Clinical and Translational Oncology (2019) 21:1398–1412 https://doi.org/10.1007/s12094-019-02069-z RESEARCH ARTICLE Evidence mapping based on systematic reviews of therapeutic interventions for soft tissue sarcomas M. Ballesteros1 · N. Montero2 · A. López‑Pousa3 · G. Urrútia4,5 · I. Solà4,5 · G. Rada6 · H. Pardo‑Hernandez4,5 · X. Bonfill4,5 Received: 26 January 2019 / Accepted: 22 February 2019 / Published online: 14 March 2019 © The Author(s) 2019 Abstract Purpose Soft tissue sarcomas are a heterogeneous group of rare tumours of mesenchymal origin. Evidence mapping is one of the most didactic and friendly approaches to organise and summarise the range of research activity in broad topic fields. The objective of this evidence mapping is to identify, describe and organise the current available evidence about therapeutic interventions on soft tissues sarcomas. Methods We followed the methodology of global evidence mapping. We performed a search of the PubMed, EMBASE, The Cochrane Library and Epistemonikos to identify systematic reviews (SRs) with or without meta-analyses published between 1990 and March 2016. Two independent literature reviewers assessed eligibility and extracted data. Methodological quality of the included systematic reviews was assessed using AMSTAR. We organised the results according to identified PICO questions and used tables and a bubble plot to display the results. Results The map is based on 24 SRs that met eligibility criteria and included 66 individual studies. Three-quarters were either observational or uncontrolled clinical trials. The quality of the included SRs was in general moderate or high. We identified 64 PICO questions from them. The corresponding results mostly favoured the intervention arm. Conclusions This evidence mapping was built on the basis of SRs, which mostly included non-experimental studies and were qualified by the AMSTAR tool as of moderate quality. The evidence mapping created from PICO questions is a useful approach to describe complex and huge clinical topics through graphical media and orientate further research to fulfil the existing gaps. However, it is important to delimitate the steps of the evidence mapping in a pre-established protocol. Keywords Soft tissue sarcomas · Evidence mapping · Evidence synthesis · Global evidence mapping Abbreviations Introduction AMSTAR​ Assessing the methodological quality of sys- tematic reviews Soft tissues sarcomas (STS) are a group of rare tumours of GEM Global Evidence Mapping Initiative mesenchymal origin, with an estimated incidence of 4.74 GIST Gastrointestinal stromal tumours per 100,000 adults per year in Europe [1–3], whilst in chil- PICO Population, intervention, comparison, dren they represent 7–10% of all childhood cancers [4]. The outcome research on STS poses some challenges due to the heteroge- RCT​ Randomised controlled trial neity and rarity of the cases, a broad range of classification SRs Systematic reviews into the different subtypes and the tendency to pool sarcoma WHO World Health Organization subtypes to show the outcomes [5]. In addition, access to summarised, comprehensive and updated information in this clinical field is limited. Electronic supplementary material The online version of this Poor access to good research evidence is the most article (https​://doi.org/10.1007/s1209​4-019-02069​-z) contains reported barrier to make well-informed clinical decisions supplementary material, which is available to authorized users. [6, 7]. New, faster and emerging strategies have been launched to overcome those difficulties [8]. Evidence map- * M. Ballesteros mopbasilva2015@gmail.com ping is one of the most didactic and friendly approaches to organise and summarise the range of research results Extended author information available on the last page of the article 13 Vol:.(1234567890) Clinical and Translational Oncology (2019) 21:1398–1412 1399 in very extensive areas, allowing to systematically char- We defined a data extraction tailored form to register the acterise the evidence, identify gaps in knowledge and pri- main characteristics and quality of the included SRs. We oritise new research questions. This strategy can be the tested this form to ensure consistency among reviewers in a first approach to conduct a further systematic review or to pilot study with 20% of the eligible SRs. Two independent provide a framework to inform policy development [9–12]. literature reviewers extracted data (MB, NM). Discrepan- The goal of this evidence mapping is to identify, cies were solved by discussion with a third author (AL). We describe and organise the current available evidence about included all types of treatment regardless of whether it was therapeutic interventions on sarcomas. Due to the vast being used or not in the current clinical practice. We col- diversity of sarcoma types, the results were split into two lected data according to three levels: groups: gastrointestinal stromal tumour (GIST) and soft tissues sarcomas (STS). In a previous paper, we reported (a) General characteristics from SRs: authors, year of the results