Supportive Care in Cancer (2023) 31:100 https://doi.org/10.1007/s00520-022-07564-8 REVIEW Systemic oncological treatments in patients with advanced pancreatic cancer: a scoping review and evidence map Josefina Salazar1 · Javier Bracchiglione1,2,3 · Roberto Acosta‑Dighero2 · Nicolas Meza2 · Adriana‑G. Meade1 · María Jesús Quintana1,4 · Carolina Requeijo1 · Gerardo Rodríguez‑Grijalva1 · Marilina Santero1 · Anna Selva4,5 · Ivan Solà1,3,4 · Xavier Bonfill1,3,4 · Appropriateness of Systemic Oncological Treatments for Advanced Cancer (ASTAC) Research Group Received: 31 August 2022 / Accepted: 22 December 2022 / Published online: 9 January 2023 © The Author(s) 2023 Abstract Purpose To identify, describe, and organise currently available evidence regarding systemic oncological treatments (SOTs) (chemotherapy, targeted/biological therapies, and immunotherapy) compared to best supportive care (BSC) for patients with advanced pancreatic cancer (PC). Methods We conducted a scoping review and evidence mapping, adhering to PRISMA-ScR checklist. We searched MED- LINE, EMBASE, Cochrane Library, Epistemonikos, PROSPERO, and clinicaltrials.gov for eligible studies. We included systematic reviews (SRs), randomised controlled trials (RCTs), quasi-experimental, and observational studies evaluating SOTs compared to BSC or no treatment in patients with advanced PC. Two independent reviewers performed the screening process and data extraction. We developed evidence maps as an interactive visualization display, including the assessed interventions and outcomes. Results Of the 50,601 records obtained from our search, we included 43 studies: 2 SRs, 16 RCTs, 4 quasi-experimental studies, 20 observational studies, and 1 protocol for a quasi-experimental study. Forty-two studies reported survival-related outcomes and most favoured SOTs, while five reported toxicity and most favoured BSC. Other patient-centred outcomes, such as quality of life, were scarcely reported. Conclusions This study highlights the current evidence gaps in studies assessing treatments for patients with advanced PC, mainly the lack of reports of non-survival-related outcomes, pointing out research areas that need further attention to make better recommendations for these patients. Keywords Pancreatic neoplasms · Antineoplastic agents · Immunotherapy · Review literature as topic Introduction Pancreatic cancer (PC) is an important public health prob- lem, as it has the highest incidence-to-mortality ratio of any solid tumour, and it represents 2.6% of total new cancer * Xavier Bonfill cases. It accounted for almost as many deaths as new cases xbonfill@santpau.cat in 2020 and represented the seventh leading cause of cancer 1 Iberoamerican Cochrane Centre, Biomedical Research death in both sexes worldwide [1]. Institute Sant Pau (IIB Sant Pau), Barcelona, Spain Survival rates are significantly lower when diagnosed at 2 Interdisciplinary Centre for Health Studies (CIESAL), an advanced stage, having a 5-year survival rate of 14.4% Universidad de Valparaíso, Viña del Mar, Chile and 3% for regional and distant stages at diagnosis, respec- 3 CIBER Epidemiología Y Salud Pública (CIBERESP), tively [2]. Therefore, patients with advanced PC have a high Barcelona, Spain risk of dying in the short or medium term, which is concep- 4 Universitat Autònoma Barcelona, Barcelona, Spain tualised as the ‘end of life’ (EoL) period [3]. Deciding the 5 most appropriate treatment for patients with advanced PC at Corporació Sanitària Parc Taulí, Sabadell, Spain 13 Vol.:(0123456789) 100 Page 2 of 14 Supportive Care in Cancer (2023) 31:100 the EoL should be based on the best available evidence and Methods considering patient’s values and preferences, since failing to do so could increase patients’ psychological distress and the We conducted a comprehensive scoping review and evi- overutilisation of treatments that may be inconsistent with dence mapping [15], adhering to the Preferred Reporting personal preferences [4, 5]. Items for Systematic reviews and Meta-Analyses extension Therapies prescribed for PC are systemic oncological for Scoping Reviews (PRISMA-ScR) checklist [16]. The treatments (SOTs) such as chemotherapy, targeted/biological protocol for this study was prospectively registered and is therapies, and immunotherapy. These treatments continue publicly available in Open Science Framework [17]. to be the preferred therapeutic approach for patients with advanced-stage