Malte Schöfer
email: malte.schoefer@gmx.net

Nicolas Maranzana

| Améziane Aoussat

Giacomo Bersano

| Stéphanie Buisine

Distinct and combined effects of disciplinary composition and methodological support on problem solving in groups

Several reasons for the use of multidisciplinary teams composed of individuals with natural science and engineering background in problem-solving processes exist. The most important are the integration of science-based technologies into products and processes, and benefits for the problem-solving process thanks to new knowledge and new perspectives on problems. In this study we analyse the implications of interdisciplinary (scienceengineering) group problem solving from a managerial as well as from a cognitive perspective. We then report on an experiment investigating the impact of problem-relevant disciplinary group composition and methodological support on the problem-solving process and its outcome. The findings of the experiment have managerial, theoretical, and pedagogical implications related to early phases of New Product/Process Design processes in high-technology and scientific knowledge-related domains.

| INTRODUCTION

The benefits of knowledge held by natural scientists for the development of innovative products and processes is evident in activities like, for example, biologically inspired design (e.g., [START_REF] Fayemi | Bioinspired design characterisation and its links with problem solving tools[END_REF]. Moreover, the need for interdisciplinary problem solving for the development of innovative products and services is evident for Open Innovation Processes and Structures, like, for example, Idea Competitions and Innovation Networks [START_REF] Marais | The definition and development of Open Innovation models to assist the innovation process[END_REF] that are adopted by an increasing number of companies [START_REF] Chesbrough | The era of open innovation[END_REF]. Some recent research suggests that novel perspectives on problems are sometimes more beneficial than the mere introduction of new idea generation stimuli [START_REF] Chan | Do the best design ideas (really) come from conceptually distant sources of inspiration[END_REF]. As early as in the 1970s it was found that cognitive styles and strategies are related to the educational background of designers and scientists [START_REF] Field | Some dimensions of a science cognitive style and their and their relevance for the classroom[END_REF][START_REF] Lawson | Cognitive strategies in architectural design[END_REF]. In order to profit from such diverse perspectives and strategies, social mechanisms which prevail in monodisciplinary design teams [START_REF] Cross | Observations of teamwork and social processes in design[END_REF] and which are amplified in multidisciplinary teams (e.g. [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF]) must be taken into account.

The purpose of this paper is to report on a quantitative experiment investigating the impact of problem-relevant disciplinary group composition-monodisciplinary teams composed of participants with a life science background against multidisciplinary teams where participants with an engineering background join-and of methodological supportin terms of intuitive or logical approaches-on the process of group problem solving in knowledge-intensive domains as well as on the creative output of that process. The results of that experiment as well as its managerial, theoretical, and pedagogical implications are discussed.

| LITERATURE REVIEW

2.1 | Technology convergence and increased interdisciplinarity in new product and process development (NPPD) Modern product and service systems are becoming increasingly complex and integrate knowledge and technologies from more and more distinct disciplines [START_REF] Qureshi | Design process commonalities in trans-disciplinary design[END_REF][START_REF] Tomiyama | Dealing with complexity in design: A knowledge point of view[END_REF]. The need to integrate expertise from different engineering and natural science disciplines arises from trends like system miniaturization, increased quality requirements, higher product or service functionality, and product life cycle issues like end-of-life treatment [START_REF] Tomiyama | Dealing with complexity in design: A knowledge point of view[END_REF]. Conventional top-down design processes predominantly divide the design task into smaller, often monodisciplinary tasks.