corresponding to GIST [13]. publication, type of SR (with or without meta-analy- sis), objective, search strategy design and number of included studies, type and number of patients included, and quality of the systematic review. The quality of Methods included SR was evaluated by two independent review- ers (MB, NM) using the AMSTAR tool. Discrepancies We carried out an evidence map according to the meth- were discussed and solved with a third author (AL). We odology of Global Evidence Mapping (GEM) [10] and obtained AMSTAR scores by summing one point for adding some new components: an exhaustive search strat- each item rated as “yes” and no points for items rated egy and the assessment of methodological quality of the as “no”, “can´t answer” and “not applicable”, result- included systematic reviews (SRs). We divided the process ing in an overall score ranging from 0 to 11. SRs were into four stages, the two first stages have been described grouped in three categories: 0–3 points (low quality), widely elsewhere [13]. 4–7 points (moderate quality) and 8–11 points (high quality) [17]. 1. Setting the boundaries and context of the evidence map: (b) Assessment of the clinical questions within the SRs:   To frame our mapping project, we consulted the 2013 we elaborated PICO questions (specifying its four key World Health Organization (WHO) classification [14] components: population, intervention, comparison and and the relevant clinical practise guidelines (CPG), com- outcomes) based on SR objectives and eligibility crite- bined with the consultation to an experienced oncologist ria. in the field. We selected SRs that evaluated therapeutic interventions in patients diagnosed with STS, which The PICOs were grouped into three main clinical sce- included either experimental or non-experimental stud- narios: localised disease, advanced disease and specific STS ies. We excluded studies focused on Kaposi sarcoma subtypes (uterine, retroperitoneal sarcomas and other rare and/or Ewing’s tumours because of their unique biologi- specific subtypes). We then retrieved details about the par- cal characteristics and management [15, 16]. ticipants’ characteristics (e.g. adult population or children, 2. Search and selection of systematic reviews: type of sarcoma, localisation of tumours); the intervention   We carried out a highly sensitive search strategy in and its referent when existing (e.g. type of intervention and PubMed, EMBASE, The Cochrane Library, and Episte- its control group broadly categorised as chemotherapy, sur- monikos databases from 1990 to November 2016. The gery, radiotherapy and others); characteristics of the inter- detailed search strategies are listed in Online Resource vention; and comparison; and the outcomes. For descriptive 1. purposes, we also classified the conclusions reported by the 3. Data analysis: authors of the included studies into five categories: “incon- clusive”, “no effect”, “harmful”, “probably beneficial” and Table 1  Classification of the conclusions according to results reported by authors “Inconclusive”: direction of results differed across or within reviews due to conflicting results or limitations of individual studies “No effect”: the conclusions provided evidence of no difference between intervention and comparator “Harmful”: the conclusions were reported as clearly indicative of a harmful effect “Probably beneficial”: the conclusions did not claim for firm benefits despite the reported positive treatment effect “Beneficial”: the conclusions reported a clear beneficial effect without major concerns regarding the supporting evidence 13 1400 Clinical and Translational Oncology (2019) 21:1398–1412 “beneficial” (see Table 1 for further detail of the criteria which represents with a black bold line the proportion followed for this categorisation). This classification does of RCTs included in the respective SR. not represent any formal evaluation of the interventions’ effectiveness. Results (c) Characteristics of other research questions addressed in the SRs, here considered as secondary PICOs: we We retrieved 1791 records once duplicates were removed. defined as secondary those research questions that had In total, 143 articles were deemed potentially relevant all the elements of the PICO question, but the con- by at least one reviewer and, therefore, the full text was clusions about the direction of the effect were barely obtained. A total of 41 citations fulfilled the eligibility described in the article. We extracted the same informa- criteria, of which 24 SRs referred to STS and the remain- tion described above for the main research question. ing 17 SRs to GIST. A flowchart is detailed in Fig. 1. The reasons for exclusion of the 102 reviews publications are Based on the PICO format, we summarised the synthesiz- detailed in Online resource 2. ing findings for each included review in: (a) Table describing the characteristics of the included Characteristics and quality of systematic reviews SRs, and another one with all identified PICOs (main and secondary). Our final sample consisted of 24 SRs focusing on STS [15, (b) Graphic display of the mapping based on bubble plots, 18–38], 8 of them included a meta-analysis [18, 21, 26, 30, where each bubble represents one SR. This graphic pro- 32, 33, 38]. All SRs were published between 2003 and 2016 vides information in three dimensions: (1) in the x-axis, which included studies carried out between 1973 and 2014. there is the rating of authors conclusions as “benefi- The search strategy was described in detail in only eight SRs cial”, “probably beneficial”, “harmful”, “no effect” [18, 21, 22, 27, 29, 31, 34, 38]. The SRs included a total of and “inconclusive” (they were further described in the 279 primary studies, out of which 195 were observational data extraction section); (2) in the y-axis, the AMSTAR studies (either prospective or retrospective), 41 were RCTs, assessment is shown; and (3) we displayed the bubble 4 were non-randomised controlled trials and 39 were experi- size proportionally to the number of individual studies mental non-controlled studies (mainly phase II trials). Nine included in the SR. Each bubble is also a pie graph SRs did not include any RCT [18, 22–24, 27, 29, 30, 35, 36], 1 was an empty review [27] and the remaining 15 included MEDLINE EMBASE COCHRANE EPISTEMONIKOS (n= 942 ) (n= 502 ) (n= 334 ) (n= 254 ) Records aer duplicates removed Titles/abstracts excluded (n= 1791 ) (n= 1648 ) Full text arcles acquired and screened (n= 143 ) Full text arcles excluded (n= 102 ) Wrong Study Type: 45 Only one database included: 24 No therapeuc intervenons: 15 Wrong populaon: 10 Records included in Global Evidence Mapping (n= 41) Duplicate: 6 17 GIST Full text not available : 2 24 So Tissue Sarcomas Fig. 1  Flow chart outlining the study selection process 13 Clinical and Translational Oncology (2019) 21:1398–1412 1401 at least one [28, 29, 31–34, 37, 38]. The total number of “probably beneficial”. Another SR compared neoadju- patients analysed in the SRs ranged from 216 to 6467, all of vant radiotherapy [19] with surgery, and as stated in the them being adults. conclusion, the authors considered this intervention as According to the evaluated treatment, 13 SRs appraised “probably beneficial”. Evidence mapping is detailed in chemotherapy therapies [15, 18, 21, 25–27, 30–32, 37–39]; Fig. 3. 5 SRs evaluated radiotherapy interventions [19, 22, 23, 33, 2. Patients with locally advanced unresectable and/or 36]; 2 SRs assessed surgical interventions [24, 34]; 1 SR metastatic STS (First Line): Six SRs [18, 21, 30, 31, assessed a combination of surgery (cytoreduction) plus intra- 37, 38] included a total of 17 RCTs, 19 non-controlled peritoneal chemotherapy [28]; and finally 3 SRs assessed a trials and 5 observational studies, addressing mainly two therapy at the forefront named isolated limb perfusion (ILP) therapeutic options in this scenario. Two SRs compared [20, 29, 35]. chemotherapy of doxorubicin-based combination versus Thirteen SRs assessed interventions with a curative inten- doxorubicin alone. In general, the combined schemes tion [19, 20, 22–24, 27, 29, 32–36, 40], whereas in the other were considered by authors as “harmful”, “no effect” 11 the interventions was palliative [15, 18, 21, 25, 26, 28, and “inconclusive” depending on the different regimens 30, 31, 37–39]. assessed. Evidence mapping is detailed in Fig. 4. The most reported outcome was overall survival, where only 3 SRs did not report this outcome [24, 29, 35]; followed Four SRs [18, 30, 31, 37] compared dose-intensive by response rate, which was informed in 13 SRs [15, 20, chemotherapy by autologous bone marrow support, stem 21, 25–27, 29, 34–39]; progression-free survival and local cell transplantation or growth factor with standard-dose or distant recurrence rate were described in nine reviews chemotherapy. Two of them in patients diagnosed of rhab- [19, 20, 22–24, 28, 32, 36, 40], whereas quality of life was domyosarcoma [18, 30]. In general, the results were stated appraised only in four SRs [15, 21, 27, 28]. Furthermore, 18 by the authors as “harmful” and “inconclusive”. Evidence reviews [15, 18–22, 25–31, 35–39] informed about adverse mapping is detailed in Fig. 5. events. Based on AMSTAR scores, the quality of the included 3. Patients with unresectable, locally advanced STS of the SRs was moderate to high, as seen in Fig. 2. The major extremities: Three SRs [20, 29, 35] evaluated the use drawbacks were: not detailing the included and excluded of hyperthermic isolated limb perfusion (ILP) in these studies, not declaring potential conflicts of interest, not eval- patients. In total, 4 RCTs were included, 9 non-con- uating the likelihood of publication bias and not assessing trolled trials, and 38 observational studies. In general, the risk of bias of individual studies. The characteristics of the authors considered the results as “probably benefi- the included SRs are reported in Table 2. cial” and “inconclusive”. Evidence mapping is detailed in Fig. 5. PICO questions identified in systematic reviews 4. Patients with locally advanced STS after failure of prior anthracyclines and ifosfamide (Second line): Two We retrieved 