Sarcomas comprise a rare and heterogeneous group of malignant tumors of mesenchymal origin. The application of perioperative chemotherapy has the potential to improve outcomes for patients with localized extremity soft tissue sarcoma. This article describes a survey among members of the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and the Bone Sarcoma Group (STBSG) to investigate the variation in the use of perioperative chemotherapy in extremity soft tissue sarcoma, including which criteria are applied when determining whether to offer perioperative chemotherapy.
Keywords: Soft tissue sarcoma, Chemotherapy, Adjuvant, Neoadjuvant, Decision‐making, Expert opinion
Abstract
Background.
The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts.
Materials and Methods.
Medical oncology experts of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group were asked to participate in this survey on the use of pre‐ and postoperative chemotherapy in STS. Experts from 12 centers in Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands agreed to participate and provided their treatment algorithm. Answers were converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies.
Results.
Several criteria used for decision‐making in extremity STS were identified: chemosensitivity, fitness, grading, location, and size. In addition, resectability and resection status were relevant in the pre‐ and postoperative setting, respectively. Preoperative chemotherapy is considered in most centers for marginally resectable tumors only. Yet, in some centers, neoadjuvant chemotherapy is used routinely and partially combined with hyperthermia. Although most centers do not recommend postoperative chemotherapy, some offer this treatment on a regular basis. Radiotherapy is an undisputed treatment modality in extremity STS.
Conclusion.
Due to lacking evidence on the utility of pre‐ and postoperative chemotherapy in localized extremity STS, treatment strategies vary considerably among European experts. The majority recommended neoadjuvant chemotherapy for marginally resectable grade 2–3 tumors; the majority did not recommend postoperative chemotherapy in any setting.
Implications for Practice.
The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts. This study analyzed the decision‐making process among 12 European experts on systemic therapy for STS. A wide range of recommendations among experts regarding the use of perioperative chemotherapy was discovered. Discrepancies in the use of decision criteria were also uncovered, including the definition of what constitutes high‐risk cancer, which is a basis for many to recommend chemotherapy. Before any standardization is possible, a common use of decision criteria is necessary.
Introduction
Sarcomas comprise a rare and heterogeneous group of malignant tumors of mesenchymal origin. Historically, sarcomas were grouped according to the tumor location into two main types: soft tissue sarcoma (STS) and primary bone sarcoma [1]. STS account for 1% of all adult malignancies and 6% of childhood cancers [2]. STS incidence is approximately 4 per 100,000 per year [3]. More than 70 histologic STS subtypes are recognized in the 2013 World Health Organization classification [4]. Although STS can arise anywhere in the body, the most common sites are the limbs or limb girdles [5]. The standard treatment of localized extremity STS is wide local excision with negative margins and the aim of functional limb preservation [6]. Radiation therapy is an additional standard treatment to improve local control in the presence of risk factors (high‐grade [grade 2–3], deep location, lesions >5 cm) [7], and can be delivered pre‐ or postoperatively [8]. The current American Joint Committee on Cancer/Union for International Cancer Control staging system [9] classifies patients with STS according to tumor size, tumor depth, nodal involvement, and distant metastases, in addition to malignancy grade [10]. Nomograms that predict prognosis in patients with STS have been developed to provide more accurate estimates of patient outcome [11]. According to EUROCARE‐5, the 5‐year survival for cancers classed as arising from soft tissue is 60% [12].
Despite numerous studies, there is no consensus on the current role of adjuvant chemotherapy in localized extremity STS in the presence of negative results from the largest studies. However, data from smaller studies suggest that it might improve local control, or at least delay distant and local recurrence in high‐risk patients.
A potential means of improving outcome for patients with localized extremity STS is the application of perioperative chemotherapy. Despite numerous studies, there is no consensus on the current role of adjuvant chemotherapy in localized extremity STS [6] in the presence of negative results from the largest studies [13]. However, data from smaller studies suggest that it might improve local control, or at least delay distant and local recurrence in high‐risk patients [14]. Two meta‐analyses of the randomized controlled trials with adjuvant chemotherapy for STS were performed and showed a benefit of adjuvant chemotherapy in terms of local and distant relapse rate [15], [16]. The more recent publication also noted a small but statistically significant benefit in terms of overall survival (OS) for doxorubicin plus ifosfamide (p = .01), with an 11% reduction in the risk of death [16]. A consideration for the recommendation on preoperative chemotherapy is enhancing resectability in marginally resectable tumors.