PC since current clinical practice guidelines (CPGs) associate them with an improvement in survival out- Eligibility criteria comes [6–8]. Nevertheless, their usage is also associated with important side effects and toxicity [9]. We used the PICOT framework (Patients, Intervention, On the other hand, a conservative strategy based on pro- Comparison, Outcomes, Type of study) to guide our eli- viding only the best supportive care (BSC) might constitute gibility criteria [18]. a valid therapeutic option. BSC constitutes a comprehensive approach focused on symptoms control and improvement of Type of patients patients’ quality of life, usually involving multidisciplinary teams [10, 11]. Therefore, it represents a therapeutic option We considered eligible studies including adult patients (over with lower toxicity, which is highly valued by patients [12, 18 years of age) with PC, primary or recurrent, in stage III 13]. or IV, or described as advanced or metastatic by the study It is crucial to note that available CPGs’ recommenda- authors at the moment of the intervention, as these stages tions are primarily based on the results of few experimental represent the EoL period. We excluded pancreatic neuroen- studies comparing SOTs with each other rather than with docrine cancers. BSC, and on their modest survival-related outcomes differ- ences. In contrast, our recent overview of systematic reviews Type of interventions (SRs) based on randomised clinical trials (RCTs) revealed contradictory results and a high uncertainty over the ben- For the intervention arm, we considered any SOT (chemo- efits of SOTs on overall survival when compared to BSC therapy, biological/targeted therapy, or immunotherapy), [14]. Furthermore, even though treatment decisions could either individual or combined, with or without supportive profoundly affect patients’ quality of life, other important care. We excluded studies that considered only surgery or outcomes were rarely reported, such as toxicity, functional radiotherapy as intervention, as well as studies that con- status, hospital admissions, symptoms, and quality of death sidered only chemotherapy as adjuvant or neoadjuvant [14]. therapy. Our overview presented an assessment of the evidence We considered as comparator any supportive treatment, from SRs and, although comprehensive, included few SRs administered with the purpose of symptomatic or pallia- with a limited number of RCTs. Hence, it is key to comple- tive control. This includes either usual treatment or BSC ment these findings with other available primary studies, [11]. Studies that did not explicitly define the interven- and thus get a clearer picture of the whole body of evidence tion of the control group, or studies with placebo as con- regarding SOTs versus BSC for patients with advanced PC. trol group, were also included. We excluded studies if the Scoping reviews and evidence maps provide a visual control group considered any type of SOT (chemotherapy, approach on the studies that have been conducted leading biological/targeted therapy, or immunotherapy). We also to the identification of areas that need further research (evi- excluded comparisons comprehending an intervention with dence gaps). Therefore, we developed a scoping review and non-palliative intent, such as surgery or radiotherapy with evidence map to identify, describe, and organise the cur- curative intent. rently available evidence about the efficacy of SOTs (chemo- therapy, biological/targeted therapies, and immunotherapy) Type of outcomes compared to BSC for patients with advanced PC, consider- ing all important patient-centred outcomes. We considered the following outcomes: 13 Supportive Care in Cancer (2023) 31:100 Page 3 of 14 100 • Overall survival: As a dichotomous outcome (at 3, 6, Search methods for identification of studies 9, 12, 24 months) and as a continuous or time to-event outcome. We performed electronic searches in MEDLINE (access • Progression-free survival: As a dichotomous outcome (at via PubMed), EMBASE (access via OVID), the Cochrane 3, 6, 9, 12, 24 months) and as a continuous or time-to- Database of Systematic Reviews, CENTRAL and Epis- event outcome. temonikos from inception until December 2, 2019. We • Quality of life: Measured with validated scales. designed search strings adapted to the requirements of • Functional status: Measured with Karnofsky or ECOG each database that combined controlled vocabulary and