51 PICO questions from the SRs about STS, SRs [15, 39] included 7 RCTs, 3 non-controlled trials whose main characteristics are detailed in Online resource and 94 observational studies addressing four different 3. According to the STS clinical stage, the PICOS were clas- therapeutic options in this scenario. One SR compared sified to encompass the full spectrum of the disease, from pazopanib versus placebo, and the authors considered initial stages to metastatic disease, in the following eight pazopanib as “probably beneficial”. Gemcitabine plus clinical scenarios: dacarbazine was compared with dacarbazine alone in one SR, in which the authors considered combination as 1. Patients with localised resectable STS (First line): Four “inconclusive”. Trabectedin was compared with stand- SRs [19, 32, 33, 40] were identified with a total of 27 ard treatment in another SR, and the conclusion was RCTs and 32 observational studies, which addressed stated as “inconclusive”. In this same SR, two different three different therapeutic options within this scenario. doses of trabectedin (1.5 mg three times per week versus Two SRs compared different regimens of adjuvant 0.58 weekly) were compared. The authors considered chemotherapy [32, 40] mainly based in doxorubicin that the use of higher doses of trabectedin as “probably or doxorubicin plus ifosfamide with surgery. Adjuvant beneficial”. Evidence mapping is detailed in Fig. 5. chemotherapy was considered by the authors as “prob- 5. Patients with endometrial stromal sarcoma localised: ably beneficial” in one SR and as “inconclusive” in One SR [34] including one RCT, one non-controlled another SR. trial and 84 observational studies evaluated three differ-   One SR compared adjuvant radiotherapy [33] with ent therapeutic options in this population. The addition surgery and its authors qualified this intervention as of lymphadenectomy to hysterectomy with salpingec- 13 1402 Clinical and Translational Oncology (2019) 21:1398–1412 Fig. 2  AMSTAR scores of the included SRs tomy, as well as ovarian sparing was qualified as “no nario. Combination chemotherapy was compared with effect” by the authors. Adjuvant radiotherapy was com- a single chemotherapy agent in two SRs [25, 26]. Com- pared to surgery; this intervention was considered as bination chemotherapy was considered as “no effect”, “probably beneficial”. Evidence mapping is detailed “inconclusive” and “probably beneficial”, depending Fig. 6. on the subtype of uterine sarcoma and the different 6. Patients with advanced, recurrent or metastatic uterine regimens used. Adjuvant hormonal therapy was com- sarcomas: Three SRs [25, 26, 34], including four RCTs, pared with surgery in one SR, where adjuvant hormonal 25 non-controlled trials and 84 observational studies therapy was qualified as “probably beneficial”. Evidence addressed mainly two therapeutic options in this sce- mapping is detailed in Fig. 6. 13 Table 2  Description of systematic reviews included ID Study design Search methods and Research question or Number RCT​ Non-ran- Non- Obser- Population/type of soft Patients (N) AMSTAR year aim of studies domised controlled vational tissue sarcoma score included trial trial studies Admiraal 2010 SR Followed Cochrane To assess the effective- 4 0 3 1 0 Children and young 498 9 Collaboration ness of high-dose adults/stage IV rhab- Guidelines; through chemotherapy with domyosarcoma December 2009 autologous stem cell rescue or allogenic stem cell rescue (versus standard-dose chemotherapy) Al-Absi 2010 SRM Standard search; To determine the 5 1 0 0 4 Adults/localised soft 1028 7 through June 2005 oncologic outcomes tissue sarcoma (local recurrence and overall survival) in Clinical and Translational Oncology (2019) 21:1398–1412 localised resectable STS after pre- versus postoperative radio- therapy Bhangu 2013 SR Standard search; To determine the 18 1 0 0 17 Patients aged 12 years 1030 7 through December efficacy and safety of and older/aggressive 2011 isolated limb perfu- and poorly differenti- sion for extremity ated extremity soft sarcoma tissue sarcoma Branwell 2003 SRM Followed Cochrane To determine the 8 8 0 0 0 Adults/incurable 2281 9 Collaboration efficacy of the use of locally advanced or Guidelines; through doxorubicin-based metastatic soft tissue September 2006 combination chemo- sarcoma therapy compared with single-agent doxorubicin Camuh 2010 SR Standard search; To assess the efficacy, 4 1 0 3 0 Adults/soft tissue 464 8 through February safety and efficiency sarcoma 2009 of trabectedin in the treatment of soft tis- sue sarcoma Cheng 2016 SR Followed meta-analysis To synthesise and 15 0 0 1 14 Adults/primary or 464 8 of observational stud- evaluate the literature recurrent retroperito- ies in epidemiology about neoadjuvant neal sarcoma (MOOSE) recom- radiation for retrop- mendations; through eritoneal sarcoma January 2014 13 1403 Table 2  (continued) 1404 ID Study design Search methods and Research question or Number RCT​ Non-ran- Non- Obser- Population/type of soft Patients (N) AMSTAR year aim of studies domised controlled vational tissue sarcoma