Given the controversies on perioperative chemotherapy, we performed a survey among members of the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) to investigate the variation in the use of perioperative chemotherapy in extremity STS and which criteria are applied in the decision to offer perioperative chemotherapy or not.
Materials and Methods
Members of the EORTC STBSG were identified at the annual meeting in Amsterdam in October 2015 and asked to participate in this survey. In a first step, 19 attendees of the EORTC STBSG annual meeting showed interest, and finally sarcoma experts from 12 centers and 7 countries (Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands) volunteered to contribute and provide their treatment algorithm for patients with localized extremity STS in November 2015. All of these experts represent sarcoma centers, where treatment decisions are made within a multidisciplinary team. The participants were initially asked to answer the following open question: “What is your treatment policy regarding pre‐ and/or postoperative chemotherapy in localized extremity STS?” For the purposes of the present analysis, additional treatment such as isolated limb perfusion (ILP) and regional hyperthermia (RH) were not considered, even though they supplement surgery, radiotherapy, and chemotherapy in some of the centers. The initial answers provided were collected and converted into decision trees [17] by the coordinating center (St. Gallen), based on the objective consensus methodology [18] as published previously [19], [20], [21]. This process consisted of an initial manual transformation of the replies into simple decision trees; once these were created, the respondents were contacted again to fill in possible empty branches of the decision trees. After the initial round of collections, all participants were contacted to confirm that the nomenclature used was valid for their trees. Two sets of decision trees were created per participant corresponding to the pre‐ and postoperative setting. Several participants mentioned high‐ or low‐risk situations consisting of combinations of tumor size, tumor grade, and location (superficial vs. deep)—however, their usage was heterogeneous in defining the risk category (e.g., one or multiple criteria constituted high‐risk). For this reason, the terms high‐ and low‐risk were replaced by combinations of the constituting elements as individually defined by the participating experts.
Histologic subtypes were mentioned by multiple participants, but as histology‐specific chemotherapy regimens were not part of the tree analysis, the criterion “chemosensitivity” was introduced for simplification. Adequate fitness (good performance status, appropriate life expectancy, limited comorbidities) was a prerequisite for all participants and was excluded from the analysis. We excluded STS with established treatment guidelines (e.g., rhabdomyosarcoma) and STS treated within clinical trials. Following presentation of new data on preoperative chemotherapy at the European Society of Medical Oncology (ESMO) congress in October 2016, which is now published [22], we contacted the participants again and asked for any changes in their treatment approach. The decision trees were finalized and confirmed by each participant by April 1, 2017. The decision trees were used as a basis to identify consensus and discrepancies by a software tool that compares all possible branches of individual trees and provides numerical representation of consensus or discrepancy.
Results
Twelve decision trees were analyzed and compared (a sample decision tree is shown in Fig. 1) in the preoperative as well as the postoperative setting. The parameters considered relevant for the decision on preoperative chemotherapy were resectability, grade, location, and size (Table 1). In this setting, “resectable” was defined as resection with no expected functional deficits or severe postoperative morbidity. Although other definitions of resectability are possible, all participants considered it feasible within this context.
Figure 1.
Sample decision tree illustrating the input from one center on preoperative chemotherapy.
Abbreviations: G, grade; STS, soft tissue sarcomas.
Table 1. Decision criteria per center.
(+) marks the use of decision criteria in decision‐making for preoperative chemotherapy in STS per center.
Abbreviation: STS, soft tissue sarcomas.
Most centers (n = 11) consider preoperative chemotherapy only in selected cases with marginally resectable STS aiming for tumor volume reduction and subsequent improved resectability, usually performed within a multimodal treatment setting. This might involve ILP and radiotherapy. However, some centers use preoperative chemotherapy as a standard regimen for primarily resectable high‐risk disease (Fig. 2). One center routinely delivers pre‐ and postoperative chemotherapy in combination with RH in all high‐risk extremity STS [23].
Figure 2.
Preoperative chemotherapy mode.