scale. search terms related to the main concepts of our clinical • Toxicity: Measured as moderate or severe adverse events, question. Since this study is part of a wider project, the according to standardised classification. search strategy included terms for pancreatic, hepatobil- • Symptoms related to the disease: Measured with vali- iary, and gastroesophageal cancer [17]. The search strategy dated scales that assess one or more symptoms. for PubMed can be found in the online resource 1. • Admissions to hospital or long-term centre, or emergency We also searched in PROSPERO and clinicaltrials.gov to consultations: Measured as the total number of admis- identify protocols of potentially eligible studies. We asked sions and days of admission during the follow-up period. experts in the field for relevant studies. We did not use any • Quality of death: other strategy to search for grey literature. – Admission to hospital at the end-of-life: Admission Selection of studies to the hospital in the last 30 days of life. – Palliative care provided during the last year: As a Two reviewers independently screened titles and abstracts dichotomous outcome. of the retrieved search results. A third reviewer solved – Place of death: Home, institutionalised (health com- disagreements. Afterwards, two reviewers independently munity centre or residence), hospitalised (intensive conducted the full-text screening, with a third author solv- care or other). ing any disagreement. For all this process we used Covi- dence (www.​covid​ence.​org). Type of studies Data extraction We included SRs, RCTs, quasi-experimental studies, and observational studies assessing the impact of SOTs in Two reviewers independently extracted data from the included advanced or metastatic PC. In the case of SRs, we consid- studies, using a previously piloted data extraction sheet (Google ered only those published from 2008 onwards. We did not Forms). For each included study, we extracted the following apply any language restrictions or publication date restric- data: year of publication, country, study design, total num- tions to primary studies. ber of studies included regarding our question (for SRs), total We considered as a SR any type of secondary research number of patients included (for primary studies), interventions that states: i) an explicit research question, ii) a structured (chemotherapy, biological/targeted therapy and/or immunother- search strategy (defined as explicit search terms and data apy), comparators (BSC, placebo, or non-specified), outcomes frame, in at least two databases), iii) explicit inclusion cri- reported, direction of effect, defined according to its statistical teria and screening methods, iv) an explicit assessment of significance as ‘favours intervention’, ‘favours comparison’, or the quality or risk of bias of each included study, and v) an ‘no differences’, and conflicts of interest. explicit approach to data analysis and synthesis [18, 19]. We considered as a RCT any experimental primary study Data synthesis and analysis with a randomised allocation of interventions. We consid- ered as quasi-experimental studies those with an inadequate We described the results of our search in a tabular view, randomisation process, or specific study designs with a classifying each included study by type of intervention non-random allocation of interventions, such as interrupted assessed, methodological design, reported outcomes and time series or before-after studies. We considered as obser- direction of the effect. We used evimappr [20], an R pack- vational studies all the case-control and cohort studies, as age, to produce the bubble plots for the evidence map. We long as they were controlled and had, at least, 30 included presented an interactive visualisation display that includes patients. the interventions (chemotherapy, biological/targeted therapy, We excluded descriptive studies, CPGs, case reports, and immunotherapy) in rows, and the outcomes in columns. The non-SRs (such as narrative reviews). grids were populated with the corresponding studies in each 13 100 Page 4 of 14 Supportive Care in Cancer (2023) 31:100 intersection, classified by study design (SR, RCT, quasi-   In addition to the 36 studies mentioned, we found one experimental study or observational study). Due to space protocol for a quasi-experimental study that will com- limits, if a column (i.e. outcome) did not contain any study pare gemcitabine-based chemotherapy to BSC (Table 1). for any intervention, this was not plotted within the interac-   Twenty-two (59.45%) of the studies did not report tive bubble plot. Thus, we showed a more detailed scheme in conflicts of interest. Of the 15 (40.54%) that did, 12 a complementary static figure where we identified evidence stated that there were no conflicts of interest to disclose gaps as those spaces on the grid that did not contain studies. (Table 1). 