score 13 included trial trial studies Deppla 2014 SR Standard search; To evaluate all publica- 74 0 0 0 74 Adults/angiosarcoma 222 5 through April 2013 tions on primary after radiation for treatment of RAAS primary breast cancer (radiation-associated angiosarcoma) to identify prognostic factors and evaluate treatment modalities Foroozan 2012 SR Standard search; To summarise evidence 23 0 0 0 23 Adults/dermatofibro- 847 8 through August 2011 about the recurrence sarcoma protuberans of dermatofibrosar- coma protuberans following Mohs micrographic surgery Gupta 2013 SR Standard search; To investigate and 6 1 1 4 0 Adults/locally 216 7 through June 2011 compare the treat- advanced, recurrent ment effects of sys- or metastatic uterine temic chemotherapy leiomyosarcoma Kanjeekal 2005 SRM Standard search; To conduct a system- 27 3 0 24 0 Adults/advanced uter- 423 5 through June 2004 atic review of the lit- ine sarcoma erature regarding the systemic treatment of advanced uterine sarcoma and provide an evidence-based summary of the available literature Ma 2010 SRM Standard search; To assess effectiveness 6 6 0 0 0 Paediatric and adults/ 836 8 through December of chemotherapy ver- soft tissue sarcoma 2008 sus non-chemother- apy in the treatment of soft tissue sarcoma Mulder 2015 SR Followed Cochrane To compare the effec- 0 0 0 0 0 Paediatric and young 0 7 Collaboration tiveness of cyclo- adults/bone and soft Guidelines; through phosphamide with tissue sarcoma December 2009 that of ifosfamide Munene SR Standard search; To evaluate the 9 1 0 0 8 Adults/peritoneal 240 5 2011 through October cytoreduction (CRS) sarcomatosis 2010 and intraperitoneal chemotherapy Clinical and Translational Oncology (2019) 21:1398–1412 Table 2  (continued) ID Study design Search methods and Research question or Number RCT​ Non-ran- Non- Obser- Population/type of soft Patients (N) AMSTAR year aim of studies domised controlled vational tissue sarcoma score included trial trial studies Noorda 2004 SR Followed evidence- To assess the best 19 0 0 0 19 Adults/soft tissue 2 based medicine, available evidence sarcoma University of Toronto for the use of isolated limb perfusion Peinemann 2011 SRM Standard search; To determine whether 40 0 3 0 37 Paediatric and adults/ 391 10 through June 2010 high-dose chemo- metastatic rhabdo- therapy followed by myosarcoma autologous hemat- opoietic stem cell transplantation in patients with meta- static RMS has addi- Clinical and Translational Oncology (2019) 21:1398–1412 tional benefit or harm compared to standard chemotherapy Peinemann 2014 SR Followed PRISMA To compare the 62 1 0 0 61 Adults/locally 377 9 guidelines; through efficacy and adverse advanced or meta- June 2014 events of autologous static non-rhabdo- haematopoietic stem myosarcoma soft cell transplantation tissue sarcomas following high- dose chemotherapy versus standard-dose chemotherapy Pervaiz 2008 SRM Standard search; To update the 1997 18 18 0 0 0 Adults/localised 1953 6 through April 2007 meta-analysis resectable soft tissue of randomised sarcoma controlled trials to reassess the efficacy of doxorubicin-based chemotherapy with respect to recurrence and survival Qu 2016 SRM Standard search; To investigate the 30 2 0 0 28 Adults/soft tissue 6467 10 through September association between sarcoma 2014 radiotherapy and survival in patients undergoing surgery 13 1405 Table 2  (continued) 1406 ID Study design Search methods and Research question or Number RCT​ Non-ran- Non- Obser- Population/type of soft Patients (N) AMSTAR year aim of studies domised controlled vational tissue sarcoma score 13 included trial trial studies Raun-Hain 2013 SR Followed meta-analysis To determine the 86 1 0 1 84 Adults/endometrial NS 4 of Observational evaluation and man- stromal sarcoma Studies in Epidemi- agement of patients and undifferentiated ology Guidelines; with endometrial endometrial sarcoma through January stromal sarcoma 2013. and undifferentiated endometrial sarcoma Sharma 2013 SR Standard search; To evaluate the inter- 100 6 0 0 94 Adults/advanced soft 2319 9 through March 2012 ventions in second- tissue sarcoma or later-line treatment of advanced STS Trabulsi 2012 SR Standard search; To evaluate the phase 12 1 0 9 2 Adults/locally 518 7 through June 2011 II trials related to advanced soft tis- hyperthermic isolated sue sarcoma of the limb perfusion as an extremities effective treatment modality of locally advanced soft tissue sarcomas of the extremities Van de voorde SR Standard search; To determine the ben- 19 0 0 0 19 Adults/retroperitoneal 1426 5 2011 through January 2011 efit of radiotherapy in sarcomas terms of local control and/or survival Verma 2008 (a) SRM Followed Cancer Care To determine the role 26 3 0 23 0 Adults/advanced soft 1402 6 Ontario’s Program in of ifosfamide-based tissue sarcoma Evidence-based Care; combination chemo- through October therapy 2007 Verma 2008 (b) SR Standard search; To determine the 20 3 0 17 0 Adults/inoperable, 1354 5 through June 2007 benefit of first-line locally advanced or dose-intensive metastatic soft tissue chemotherapy sup- sarcoma ported