Abbreviations: G, grade; STS, soft tissue sarcomas.
In light of data on standard versus histology‐tailored preoperative chemotherapy recently presented at the EMSO 2016 Congress [24], one center adopted routine preoperative chemotherapy in high‐risk STS, whereas other centers did not change their policies after these data became available.
In the postoperative setting, relevant decision criteria on chemotherapy were resection status, grade, location, and size (Table 2).
Table 2. Decision criteria per center.
(+) marks the use of decision criteria in decision making for postoperative chemotherapy in STS per center.
Abbreviation: STS, soft tissue sarcomas.
In relation to resection status, for R1‐resection we assumed that an attempt for R0‐resection was impossible or reresection had already been attempted.
Half the centers do not recommend adjuvant chemotherapy, whereas 6 of the 12 experts routinely use adjuvant chemotherapy in patients with high‐risk STS (Figs. 3, 4). Among the experts who do not use adjuvant chemotherapy routinely, some might consider it in individual case‐by‐case decisions, and others do not consider adjuvant chemotherapy as a treatment option at all.
Figure 3.
Postoperative chemotherapy mode.
Abbreviations: G, grade; STS, soft tissue sarcomas.
Figure 4.
Distribution of chemotherapy versus no chemotherapy in high‐risk STS by center.
Abbreviations: G, grade; STS, soft tissue sarcomas.
High‐risk STS was usually defined as tumor size >5 cm and tumor location deep in the limb, no lymph node involvement, no metastatic spread, and grade 3 [9]. Some experts require the presence of all high‐risk features for classification as high‐risk. However, other experts also give pre‐ and/or postoperative chemotherapy in patients fulfilling only two of three high‐risk criteria (Fig. 5). Interestingly, R1‐resection for some experts is a criterion to recommend adjuvant chemotherapy; for other experts, it is a reason to withhold adjuvant chemotherapy, and some experts do not use resection status as a criterion.
Figure 5.
Sample decision tree illustrating the input from one center on postoperative chemotherapy.
Abbreviations: G, grade; STS, soft tissue sarcomas.
Most experts named patient factors such as age <70 years or fitness as the decision criteria. We decided to not consider these in the analysis, forasmuch that we would assume biologic conditions, absence of contraindications, and absence of severe medical conditions (such as congestive heart failure or renal insufficiency) a universal prerequisite when considering pre‐ or postoperative chemotherapy.
In addition to the criteria used for decision‐making on the use of chemotherapy, we asked the experts to provide the chemotherapy agents or regimens used in their respective center.
In the preoperative setting for marginally resectable STS, doxorubicin is usually given in combination with ifosfamide; doses range from doxorubicin 60 mg/m2 on day 1 to doxorubicin 30 mg/m2 on days 1–3, and ifosfamide is given in doses from 7.5 g/m2 to 10 g/m2 over 3–5 days. In patients with marginally resectable leiomyosarcoma, doxorubicin is combined with dacarbazine in three centers, whereas in patients with marginally resectable synovial sarcoma, four centers give ifosfamide in combination with radiotherapy, and two centers chose trabectedin and radiotherapy in myxoid liposarcoma. The number of preoperative chemotherapy cycles is variable from three to six, or until best response.
In centers where patients with primarily resectable extremity STS are routinely considered for preoperative chemotherapy, treatment is with three cycles doxorubicin/ifosfamide or epirubicin/ifosfamide. The chemotherapy in combination with RH at one center consists of four cycles doxorubicin/ifosfamide preoperatively and four cycles postoperatively [23]. Adjuvant chemotherapy is usually applied with doxorubicin/ifosfamide or epirubicin/ifosfamide; however, in angiosarcoma, three cycles doxorubicin/ifosfamide are supplemented with three cycles gemcitabine 900 mg/m2 day 1 and 8 and docetaxel 75 mg/m2 day 8 in two centers.
Histologic subtypes not considered eligible for perioperative chemotherapy included solitary fibrous tumor, epithelioid hemangioendothelioma (EHE), alveolar soft part sarcoma, clear cell sarcoma, follicular dendritic cell sarcomas, PEComa, dermatofibrosarcoma protuberans, and any low‐grade STS. Opinions on chemosensitivity differed among experts (e.g., concerning well‐differentiated/dedifferentiated liposarcoma or EHE). Obviously, the subtypes mentioned are heterogeneous and the list is not exhaustive; some histologies may be potential chemotherapy responders.