2. Immunotherapy   Four studies published from 2010 to 2017, compared Results immunotherapy to either BSC (n = 2) or placebo (n = 2) for advanced PC. Among these, two were RCTs and two Study selection were quasi-experimental studies and included a number of participants that ranged from 47 to 154. All the stud- Our search returned 50,601 records for all cancer locations ies assessed different immunotherapy agents, two as first (hepatobiliary, gastroesophageal and pancreatic) once dupli- line therapy and two did not specify the therapy line cates were removed. After title and abstract screening, we (Table 1). excluded 47,667 references. Of the 2,934 references, we   All studies reported their conflicts of interest, of were not able to retrieve 106 reports. Therefore, we reviewed which three (75%) stated that there were no conflicts of the full text of 2,828 articles. We included a total of 177 interest to disclose (Table 1). studies for all cancer locations, of which 43 included par- 3. Targeted/biological therapy ticipants with PC. Of these, 2 were SRs, 16 RCTs, 4 quasi- experimental studies, 20 were observational studies, and 1 was a protocol for a quasi-experimental study. Figure 1 sum- Four studies published from 2013 to 2019 compared tar- marises the screening process. geted or biological therapy to either placebo (n = 2) or to an intervention not clearly specified (n = 2) for advanced PC. Characteristics of the included studies Three were RCTs and one was an observational study and included a number of participants that ranged from 56 to 1. Chemotherapy 207.   36 studies published from 1979 to 2018, compared Two studies evaluated erlotinib, one olaparib, and one chemotherapy to either BSC (n = 24), or to an inter- sunitinib, all without specifying the line of therapy (Table 1). vention not clearly specified (n = 12) for advanced PC. All studies reported their conflicts of interest, of which Among these, 34 were primary studies (11 RCTs, 3 one (25%) %) stated that there were no conflicts of interest quasi-experimental, and 20 observational) and included to disclose (Table 1). a number of participants that ranged from 31 to 303 for Figure 2 shows an overall summary of the evidence RCTs, 47 to 90 for quasi-experimental and 39 to 1085 retrieved, classified by type of SOT administered, reported for observational studies. We included two SRs with a outcomes, and study design. total number of primary studies of 50 and 60, while the number of primary studies included in those SRs rel- Outcomes evant to our question were six and nine (Table 1).   The interventions assessed in primary studies 1. Chemotherapy included both monotherapy and combination therapy.   All the 36 included studies reported survival-related Of those evaluating monotherapy, seven used gemcit- outcomes, with most reporting an effect favouring the abine, three fluorouracil, two S-1 and one glufosfamide. intervention [22–40, 42–45, 47, 48, 51, 54, 55]. Func- Combination therapies were 5-FU based (n = 9), gem- tional status was reported by four studies, including one citabine–based (n = 3) and both 5-FU and gemcitabine- SR [56], two RCTs [49, 51], one quasi-experimental based (n = 5). Four studies did not specify the type of design [41], with most showing no difference between chemotherapeutic agent used. Both SRs assessed com- both interventions, and only one RCT favouring the bination therapy. Most studies (64%) did not specify intervention [51]. Quality of life showed different results the line of therapy. Fifteen primary studies reported co- among the included studies, with a SR showing no dif- interventions, namely stents (n = 2), endoscopic proce- ference [56], two RCTs favouring the intervention [47, dures (n = 2), palliative surgery (n = 3), and radiotherapy 48], and one favouring the comparison [53]. Few RCTs (n = 8). One SR included radiotherapy and palliative sur- reported toxicity [52, 54], symptoms [48, 52], and hos- gery as co-interventions (Table 1). pital admissions [51], and no study reported outcomes 13 Supportive Care in Cancer (2023) 31:100 Page 5 of 14 100 Fig. 1  PRISMA flowchart related to quality of death. Figure 3 provides a summary results in favour of the control group for toxicity [59]. of the direction of the effect reported by each study for None of the studies reported symptoms related to the each outcome. disease, quality of life, admissions to the hospital or 2. Immunotherapy quality of death (Fig. 3).   