As a consequence, strong relationships between these sub-tasks due to physical laws which affect several disciplinary domains are not taken into account by current processes [START_REF] Erden | A review of function modeling: Approaches and applications[END_REF][START_REF] Tomiyama | Dealing with complexity in design: A knowledge point of view[END_REF]. Especially when the integration of a technology causes tradeoff problems related to, for example efficiency or costs, a need for basic mutual understanding of the concepts-e.g. cause-and-effect relationships [START_REF] Yoshioka | Physical concept ontology for the knowledge intensive engineering framework[END_REF])-of other involved disciplines arises [START_REF] Batzias | Creating a specific domain ontology for supporting R&D in the science-based sector-The case of biosensors[END_REF]. However, several studies [START_REF] Chulvi | Influence of type of idea-generation method on the creativity of solutions[END_REF][START_REF] Gericke | Comparisons of design methodologies and process models across disciplines: A literature review[END_REF] reveal that interdisciplinary collaboration in design started to be discussed in the literature on design methodology only recently.

The importance of interdisciplinarity in NPPD has been proven by several authors. In industry, cross-functional interfaces between research departments and product development units, including direct personal contact in cross-functional teams, have been found to be beneficial. They increase a unit's capacity to assimilate and integrate new information, they reduce product development times [START_REF] Clark | Overlapping problem solving in product development[END_REF][START_REF] Cohen | Absorptive capacity: A new perspective on learning and innovation[END_REF] and they increase the level of creativity of generated ideas [START_REF] Alves | Creativity and innovation through multidisciplinary and multisectoral cooperation[END_REF]. One main argument for the value of multidisciplinary team composition is that it entails information diversity, which has been found to be important for team performance and team effectiveness [START_REF] Jehn | Why differences make a difference: A field study of diversity, conflict, and performance in workgroups[END_REF]. In addition, background diversity in groups is supposed to bring forth an increased variety of ways to process information [START_REF] Hinsz | The emerging conceptualization of groups as information processors[END_REF]. Moreover, multidisciplinary team composition is suitable for the application of extradomain knowledge for the resolution of problems by functionally diverse individuals that are not capable of codifying this very knowledge [START_REF] Berry | The combination of explicit and implicit learning processes in task control[END_REF], a prerequisite for the explicit transfer between teams.

With the increasing application of Open Innovation processes and structures in industry, interdisciplinary teams are supposed to work in collaborative frames, where the provided time for team building, joint problem analysis, and idea generation is very limited or-in the case of Innovation Networks, where problem settings are posted to a pool of problem solvers via an internet portal [START_REF] Marais | The definition and development of Open Innovation models to assist the innovation process[END_REF]-virtually non-existent. So-called "hackathons" [START_REF] Olson | Health hackathons: Theatre or substance? A survey assessment of outcomes from healthcare-focused hackathons in three countries[END_REF] are one example where collaborative problem solving occurs in physically co-located teams. Within this concept of workshops, life scientists, engineers, and computer scientists work together on technological innovations during typically one or two days. Even though Olson et al. have found this collaborative framework to be fruitful, there is also research [START_REF] Kane | Knowledge transfer between groups via personnel rotation: Effects of social identity and knowledge quality[END_REF] that suggests that members of a group are more likely to apply superior knowledge to a task at hand that stems from an individual from the same social group, social integration being a process that would require much larger collaborative time frames.

| Implications of interdisciplinarity on the group level

In order to understand how interdisciplinary NPPD processes can be methodologically supported, the impact of multidisciplinary group composition on the mechanisms of reasoning in teams as well as in individuals must be understood. Research in this respect has been carried out mainly in the fields of cognitive and management science.

Disciplinary diversity or cross-functionality in teams-the terms will be used synonymously here-are defined as the degree to which members of a team differ with regard to their disciplinary or functional background [START_REF] Jackson | Understanding the dynamics of diversity in decision-making teams[END_REF][START_REF] Milliken | Searching for common threads: Understanding the multiple effects of diversity in organizational groups[END_REF].