by growth factor or autologous bone marrow/stem cell transplantation SRM: Systematic review with meta-analysis, SR: Systematic review without meta-analysis, SN: Non stated Clinical and Translational Oncology (2019) 21:1398–1412 Clinical and Translational Oncology (2019) 21:1398–1412 1407 12 11 10 30 9 8 6 AMSTAR 7 5 6 5 10 18 5 4 3 2 1 REPORTED AS REPORTED AS REPORTED AS REPORTED AS REPORTED AS BENEFICIAL PROBABLY HARMFUL NO EFFECT INCONCLUSIVE BENEFICIAL Adjuvant chemotherapy vs no adjuvant chemotherapy Radiaon + surgery vs surgery alone Adjuvant doxorubicin based chemotherapy vs local treatment alone Preoperave radiaon vs postoperave radiaon Adjuvant doxorubicin based chemotherapy + ifosfamide vs local treatment Fig. 3  Evidence mapping of the therapeutic interventions for patients with localisable resectable STS (first line) 11 10 9 8 1 1 1 1 1 1 2 2 8 7 AMSTAR 6 2 3 1 5 4 3 2 1 REPORTED AS REPORTED AS REPORTED AS REPORTED AS REPORTED AS BENEFICIAL PROBABLY HARMFUL NO EFFECT INCONCLUSIVE BENEFICIAL Doxorubicin based combinaon vs single-agent doxorubicin Doxorubicin + ifosfamide vs doxorubicin alone Doxorubicin+ streptozotocin vs doxorubicin alone Doxorubicin + mitomicyn and cisplan vs doxorubicin alone Doxorubicin + vincrisne+ cyclophosphamide vs doxorubicin alone Doxorubicin + vincrisn + cyclofosfamide+ dacarbazine vs doxorubicin alone Doxorubicin + dacarbazine vs doxorubicin alone Combinaon chemotherapy with ifosfamide vs chemotherapy without ifosfamide Doxorubicin + cyclophosfamide vs doxorubicin alone Doxorubicin + ifosfamide+ dacarbazine vs doxorubicin + dacarbazine Doxorubicin + vindesine vs doxorubicin alone Fig. 4  Evidence mapping of the therapeutic interventions for patients with locally advanced unresectable and/or metastatic STS (first line) 7. Patients with retroperitoneal sarcoma: Two SRs [22, one SR [23]. Surgery plus radiotherapy was considered 36] evaluated different combinations of radiotherapy. as “probably beneficial” compared with surgery alone, In total, two non-controlled trials and 33 observational and surgery plus chemotherapy was considered as “no studies were included. The results were evaluated by effect” compared with surgery alone. the authors and considered as “probably beneficial” and “no effect” depending on different regimens assessed. In patients with dermatofibrosarcoma protuberans Mohs, Evidence mapping is detailed in Fig. 7. micrographic surgery was considered as “probably benefi- 8. Special entities: Two comparisons were evaluated in cial” compared with wide local excision in one SR [24]. patients with radiation-associated angiosarcoma within 13 1408 Clinical and Translational Oncology (2019) 21:1398–1412 Fig. 5  Evidence mapping of the therapeutic interventions for patients with locally advance STS 11 10 9 8 8 7 AMSTAR 1 6 5 1 8 1 1 4 4 2 3 1 1 3 2 1 REPORTED AS REPORTED AS REPORTED AS REPORTED AS REPORTED AS BENEFICIAL PROBABLY HARMFUL NO EFFECT INCONCLUSIVE BENEFICIAL Histerectomy + salpingectomy + linfadenectomy vs histerectomy + salpingectomy Combinaon chemotherapy in first line vs single agent chemotherapy in paents with Ovary sparing vs no ovary sparing advanced, recurrent or metastac uterine mixed mesodermal tumor Surgery plus adjuvant radiotherapy vs surgery alone Ifosfamide + cisplanum vs ifosfamide alone Doxorubicin+ cyclophosphamide vs doxorubicin alone Combinaon chemotherapy in first line vs single agent chemotherapy in paents with Doxorubicin + dacarbazine vs doxorubicin alone advanced, recurrent or metastac uterine leiomyosarcoma Surgery plus adjuvant hormonal therapy vs surgery alone Gemcitabine + docetaxel vs gemcitabine alone Combinaon chemotherapy in second line vs single agent chemotherapy Fig. 6  Evidence mapping of the therapeutic interventions for patients with uterine sarcomas Finally, in patients diagnosed with peritoneal sarcomatosis Discussion the addition to intraperitoneal chemotherapy to cytoreduc- tion was considered as “no effect” in one SR [28]. Currently, there are several options to perform rapid sys- tematic reviews to assess the effects of interventions among 13 Clinical and Translational Oncology (2019) 21:1398–1412 1409 10 9 8 3 15 7 AMSTAR 6 5 4 2 5 1 19 8 1 4 3 2 1 REPORTED AS REPORTED AS REPORTED AS REPORTED AS REPORTED AS BENEFICIAL PROBABLY HARMFUL NO EFFECT INCONCLUSIVE BENEFICIAL Radiotherapy + surgery vs surgery alone EBRT + IORT vs EBRT alone Neoadjuvant radiotherapy vs Surgery without neoadjuvant radiotherapy HDR IORT +EBRT vs HDR IORT alone EBRT + surgery vs surgery Cytoreducon+ intraperitoneal chemotherapy vs Cytoreducon alone EBRT preoperave vs EBRT postoperave Cytoreducon+ early postoperave chemotherapy vs Cytoreducon alone Intraoperave radiotherapy + neoadjuvant radiotherapy vs Neoadjuvant radiotherapy Fig. 7  Evidence mapping of the therapeutic interventions for patients with retroperitoneal sarcomas and peritoneal sarcomatosis which are: rapid reviews, scoping review, evidence mapping, would only be justified if the specific therapeutic goal is etc. The decision about the type to use should be selected tumour shrinkage [43]. depending