All four included studies reported survival-related 3. Targeted/biological therapy outcomes, with most reporting an effect favouring the intervention [43, 58, 59]. One RCT reported no differ- Four studies reported overall survival, with three RCTs ences between the interventions in functional status and showing no difference [61–63] and one observational design 13 100 Page 6 of 14 Supportive Care in Cancer (2023) 31:100 Table 1  Characteristics of included studies Study ID Country Study design Na Intervention Treatment line Co-interven- Comparison Conflicts of tions interest Chemotherapy Smeenk, 2005 Netherlands OBS 83 5-FU Not specified/ RT BSC NR [21] Not clear Takasawa, 2006 Japan OBS 45 Gem Not specified/ Endoscopic BSC NR [22] Not clear procedures Tada, 2008 [23] Japan OBS 167 Gem Not specified/ RT BSC NR Not clear Fujino, 2008 Japan OBS 116 Gem Not specified/ Palliative pan- Not specified/ NR [24] Not clear createctomy Not clear Nakai, 2008 Japan OBS 147 Gem Not specified/ Stent BSC NR [25] Not clear Mukherjee, UK OBS 294 Gem, Gem- Not specified/ RT Not specified/ NR 2008 [26] based Not clear Not clear Yamagishi, Japan OBS 66 Gem First line - BSC NR 2010 [27] *Some patients also received second-line CT Matsumoto, Japan OBS 68 Gem Not specified/ - BSC NR 2011 [28] Not clear Hiramoto, 2011 Japan OBS b 128 Gem, S-1 Not specified/ - BSC NR [29] Not clear Hentic, 2011 France OBS 38 Gem, Oxa Not specified/ - BSC NR [30] Not clear Aldoss, 2011 USA OBS 419 Not specified / Not specified/ - Not specified/ Nothing to [31] not clear Not clear Not clear disclose Vijayvergia, USA OBS 579 5-FU, Gem, Not specified/ - Not specified/ Nothing to 2015 [32] Iri, Platin, Not clear Not clear disclose Taxanes Bednar, 2016 USA OBS 107 5-FU, Gem, Iri, Not specified/ - Not specified/ Declaredd [33]c Oxa, Pac Not clear Not clear Chakupurakal, Germany OBS 324 5-FU, Cap, Not specified/ RT BSC Nothing to 2017 [34] Gem, Oxa, Not clear disclose nab-Pac, FOL- FIRINOX, FOLFOX, FOLFIRI, Leucovorin Henze, 2018 Germany OBS b 100 5-Fu, Gem, Iri, Not specified/ RT Not specified/ Nothing to [35] Oxa, Pac Not clear Not clear disclose Terashima, Japan OBS 1085 Not specified / Not specified/ - BSC Nothing to 2018 [36] not clear Not clear disclose Kang, 2020 South Korea OBS 161 5-FU, Gem, Not specified/ Endoscopic BSC Nothing to [37] Iri, Oxa, Not clear procedures disclose Leucovorin, Gem-based Iede, 2020 [38] Japan OBS 39 S-1 Second line - BSC Nothing to disclose Fukahori, 2020 Japan OBS b 255 Not specified / Not specified/ - BSC Declarede [39] not clear Not clear Tralongo, 2020 USA OBS b 78 Not specified / Not specified/ - BSC Nothing to [40] not clear Not clear disclose 13 Supportive Care in Cancer (2023) 31:100 Page 7 of 14 100 Table 1  (continued) Study ID Country Study design Na Intervention Treatment line Co-interven- Comparison Conflicts of tions interest Andren Sand- Sweden Q-Exp 47 5-FU, Vincris- First line - BSC NR berg, 1983 tine, CCNU [41] Tsavaris, 1998 Greece Q-Exp 90 5-FU, Epiru- Not specified/ - BSC NR [42] bicin, Leucov- Not clear orin Jiang, 2017 [43] China Q-Exp 47 S-1 First line - BSC Nothing to disclose The Gastroin- USA RCT​ 89 5-FU First line RT Not specified/ Nothing to testinal Tumor Not clear disclose Study Group, 1979 [44] Mallinson, UK RCT​ 40 5-FU, Cincris- First line - BSC Nothing to 1980 [45] c tine, Cyclo- disclose phsphamide, Methotrexate Frey, 1981 [46] USA RCT​ 152 5-FU, CCNU First line Palliative Not specified/ Nothing to surgery Not clear disclose Palmer, 1994 UK RCT​ 46 5-FU, Adriamy- Not specified/ - Not specified/ Nothing to [47] cin, Mitomy- Not clear Not clear disclose cin Glimelius, 1996 Sweden RCT​ 53 5-FU, Leu- First line RT BSC Nothing to [48] covorin, disclose Etoposide Takada, 1998 Japan RCT​ 83 5-FU, Doxoru- Not specified/ Palliative Not specified/ Nothing to [49] bicin, Mito- Not clear surgery Not clear disclose mycin Huguier, 2001 France RCT​ 45 5-FU, Cisplatin, First line - BSC Nothing to [50] Leucovorin disclose