Those types of diversity in teams are supposed to cause informational diversity [START_REF] Jehn | Why differences make a difference: A field study of diversity, conflict, and performance in workgroups[END_REF] and value diversity [START_REF] Jackson | Understanding the dynamics of diversity in decision-making teams[END_REF] among the team members. According to [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF], informational and value diversity lead to several types of conflicts, the most important being relationship conflict, value conflict, and task conflict [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF]. Relationship conflicts are based on emotional tensions between group members and will not be discussed further here. Value conflicts relate to differing or opposing perceptions regarding the outcome of the team process [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF]. They have been found to reduce the effectiveness and efficiency of a team [START_REF] Jehn | Why differences make a difference: A field study of diversity, conflict, and performance in workgroups[END_REF]. Task conflicts describe situations in which there is disagreement on what procedures and processes to choose in order to fulfil a certain task [START_REF] Pelled | Exploring the black box: An analysis of work group diversity, conflict, and performance[END_REF].

Whereas relationship conflicts and value conflicts are considered undesirable phenomena in team processes, research has provided mixed results regarding the evaluation of task conflict [START_REF] Van Knippenberg | Work group diversity[END_REF]. Unmanaged and hence manifested conflicts have detrimental effects on group performance [START_REF] De Dreu | Task versus relationship conflict, team performance, and team member satisfaction: A metaanalysis[END_REF][START_REF] Jehn | A qualitative analysis of conflict types and dimensions in organizational groups[END_REF][START_REF] Jehn | Why differences make a difference: A field study of diversity, conflict, and performance in workgroups[END_REF]. They can reduce cooperation and thus induce dissipation of energy during team work [START_REF] Baron | Positive effects of conflict: A cognitive perspective[END_REF]. However, when carefully managed in order to limit their impact, some conflicts have been found to bear the potential to enhance group performance [START_REF] Gruenfeld | Group composition and decision making: How member familiarity and information distribution affect process and performance[END_REF][START_REF] Tjosvold | Coordination to market technology: The contribution of cooperative goals and interaction[END_REF]. They may lead to reduced conformity pressure and increased generation of alternative solutions to a problem, thus improving decision-making performance [START_REF] Schwenk | Effects of devil's advocacy and dialectical inquiry on individuals versus groups[END_REF]. As carefully managed and thus limited conflicts are perceived to have a positive impact on group performance, several methodological approaches for conflict induction and management in groups have been developed. Related to conflicts in multidisciplinary teams are communication and comprehension barriers caused by incoherent interpretive schemes [START_REF] Dougherty | Interpretive barriers to successful product innovation in large firms[END_REF][START_REF] Fleck | Genesis and development of a scientific fact[END_REF], such as formalities, goals, perceptions, and languages. One solution to problems induced by incoherent interpretative schemes and unshared frames of reference [START_REF] Van Knippenberg | Work group diversity[END_REF] within multifunctional and multidisciplinary teams are shared mental models [START_REF] Hinsz | The emerging conceptualization of groups as information processors[END_REF]. Mental models refer to "organized knowledge structures that allow individuals to interact with their environment […] to predict and explain the behavior of the world around them [,] to recognize and remember relationships among components [and] to construct expectations for what is likely to occur next" (Mathieu, Heffner, Goodwin, Salas, & Cannon-Bowers, 2000, p. 274). Further functions of mental models are "descriptions of system purpose [and] explanations of system functioning" (Rouse & Morris, 1985, p. 7). Shared mental models in a team have several advantages. First, they help to discover conflicts which are due to divergent personal perceptions of a problem, thus making those conflicts explicit [START_REF] Hinsz | The emerging conceptualization of groups as information processors[END_REF]. Second, during creative problem-solving tasks, shared mental or problem models lead to a reduction of the time required for consensus building, facilitate the elaboration and extension of conceptual ideas, and improve the coordination of group members [START_REF] Mumford | Tradeoffs between ideas and structure: Individual versus group performance in creative problem solving[END_REF]. In order to be beneficial for interdisciplinary design tasks, the mere quality of a shared mental model in terms of accuracy with individual models and high sharedness is not sufficient. The team's capacity to enact the shared model, i.e. to use it effectively in order to solve the design goal by managing conflicting requirements, has been found to be of equal importance [START_REF] Dong | Investigating design cognition in the construction and enactment of team mental models[END_REF].

| Conflict management methods and techniques in groups

In order to perform the induction and the management of conflicts, which seem to be at the same time beneficial and harmful to group performance, several approaches have been developed. Two methods or techniques that are described and tested in the literature are dialectical inquiry and devil's advocacy [START_REF] Mason | A dialectical approach to strategic planning[END_REF][START_REF] Schwenk | Effects of devil's advocacy and dialectical inquiry on decision making: A meta-analysis[END_REF].