on the topic, time for conduction and resources. Furthermore, CPGs recommend pazopanib as second-line In contrast, evidence mapping is a new methodological sys- chemotherapy in patients with advanced STS after failure of tematic approach whose purpose is to identify gaps in the prior anthracyclines and ifosfamide [4, 44, 45]. However, the existing knowledge and prioritise further research in very unique SR that addresses this issue reported this intervention broad fields by displaying it in a friendly format. [9]. Its as “probably beneficial” based on a single RCT where the potential advantages include summarizing and displaying control group was placebo [15]. large quantity of information in an efficient and friendly way. According to our results, the majority of SRs addressed As a part of an evidence mapping project about sarcomas, palliative treatments and only four SRs included quality we identified, described and organised the current available of life as an outcome [15, 21, 27, 28], meanly because the evidence about soft tissue sarcomas. In a previous paper, majority of primary studies did not measure this outcome. we reported the evidence mapping on gastrointestinal stro- Due to the fact that palliative care seeks the prevention and mal tumours (GIST) [13], and now we focus on soft tis- relief of suffering derived from pain and other physical prob- sue sarcomas. We found 24 SRs including 279 individual lems, which in turn may positively affect quality of life, it is studies. Same as described in the evidence maps for GIST, outstanding that most studies do not include this outcome the majority of studies retrieved for STS (85%) were also to provide a comprehensive perspective of treatment effect. non-randomised controlled trials (observational studies, or On the other hand, this outcome is essential to distinguish non-controlled, or non-randomised clinical trials), and in between treatments which have an effect on symptoms, but all but one the control group was placebo. For this reason, not necessarily equal impact over quality of life. Therefore, the evidence base in this area is weak, as non-experimental it should be measured in all studies conducted in sarcomas designs include information about treatment effects which patients [46]. may probably be biased or unreliable [41]. For instance, Our evidence maps used a new format to display the although some clinical practice guidelines (CPGs) recom- results graphically in order to facilitate the understanding mend the combination of doxorubicin and ifosfamide as and interpretation of them and make them user friendly. the most effective first-line chemotherapy for patients with However, it should be noted that some graphs (bobble plots) locally advanced unresectable and/or metastatic STS [42], included treatments that are not currently used, or are used the authors of two SRs report this option as “inconclusive”. only in specific clinical settings. For instance, it was the case Likewise, one recent randomised controlled trial published for the bubble plot number two (different schemes of doxo- did not observe any effect on overall survival and its use rubicin in patients with locally advanced unresectable and/or 13 1410 Clinical and Translational Oncology (2019) 21:1398–1412 metastatic STS were plotted). In consequence, this graphic identify the gaps in the knowledge instead of supporting format itself does not inform about the best treatment option, clinical decisions. In relation to this point, we considered but allows us to display the history of treatment along time. that is important to establish what is the best type of study Hence, clinical experience is needed to identify the clinical design to do the evidence maps (randomised controlled trial utility and implications of it. and/or observational studies), taking into account the subject The overall quality of SRs applying the AMSTAR cri- of study, the time to do the mapping, and the objective of teria was moderate to high. Nervertheless, as we detected mapping the evidence (define the research gap to propose a in the GIST mapping, there are some domains that are less research question or to conduct a SR). Secondly, as afore- frequently reported: the reporting of excluded studies (only mentioned in the GIST mapping, a drawback of this meth- 4 studies out of 24 did it), the methods used to combine the odology is that it solely organises and describes the evidence findings of studies (7 out 24 did it), and the assessment of as reported by the respective authors. Hence, some results publication bias (3 out 24 did it). could be described as beneficial even if they are based on non-experimental studies or low quality evidence. For this Strengths reason, this is not an appropriate tool for making clinical decision in health care. Although several methodologies have been proposed, we selected the one widely used and incorporated new compo- nents to make the tool more useful. Conclusions Although the evidence mapping methodology does not usually describe the type and quality of included studies, our This evidence mapping was built