Shinchi, 2002 Japan RCT​ 31 5-FU Not specified/ RT Not specified/ Nothing to [51] Not clear Not clear disclose Ciuleanu, 2009 Romania RCT​ 303 Glufosfamide Second line - BSC Declarede [52] Xinopoulos, Greece RCT​ 49 Gem First line Stent Not specified/ NR 2008 [53] c Not clear Pelzer, 2011 Germany RCT​ 46 5-FU, Oxa, Second line - BSC Nothing to [54] c Leucovorin disclose Yip, 2006 [55] Australia SR 9 of 50 5-FU, Adriamy- Not specified/ RT, palliative BSC NR cin, Cisplatin, Not clear surgery Doxo, Mito- mycin, Cyclo- phosphamide, Leucovirin, Vincristine, Etoposide, Metrothex- ate, CCNU, BCNU, FAM Chin, 2018 Australia SR 6 of 60 5-FU, Cisplatin, First line - BSC Nothing to [56] c Doxo, Gem, disclose Mitomycin, CCNU, Vincristine, Leucovorin, Etoposide 13 100 Page 8 of 14 Supportive Care in Cancer (2023) 31:100 Table 1  (continued) Study ID Country Study design Na Intervention Treatment line Co-interven- Comparison Conflicts of tions interest Betge, 2018 Germany Protocol for - Gem, First line - BSC Nothing to [57] Q-Exp Gem + nab- disclose Pac Immunotherapy Asahara, 2013 Japan Q-Exp 112 HLA-A24-re- Not specified/ - BSC Nothing to [58] stricted pep- Not clear disclose tide vaccine derived from KIF20A Jiang, 2017 [43] China Q-Exp 47 DC-CIK First line - BSC Nothing to disclose Oortgiesen, USA RCT​ 154 PAS Not specified/ - Placebo Declaredf 2010 [59] Not clear Gilliam, 2012 UK RCT​ 154 G17DT: First line - Placebo Nothing to [60] c antigastrin disclose immunogen Targeted/biological therapy Henze, 2018 Germany OBS b 100 Erlotinib Not specified/ RT Not specified/ Nothing to [35] Not clear Not clear disclose Reni, 2013 Italy RCT​ 56 Sunitinib Not specified/ - Not specified/ Declaredg [61] c Not clear Not clear Propper, 2014 UK RCT​ 207 Erlotinib Not specified/ - Placebo Declarede [62] c Not clear Golan, 2019 Israel RCT​ 154 Olaparib Not specified/ - Placebo Declarede [63] c Not clear OBS observational Study; Q-Exp quasi-experimental Study; RCT​ randomised clinical trial; SR systematic review; 5-FU fluorouracil; Gem gem- citabine; Oxa oxaliplatin; Iri irinotecan; Pac paclitaxel; Cap capecitabine; Doxo doxorubicin; DC-CIK dendritic cells and cytokine induced killer cells; PAS polyclonal antibody stimulator; RT radiotherapy; BSC best supportive care; NR not reported a Number of included participants for primary studies and number of included studies relevant to our clinical question/total of included studies for systematic reviews b Congress abstract c See references for additional publications in online resource 2 d Two authors reported consulting or advisory roles with Healthcare Companies e Authors are employees or have stocks on the Healthcare Company that funded the study f Authors reported financial interests in the study product g First author received consulting fees from the Pharmaceutical Manufacturing Company favouring the intervention [35]. PFS was reported by the same or no SOT for patients with advanced PC. The evidence map three RCTs, with two favouring the intervention [61, 63] and presents results from 42 studies, 40 of which were either one showing no difference [62]. Toxicity was reported in two observational (n = 20) or experimental studies (n = 20), and RCTs, one favouring the control group [61], and one showing with most of them reporting survival outcomes favouring no difference [63]. Quality of life was reported by one RCT the use of SOTs. Few studies reported other outcomes, with showing no differences between interventions [63]. None of most reporting no difference in terms of functional status, the studies reported functional status, symptoms related to the most reporting results in favour of BSC in terms of toxicity, disease, admissions to the hospital or quality of death (Fig. 3). and heterogeneous results in terms of quality of life. Symp- toms related to the disease and hospital admissions were scarcely reported, and no study reported outcomes related Discussion to quality of death. Our exhaustive search resulted in the inclusion of only Our scoping review offers a broad overview of the currently 42 studies to answer our question. Most studies evaluated available evidence of primary and secondary studies on the chemotherapy as the intervention, and a high proportion effectiveness and safety of SOTs compared to BSC, placebo were conducted before the year 2000. This could be due to 13 Supportive Care in Cancer (2023) 31:100 Page 9 of 14 100 Fig. 2  Evidence gap map of Systemic