Based on a meta-analysis of 16 experiments, [START_REF] Schwenk | Effects of devil's advocacy and dialectical inquiry on decision making: A meta-analysis[END_REF] argues for the value of devil's advocacy and-to a lesser degree-dialectical inquiry. However, [START_REF] Nemeth | Devil's advocate versus authentic dissent: Stimulating quantity and quality[END_REF] found that artificial dissent in groups, introduced by devil's advocacy, contrary to genuine dissent does not significantly stimulate the generation of more solutions. Furthermore, original dissent has been found to be more effective than contrived dissent in keeping group information search balanced [START_REF] Schulz-Hardt | Productive conflict in group decision making: Genuine and contrived dissent as strategies to counteract biased information seeking[END_REF].

| Conflicts and conflict management methods in individual reasoning

From a cognitive science perspective, the parallel development of a priori incongruent [START_REF] Finke | Creative cognition: Theory, research, and applications[END_REF][START_REF] Koestler | The act of creation[END_REF], opposite, antithetic [START_REF] Rothenberg | Psychopathology and creative cognition: A comparison of hospitalized patients, Nobel laureates and controls[END_REF][START_REF] Rothenberg | Einstein, Bohr, and creative thinking in science[END_REF] and hence somewhat conflicting concepts and their synthesis has been identified as one main characteristic of creative thought under laboratory conditions [START_REF] Finke | Creative cognition: Theory, research, and applications[END_REF][START_REF] Rothenberg | Einstein, Bohr, and creative thinking in science[END_REF] as well as in historical case studies of, for example, Albert Einstein and Niels Bohr [START_REF] Rothenberg | Psychopathology and creative cognition: A comparison of hospitalized patients, Nobel laureates and controls[END_REF].

Widely used approaches to induce conceptual-in particular performance-related-conflicts and their resolution in creative reasoning are methods of TRIZ (orthographic transcription from Russian ТРИЗ: Теория Решения Изобретательских Задач meaning Theory of Inventive Problem Solving [TIPS)] [START_REF] Altshuller | And Suddenly the Inventor Appeared: Triz, the Theory of Inventive Problem Solving[END_REF]. The TRIZ complex also includes derived methods like Advanced Systematic Inventive Thinking (ASIT) [START_REF] Horowitz | Creative problem solving in engineering design[END_REF] and Unified Structured Inventive Thinking (USIT) [START_REF] Sickafus | Unified structured inventive thinking: How to invent[END_REF], which share several underlying principles:

• First of all, the approaches can be categorized as analytical, i.e. a considerable-often the main-part of the creative process consists in the analysis and modelling of the problem.

• Second, the concept of the ideality of the searched solution plays an important role. In TRIZ, ideality is defined as the ratio between the benefits of a solution as numerator and the negative sideeffects of the solution as well as the effort to realize it as denominator. In A/USIT, the ideality of a solution increases with the degree to which it can be obtained without changing the given problem setting.

• Third, the analysis of required functions, undesired negative sideeffects and their systematic attribution to the behaviour and structure of elements present in the problem setting is characteristic of those approaches.

• Fourth, all approaches to some extent describe design problems as some sort of conflict. In TRIZ, those conflicts consist in sets of a priori conflicting evaluation parameters of a system (Technical contradiction, e.g. "The power generated by a combustion engine must be increased without increasing the engine's fuel consumption") or in sets of opposed values of an object's structural parameters (Physical contradiction, e.g. "An engine's cylinder capacity should be increased in order to generate more power and it should be reduced in order to reduce fuel consumption"). In A/ USIT, those conflicts are circumscribed in the Qualitative Change condition [START_REF] Horowitz | Creative problem solving in engineering design[END_REF][START_REF] Sickafus | Unified structured inventive thinking: How to invent[END_REF].