Pre‐ or postoperative radiotherapy was considered by all experts and is an undisputed component of the treatment in high‐risk extremity STS; however, it was not within the scope of this survey to assess this treatment modality. Nevertheless, the sequence of treatments is of interest: whereas in most centers preoperative chemotherapy is followed by surgery and adjuvant radiotherapy, in one center concomitant preoperative radiochemotherapy is standard [25]. Among centers that consider adjuvant chemotherapy, this is given prior to adjuvant radiotherapy in four centers. Two centers first perform adjuvant radiotherapy followed by adjuvant chemotherapy. The choice of chemotherapy agents is not influenced by the sequence of treatments.
Discussion
This is the first report on a comparison of treatment algorithms for extremity STS using the objective consensus methodology. We performed a survey among 12 experts of the EORTC STBSG assessing criteria for the use of pre‐ or postoperative chemotherapy in localized extremity STS. The selection of participants and the group size is debatable; however, it is not expected that a larger group or a different set of experts would have resulted in higher levels of consensus.
Among these experts, we revealed substantial heterogeneity in the use of pre‐ and postoperative chemotherapy in different European centers. Several experts completely refrain from using systemic treatment in primarily resectable extremity STS. On the other side of the spectrum, up to eight cycles of combination chemotherapy are given pre‐ and postoperatively in combination with RH in one center. This reflects the inconclusive and contradicting publications on chemotherapy in localized STS [26].
At longer follow‐up of the Italian and Spanish Sarcoma Group study, noninferiority of three cycles of a full‐dose conventional preoperative chemotherapy in comparison with five cycles (three preoperative and two postoperative) was confirmed [27]. Response to therapy was demonstrated to be associated with better survival. However, the study did not provide a comparison with no chemotherapy. Similarly, the randomized controlled trial to assess the safety and efficacy of RH with chemotherapy by the EORTC STBSG and the European Society for Hyperthermic Oncology demonstrated that RH increases the benefit of chemotherapy, but no chemotherapy‐free arm was executed [23]. Hence, both trials did not irrevocably anchor chemotherapy as standard treatment in localized extremity STS. In a pooled analysis of two EORTC phase III trials [13], [28], adjuvant chemotherapy was not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery was the most important prognostic and predictive factor for utility of adjuvant chemotherapy in STS, although it is known that chemotherapy cannot compensate for poor surgery. Based on these data, the investigators conclude that adjuvant chemotherapy for STS remains an investigational procedure and is not a routine standard of care [29]. Yet, it is noteworthy that those patients with R1‐resection had a significantly better relapse‐free survival (RFS) and OS favoring adjuvant chemotherapy, and that in our analysis several experts do not consider resection status a relevant criteria for the decision for or against adjuvant chemotherapy.
Until now, only one randomized trial comparing neoadjuvant chemotherapy followed by surgery with direct surgery in 150 high‐risk STS patients was published and showed no benefit of doxorubicin 50 mg/m2 and ifosfamide 5 g/m2 in terms of RFS or OS [30].
Data from the interim analysis of the Italian and French Sarcoma Group trial presented at ESMO 2016 comparing a standard regimen of preoperative chemotherapy with three cycles epirubicin/ifosfamide versus three cycles histology‐tailored chemotherapy drew much attention [24]. The study randomized 287 patients. In the interim analysis, at a median follow‐up of 12.3 months, the number of events was 25 (17.4%) in the standard arm compared with 45 events (37.1%) in the histology‐tailored arm, translating into a projected Kaplan‐Meier RFS probability at 46 months of 0.62 (as expected by previous trials in this area) in the standard arm and 0.38 (log‐rank p = .004) in the histology‐tailored arm, respectively. The results must be interpreted with caution: the follow‐up time was short, and although standard chemotherapy may be advantageous, it may also be that histology‐tailored chemotherapy conveys harm in delaying curative surgery. There was no control arm without chemotherapy. However, this study provides important information on response to preoperative chemotherapy: in the standard arm, 81% of patients had stable disease and 16% of patients obtained a partial response by Response Evaluation Criteria in Solid Tumors. The R0‐resection rate was 90% in the standard chemotherapy arm and comparable to a previous study assessing the same preoperative chemotherapy regimen [25]. In contrast, the R0‐resection rate in the French Sarcoma study group investigating adjuvant chemotherapy was only 50% [14]. Facilitating surgery and increasing the R0‐resection rate by administration of preoperative chemotherapy may positively impact STS outcome. The importance of achieving an R0‐resection was just recently highlighted in a publication assessing adherence to clinical practice guidelines for surgery and treatment in an expert center for sarcoma, both of which are independent positive factors affecting progression‐free survival and OS in STS patients [31].