Oncological Treatments in patients with advanced pancreatic cancer newer studies tending to assess the comparative effective- intervention arm, but no information about the control, ness of two SOTs, rather than with BSC as a sole compara- which limited the interpretation of the results. Lastly, we tor [64, 65]. Moreover, some authors may even consider it included only two SRs, which may be due to our strict eligi- unethical to conduct an experimental study with one arm bility criteria for this type of studies. receiving only BSC, since most guidelines recommend SOTs Our evidence map shows the current landscape of existing as the standard of care [66]. However, we consider that the research and highlights evidence gaps. Our map shows that a trade-off between survival and other relevant outcomes, such small number of studies have been conducted to assess SOT as toxicity and quality of life, is not clear enough and could compared to BSC, and even less reported critical patient justify the conduction of RCTs comparing active treatment centred outcomes. We found absolute evidence gaps, mean- against supportive care in patients with advanced PC at the ing no study reporting data, in the following outcomes: EoL. quality of death for all SOTs; quality of life for immuno- Almost all observational studies reported results favour- therapy, and symptoms related to the disease, admissions ing SOT in terms of survival. In contrast, about half of the to the hospital and quality of death for immunotherapy and RCTs assessing chemotherapy or immunotherapy and all biological/targeted therapies. In addition, it is important to RCTs assessing biological/targeted therapies reported no note that caution is necessary when interpreting the study difference for the same outcome. This difference may be results that show a potential benefit of some treatments. The explained by the higher risk of selection bias in the obser- reporting of information about the lines of treatment is so vational studies, since it was frequent that the patients’ scarce that patients with unequal prognosis would wrong- initial clinical assessment determined the type of therapy fully be equated, which is something particularly relevant in prescribed. Additionally, we do not know the degree of a scenario where the more advanced the incurable disease exhaustiveness of the disclosure of conflicts of interest since the less likely it is that treatments will provide any benefit it was not reported by the authors of over 50% of the stud- [67]. Therefore, it makes it very difficult to determine which ies. Therefore, it is difficult to examine the extent to which specific patients are the ones that might benefit from spe- potential conflicts may be associated with findings favouring cific lines of treatments and the limit beyond which there SOTs. is no evidence to start a new therapeutic regimen [68]. In Overall, there were very few studies reporting outcomes consequence, we claim for a more detailed description of other than survival-related ones and none of the observa- administered treatments (i.e., number of cycles, previous tional studies reported a non-survival outcome. Among treatments, co-interventions). the other methodological designs, toxicity was reported in The main limitation of our review is related to the inter- only five studies, which can be explained by our inclusion pretation of the magnitude of effect of the results. Since this of reports that assessed toxicity only as a comparison, that study was designed as a scoping review and evidence map- is, being reported in both the intervention and the control ping, we planned to descriptively show only the direction of group. Some studies did provide data about toxicity in the the effect of each SOT compared to BSC for the considered 13 100 Page 10 of 14 Supportive Care in Cancer (2023) 31:100 13 Supportive Care in Cancer (2023) 31:100 Page 11 of 14 100 ◂Fig. 3  Direction of the effects reported by each study for each outcome. admissions to the hospital and quality of death, through well OBS observational study; Q-Exp quasi-experimental study; RCT ran- powered, independent, and valid RCTs, included afterwards domised clinical trial; SR systematic review; OS overall survival; PFS pro- gression-free survival; m months; FS functional status; QoL quality of in the corresponding SR. life; QoD quality of death; FI favours intervention (Systemic Oncological Supplementary Information The online