailed analysis of their overall characteristics, quality and overlap. We also performed de novo meta-analyses for all relevant comparisons (avoiding the overestimation of the results due to double-counting data from primary studies), complementing the results with a description of the find- ings from network meta-analyses, and assessing the certainty of evidence according to GRADE guidelines. Cancers 2023, 15, 766 16 of 21 5. Conclusions Our findings show that in patients with advanced HCC, sorafenib is a valid therapeutic option as first-line therapy and other SOTs (cabozantinib, ramucirumab and regorafenib) as second-line therapy. However, these conclusions are mainly based on survival and toxicity outcomes. Future primary studies should consider and explicitly report other patient-important outcomes (such as QoL, symptom control and quality of EoL care), in order to provide useful data for evidence syntheses and clinical practice guidelines. Future SRs should also consider these outcomes in their protocols, planning to meta-analyse data from primary studies or explicitly report evidence gaps in primary research. Our overview has identified a gap in the evidence for comparisons of SOTs versus UPSC in patients with advanced bile duct cancers, for which conclusions regarding these patients are limited. Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/cancers15030766/s1, Figure S1: General characteristics and risk of bias of relevant primary studies (as reported by SR authors); Figure S2: Summary of Findings tables; Figure S3: Funnel plot for targeted/biological therapies versus placebo/ UPSC as second line therapy for advanced HCC; (a) Outcome: Overall survival, time-to-event; (b) Outcome: Progression free survival time-to-event; Table S1: Initial search strategy for MEDLINE/PubMed; Table S2: Updated search strategy for MEDLINE/PubMed, Table S3: Excluded references after full-text screening, with reasons. Author Contributions: All authors have made substantial contributions to the conception or design of the work or interpretation of data and have approved the submitted version of the article. Con- ceptualization, J.B., G.R.-G., C.R., I.S. and X.B.C.; Methodology, J.B., G.R.-G., C.R., I.S. and X.B.C.; Formal Analysis and Data Curation, J.B., G.R.-G., C.R., M.S., J.S., K.S.-G., A.-G.M., A.A., A.A.-R., M.J.Q. and R.A.-D.; Writing—original draft preparation, J.B., G.R.-G., C.R. and M.S.; Writing—review and editing, J.B., G.R.-G., C.R., M.S., J.S., K.S.-G., A.-G.M., A.A., A.A.-R., M.J.Q., I.S., G.U., R.A.-D. and X.B.C.; Supervision, G.U., M.J.Q. and X.B.C.; Project Administration, J.B. and X.B.C.; Funding Acquisition, X.B.C. All authors have read and agreed to the published version of the manuscript. Funding: This study is funded through a grant from Instituto de Salud Carlos III (PI18/00034), co-financed by funds from the European Regional Development Fund. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The supplementary data presented in this study are openly available in Open Science Framework at https://doi.org/10.17605/OSF.IO/7CHX6 (accessed on 9 November 2022). Other data are available through contact with the corresponding author at reasonable request. Acknowledgments: Carolina Requeijo is a doctoral candidate for the Ph.D. in Methodology of Biomedical Research and Public Health (Department of Paediatrics, Obstetrics, Gynaecology, and Preventive Medicine), Universidad Autònoma de Barcelona, Barcelona, Spain. We would like to thank Yang Song for her help in translating and extracting one of the included reviews. Conflicts of Interest: The authors declare no conflict of interest. References 1. Benson, A.B.; D’Angelica, M.I.; Abbott, D.E.; Anaya, D.A.; Anders, R.; Are, C.; Bachini, M.; Borad, M.; Brown, D.; Burgoyne, A.; et al. Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology. J. Natl. Compr. 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