It remains unclear whether epirubicin/ifosfamide should be the standard preoperative treatment in all high‐risk extremity STS, and the duration of induction chemotherapy is uncertain.
Studies on adjuvant chemotherapy in extremity STS are confounded by variable chemotherapy dosing and variable patient selection, as determined by risk. The uncertainties concerning pre‐ and postoperative chemotherapy in localized extremity STS are reflected in the National Comprehensive Cancer Network and ESMO guidelines, which state that there are limited and conflicting data regarding the potential benefits of adjuvant chemotherapy in stage II and III patients [6], [32], [33]. Shared decision‐making with high‐risk individual patients (high‐grade, deep, >5 cm tumor) is proposed [6].
The uncertainties concerning pre‐ and postoperative chemotherapy in localized extremity STS are reflected in the National Comprehensive Cancer Network and ESMO guidelines, which state that there are limited and conflicting data regarding the potential benefits of adjuvant chemotherapy in stage II and III patients. Shared decision‐making with high‐risk individual patients (high‐grade, deep, >5 cm tumor) is proposed.
What is urgently needed are techniques to predict relapse and metastatic spread in patients with STS and to identify patients who might benefit from the addition of chemotherapy either pre‐ or postoperatively. Tumor cells release circulating free DNA into the blood and it is now possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions as well as the opportunity to systematically track genomic evolution [33]. In a recently published case, serial liquid biopsies were used to monitor the disease course and detect disease recurrence in a sarcoma patient [34]. In addition, insight in molecular STS profiles might provide guidance in treatment selection in the future.
The analysis is, of course, a simplification of daily care for sarcoma patients as it does not reflect differences in all the histologic subtypes, anatomic regions, or specific clinical scenarios. However, it may apply and relate to the typical extremity STS. The complexities of patient preference were also not addressed in this analysis. It also does not reflect the multidisciplinary approach to treatment, specifically utilization and scheduling of radiation treatment.
Conclusion
The aim of this survey was to obtain an impression on the use of pre‐ and postoperative chemotherapy in European sarcoma centers for localized extremity STS and to elucidate decision criteria, while aware that no conclusive evidence is available on this topic. The variability of strategies demonstrates an urgent need for data on perioperative chemotherapy, either from further well‐designed trials or cohort studies. We believe that a standardization of risk levels and a homogeneous use of decision criteria could be the first step toward efforts to harmonize treatment strategies in localized extremity STS.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
Author Contributions
Conception/design: Christian Rothermundt, Galina F. Fischer, Paul Martin Putora
Provision of study material or patients: NA
Collection and/or assembly of data: Christian Rothermundt, Galina F. Fischer, Paul Martin Putora
Data analysis and interpretation: Christian Rothermundt, Galina F. Fischer, Sebastian Bauer, Jean‐Yves Blay, Viktor Grünwald, Antoine Italiano, Bernd Kasper, Attila Kollár, Lars H. Lindner, Aisha Miah, Stefan Sleijfer, Silvia Stacchiotti, Paul Martin Putora
Manuscript writing: Christian Rothermundt, Galina F. Fischer, Paul Martin Putora
Final approval of manuscript: Christian Rothermundt, Galina F. Fischer, Sebastian Bauer, Jean‐Yves Blay, Viktor Grünwald, Antoine Italiano, Bernd Kasper, Attila Kollár, Lars H. Lindner, Aisha Miah, Stefan Sleijfer, Silvia Stacchiotti, Paul Martin Putora
Disclosures
Christian Rothermundt: Novartis, Pfizer, Astellas Pharma, Bristol‐Myers Squibb (C/A), Astellas Pharma (RF); Sebastian Bauer: Eli Lilly & Co. (C/A), Incyte, Novartis (RF), Pharmamar (H); Viktor Grünwald: Novartis (RF), Lilly, Novartis (H), Lilly (SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
References
- 1. Skubitz KM, D'Adamo DR. Sarcoma. Mayo Clin Proc 2007;82:1409–1432. [DOI] [PubMed] [Google Scholar]
- 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7–30. [DOI] [PubMed] [Google Scholar]
- 3. Gatta G, van der Zwan JM, Casali PG et al. Rare cancers are not so rare: The rare cancer burden in Europe. Eur J Cancer 2011;47:2493–2511. [DOI] [PubMed] [Google Scholar]
- 4.WHO classification of tumors of soft tissue and bone . International Agency for Research on Cancer (IARC), 69372 Lyon Cedex 08, France, 2013: 4th Edition, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, eds. 10–11.