on the basis of SRs, which mapping provided this type of information, which will even- mostly included non-experimental studies and were qualified tually facilitate stakeholders to take a decision of the most by the AMSTAR tool as of moderate quality. The evidence suitable design in future research and identify the quality of mapping created from PICO questions is a useful approach the evidence in which clinical decisions are based. to describe complex and huge clinical topics through graphi- We used the PICO format to organise the available infor- cal media and orientate further research to fulfil the existing mation and describe the results applied to more specific sce- gaps. However, is important to delimitate the steps of the narios according to current clinical practice. We believed evidence mapping in a pre-established protocol. that this approach is appropriate in clinical settings as it gives a better understanding and clarity to the description Acknowledgements The authors would like to acknowledge Montse of the results. However, it is essential to define the PICOs Leon for their assistance with the edition of this paper. Also to the Iberoamerican Cochrane Centre to support this study as part of Mónica from the beginning of the project, that is, since the protocol Ballesteros’ PhD thesis in the Universitat Autònoma de Barcelona. was designed. We also considered essential to include an expert on the topic and a methodologist as well, to improve Authors’ contributions Conceived the study: XB, GU, MB, NM. and include the relevant perspectives in the analysis, pres- Designed the study: MB, NM, XB, GU, IS, HP. Analysed the data: entation of results, discussion and conclusions. MB, NM, ALP. Wrote the first draft of the manuscript: MB, NM. Con- tributed to the writing of the manuscript: MB, NM, IS, XB, GU, GR. The results of evidence mapping should ideally be Approved the final manuscript and conclusions: MB, NM, ALP, GU, displayed graphically, to synthesise the information in a GR, IS, HP, XB. friendly format. We considered that according to the amount the information is available it is important to define what Funding This work was supported by a grant by the Grupo Español type of specific graphic format is more illustrative. In fields de Sarcomas (GEIS) (­ 8a Beca GEIS José M ­ a Buesa de Ayuda a la Investigación en Sarcomas-Convocatoria 2014). The initiative and sole where a huge amount of information is available, the bubble responsibility for this research lies entirely and exclusively with the plots are a good option. authors who have acted with complete independence from the funder. Limitations Compliance with ethical standards As in the mapping of GIST we faced some limitations. Conflict of interest The authors declare that they have no competing interests. Firstly, our SRs search was done in 2016, but their respec- tive study searches were conducted in 2014 or earlier. There- Ethical approval Not applicable. fore, we have not detected other studies that may publish but are not included in the systematic reviews. Nevertheless, Informed consent None. we are confident that these limitations would not substan- Availability of data and material The datasets generated and/or ana- tially modify our results bearing in mind that the aim is to lysed during the current study are available in the figshare repository: 13 Clinical and Translational Oncology (2019) 21:1398–1412 1411 https:​ //www.figsha​ re.com/s/9a3047​ 98a6f​ 8d313​ 46fb.​ https:​ //www.figsh​ 14. Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak are.com/s/a9fbd​04d4b​898de​cee63​. KF, et al. Gastrointestinal stromal tumors in a cohort of Chi- nese patients in Hong Kong. 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Meta-analysis of ifosfamide-based combination chemotherapy in Publisher’s Note Springer Nature remains neutral with regard to advanced soft tissue sarcoma. Cancer Treat Rev. 2008;34(4):339–47 jurisdictional claims in published maps and institutional affiliations. Epub 2008/03/04. 39. (CAMUH) CdAdMdUH. Trabectedin (Yondelis) in the treatment of soft tissue sarcomas. Trabectedina (Yondelis) en el tracta- ment de sarcomes de teixits tous. Catalunya: Catalan Agency for Affiliations M. Ballesteros1 · N. Montero2 · A. López‑Pousa3 · G. Urrútia4,5 · I. Solà4,5 · G. Rada6 · H. Pardo‑Hernandez4,5 · X. Bonfill4,5 1 N. Montero C/Sant Antoni Maria Claret, 167, Pavelló 18, Ground Floor, nadiamonteromd@gmail.com 08025 Barcelona, Spain 2 A. López‑Pousa Centro de Investigación en Salud Pública y Epidemiología ALopezP@santpau.cat Clínica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador G. Urrútia 3 GUrrutia@santpau.cat Oncología Médica y Unidad de Curas Paliativas, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain I. Solà 4 ISola@santpau.cat Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain G. Rada 5 radagabriel@gmail.com CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain H. Pardo‑Hernandez 6 HPardo@santpau.cat Evidence Based Health Care Program, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile X. Bonfill XBonfill@santpau.cat 13