version contains supplemen- Treatment); ND no differences; FC favours comparison (Best Supportive tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00520-0​ 22-0​ 7564-8. Care/placebo/not specified); NR not reported. TGISG The Gastrointesti- nal Study Group Acknowledgements Appropriateness of Systemic Oncological Treat- ments for Advanced Cancer (ASTAC) Research Group: Javier Brac- chiglione, Adriana-G Meade, Josefina Salazar, Gerardo Rodriguez- outcomes, as reported by the respective authors, but we did Grijalva, Carolina Requeijo, Xavier Bonfill, Ivan Solà, María Jesús not consider reporting the magnitude of the effect nor to Quintana, Marilina Santero, Roberto Acosta-Dighero, Nicolas Meza, perform a quantitative summary of the results (e.g. meta- Anna Selva, Karla Salas, Alba Antequera, Ariadna Auladell-Rispau, analysis). Also, we did not assess the risk of bias of each Gerard Urrútia, Pamela Meinardi, Juan Irassar, Daniel Simancas, Rosa- rio Dorantes, Angela Merchán, Yahveth Cantero, Edgar Hernandez, included study. However, our study has several strengths. To Miguel Sugrañes. our knowledge, this is the only scoping review and evidence map of SOTs compared to BSC in patients with advanced Author contribution All authors contributed to the study conception PC. We conducted a comprehensive search including seven and design. Material preparation, data collection, and analysis were performed by Josefina Salazar, Javier Bracchiglione, Roberto Acosta- electronic databases, with a screening and data extraction Dighero, and Nicolas Meza. The first draft of the manuscript was writ- process involving independent reviewers to minimise pos- ten by Josefina Salazar and Xavier Bonfill, and all authors commented sible errors. Furthermore, we looked for all potentially on previous versions of the manuscript. All authors read and approved relevant outcomes for patients at the EoL and we present the final manuscript. the results in a reader-friendly graphical display, which Funding Open Access Funding provided by Universitat Autònoma strengthened the visibility of both primary and secondary de Barcelona. This study is funded through a grant from Instituto de research. In addition to this, we plan to conduct a new SR Salud Carlos III (PI18/00034) co-financed by funds from the European to update previous ones and include available RCTs to date. Regional Development Fund. We will follow rigorous guidelines to assess the studies’ risk Data availability Not applicable. of bias and explore the magnitude of effect of the reported outcomes. Declarations The use of SOTs will likely expand and become a com- mon intervention for advanced PC. However, our results Ethics approval and consent to participate Not applicable. show that much about their effectiveness and safety, when Consent for publication Not applicable. compared to BSC, is still unknown. This uncertainty pre- sents a challenge for health professionals, patients, and their Competing interests The authors declare no competing interests. relatives since it is necessary for clinicians to have objective criteria and relevant information in order to weigh poten- Open Access This article is licensed under a Creative Commons Attri- tial benefits and side effects before prescribing treatments. bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long Additionally, healthcare professionals must ensure that the as you give appropriate credit to the original author(s) and the source, patients understand this balance, especially in their particu- provide a link to the Creative Commons licence, and indicate if changes lar context. were made. The images or other third party material in this article are There is increasing recognition of the need to prioritise included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in patient-centred communication and to have a focus on the the article's Creative Commons licence and your intended use is not patients’ goals of care [5]. For patients with advanced PC permitted by statutory regulation or exceeds the permitted use, you will with a poor prognosis, these goals inevitably vary and may need to obtain permission directly from the copyright holder. To view a not necessarily be related only to an increase in survival [5]. copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Based on the results of our study, these other goals of care are not sufficiently reported. 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