- 5. Clark MA, Fisher C, Judson I et al. Soft‐tissue sarcomas in adults. N Engl J Med 2005;353:701–711. [DOI] [PubMed] [Google Scholar]
- 6.ESMO/European Sarcoma Network Working Group. Soft tissue and visceral sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow‐up. Ann Oncol; 2014;25(suppl 3):iii102–iii112. [DOI] [PubMed] [Google Scholar]
- 7. Yang JC, Chang AE, Baker AR et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. [DOI] [PubMed] [Google Scholar]
- 8. O'Sullivan B, Davis AM, Turcotte R et al. Preoperative versus postoperative radiotherapy in soft‐tissue sarcoma of the limbs: A randomised trial. Lancet 2002;359:2235–2241. [DOI] [PubMed] [Google Scholar]
- 9. Amin MB, Edge S, Greene F et al, eds. AJCC Cancer Staging Manual. 8th ed. Cham, Switzerland: Springer International Publishing, 2017:489–545. [Google Scholar]
- 10. Coindre JM, Trojani M, Contesso G et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer 1986;58:306–309. [DOI] [PubMed] [Google Scholar]
- 11. Callegaro D, Miceli R, Bonvalot S et al. Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft‐tissue sarcomas of the extremities: A retrospective analysis. Lancet Oncol 2016;17:671–680. [DOI] [PubMed] [Google Scholar]
- 12. Baili P, Di Salvo F, Marcos‐Gragera R et al. Age and case mix‐standardised survival for all cancer patients in europe 1999–2007: Results of EUROCARE‐5, a population‐based study. Eur J Cancer 2015;51:2120–2129. [DOI] [PubMed] [Google Scholar]
- 13. Woll PJ, Reichardt P, Le Cesne A et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft‐tissue sarcoma (EORTC 62931): A multicenter randomised controlled trial. Lancet Oncol 2012;13:1045–1054. [DOI] [PubMed] [Google Scholar]
- 14. Frustaci S, Gherlinzoni F, De Paoli A et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial. J Clin Oncol 2001;19:1238–1247. [DOI] [PubMed] [Google Scholar]
- 15.Adjuvant chemotherapy for localised resectable soft‐tissue sarcoma of adults: Meta‐analysis of individual data. Sarcoma meta‐analysis collaboration. Lancet 1997;350:1647–1654. [PubMed] [Google Scholar]
- 16. Pervaiz N, Colterjohn N, Farrokhyar F et al. A systematic meta‐analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft‐tissue sarcoma. Cancer 2008;113:573–581. [DOI] [PubMed] [Google Scholar]
- 17. Panje CM, Glatzer M, von Rappard J et al. Applied swarm‐based medicine: Collecting decision trees for patterns of algorithms analysis. BMC Med Res Methodol 2017;17:123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Putora PM, Panje CM, Papachristofilou A et al. Objective consensus from decision trees. Radiat Oncol 2014;9:270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Rothermundt C, Bailey A, Cerbone L et al. Algorithms in the first‐line treatment of metastatic clear cell renal cell carcinoma–Analysis using diagnostic nodes. The Oncologist 2015;20:1028–1035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Rothermundt C, von Rappard J, Eisen T et al. Second‐line treatment for metastatic clear cell renal cell cancer: Experts' consensus algorithms. World J Urol 2017;35:641–648. [DOI] [PubMed] [Google Scholar]
- 21. Hundsberger T, Hottinger AF, Roelcke U et al. Patterns of care in recurrent glioblastoma in Switzerland: A multicenter national approach based on diagnostic nodes. J Neurooncol 2016;126:175–183. [DOI] [PubMed] [Google Scholar]
- 22. Gronchi A, Ferrari S, Quagliuolo V et al. Histotype‐tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high‐risk soft‐tissue sarcomas (ISG‐STS 1001): An international, open‐label, randomised, controlled, phase 3, multicenter trial. Lancet Oncol 2017;18:812–822. [DOI] [PubMed] [Google Scholar]
- 23. Issels RD, Lindner LH, Verweij J et al. Neo‐adjuvant chemotherapy alone or with regional hyperthermia for localised high‐risk soft‐tissue sarcoma: A randomised phase 3 multicenter study. Lancet Oncol 2010;11:561–570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Gronchi A, Ferrari S, Quagliuolo V et al. Full‐dose neoadjuvant anthracycline and ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high‐risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial. Ann Oncol 2016;27:vi552–vi587. [Google Scholar]
- 25. Palassini E, Ferrari S, Verderio P et al. Feasibility of preoperative chemotherapy with or without radiation therapy in localized soft tissue sarcomas of limbs and superficial trunk in the Italian sarcoma group/grupo Espanol de investigacion en sarcomas randomized clinical trial: Three versus five cycles of full‐dose epirubicin plus ifosfamide. J Clin Oncol 2015;33:3628–3634. [DOI] [PubMed] [Google Scholar]
- 26. Saponara M, Stacchiotti S, Casali PG et al. (Neo)adjuvant treatment in localised soft tissue sarcoma: The unsolved affair. Eur J Cancer 2017;70:1–11. [DOI] [PubMed] [Google Scholar]
- 27. Gronchi A, Stacchiotti S, Verderio P et al. Short, full‐dose adjuvant chemotherapy (CT) in high‐risk adult soft tissue sarcomas (STS): Long‐term follow‐up of a randomized clinical trial from the Italian sarcoma group and the Spanish sarcoma group. Ann Oncol 2016;27:2283–2288. [DOI] [PubMed] [Google Scholar]
- 28. Bramwell V, Rouesse J, Steward W et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma–reduced local recurrence but no improvement in survival: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1994;12:1137–1149. [DOI] [PubMed] [Google Scholar]
- 29. Le Cesne A, Ouali M, Leahy MG et al. Doxorubicin‐based adjuvant chemotherapy in soft tissue sarcoma: Pooled analysis of two STBSG‐EORTC phase III clinical trials. Ann Oncol 2014;25:2425–2432. [DOI] [PubMed] [Google Scholar]
- 30. Gortzak E, Azzarelli A, Buesa J et al. A randomised phase II study on neo‐adjuvant chemotherapy for ‘high‐risk’ adult soft‐tissue sarcoma. Eur J Cancer 2001;37:1096–1103. [DOI] [PubMed] [Google Scholar]
- 31. Derbel O, Heudel PE, Cropet C et al. Survival impact of centralization and clinical guidelines for soft tissue sarcoma (a prospective and exhaustive population‐based cohort). PLoS One 2017;12:e0158406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Helmer C, Peres K, Pariente A et al. Primary and secondary care consultations in elderly demented individuals in France. Results from the Three‐City Study. Dement Geriatr Cogn Disord 2008;26:407–415. [DOI] [PubMed] [Google Scholar]
- 33. Crowley E, Di Nicolantonio F, Loupakis F et al. Liquid biopsy: Monitoring cancer‐genetics in the blood. Nat Rev Clin Oncol 2013;10:472–484. [DOI] [PubMed] [Google Scholar]
- 34. Namlos HM, Zaikova O, Bjerkehagen B et al. Use of liquid biopsies to monitor disease progression in a sarcoma patient: A case report. BMC Cancer 2017;17:29. [DOI] [PMC free article] [PubMed] [Google Scholar]