Besides methods for the modelling of engineering design problems, the TRIZ complex also provides sets of heuristics for problem solving. The heuristics consist in strategies that were found to have been used by other designers for overcoming similar conflicts in the past.

| HYPOTHESES

In modern product and service design processes, the integration of science-related knowledge, especially for the resolution of trade-off problems, is of increasing importance. Likewise, since the beginning of the Open Innovation era, the input of engineers to problem solving in the life science sector is increasingly required. In order to facilitate the integration of extra-disciplinary knowledge and perspectives, creative problem solving in multidisciplinary teams can be considered essential. Interdisciplinarity as well as cross-functionality have been Hypothesis 2. The methodological framework which is used in order to facilitate and support creative group problem solving impacts the process (H2a) and outputs (H2b) of creative problem solving of groups in knowledge-intensive domains.

Hypothesis 3. There exists a mediating effect between disciplinary group composition and the applied methodological approach with regard to the creative group problem solving process (H3a) and its output (H3b).

In order to test these hypotheses, a laboratory experiment was set up. The experiment is described in the following sections.

| METHOD

Teams composed of three students were asked to generate creative solutions to an ill-structured medical sector problem by following a generic problem-solving process characterized by problem definition, problem analysis, (divergent) idea generation, and (convergent) solution generation.

The conditions under which the groups engaged in the problemsolving process differed along two dimensions, a disciplinary one and a methodological one. There were 11 monodisciplinary groups. Nine of those groups were composed of three members with a life-science background (LS). Two groups, which served as controls, were composed of three members with a mechanical engineering background (ME). The nine multidisciplinary groups were composed of two members with a life-science and one member with a mechanical engineering background (L2M). Furthermore, half of the teams (10), previous to the problem-solving task, had been trained in Brainstorming and Mindmapping, which are considered instances of intuitive [START_REF] Shah | Evaluation of idea generation methods for conceptual design: Effectiveness metrics and design of experiments[END_REF] general creativity techniques (GT). The other half (10) had followed a training in TRIZ and USIT, which are regarded as logical [START_REF] Shah | Evaluation of idea generation methods for conceptual design: Effectiveness metrics and design of experiments[END_REF], rational [START_REF] Cross | Engineering design methods: Strategies for product design[END_REF] problem-solving approaches (TD = TRIZ and derivatives). The classification of the 20 groups according to the two conditional dimensions is synthesized in Figure 1.

| Participants

As one goal of the experiment consisted in the investigation of the impact of disciplinary group composition in terms of disciplinary and knowledge diversity, two sets of participants took part in the experiment. The first group consisted of 45 graduate students from Ecole de Biologie Industrielle. This school is an engineering school, the students of which have followed both undergraduate and graduate studies in the fields of biology, biotechnology, pharmacology, and medicine.

Hence the students had an academic background in life sciences (LS).

The second group of participants was composed of 15 graduate students from Arts et Métiers ParisTech, an engineering school specialized in the education of mechanical and industrial engineers. These participants had followed both undergraduate as well as graduate classes in the field of mechanical engineering (ME). All 60 participants were at similar stages of professional education and validated a certain part of their innovation classes in exchange for their participation.

| Training

In order to compare the impact of rational analytical design methodology and of relevant general creativity methods on the process of creative group problem solving and its products, the participants were The training in the general creativity techniques consisted in an introduction to Brainstorming [START_REF] Osborn | Unlocking your creative power: How to use your imagination to brighten life, to get ahead[END_REF] and Mindmapping [START_REF] Buzan | Use your head[END_REF][START_REF] Kokotovich | Problem analysis and thinking tools: An empirical study of non-hierarchical mind mapping[END_REF]. During the training, fundamental principles of the creative process and analogical problem solving were briefly introduced. Further, basic principles and rules of Brainstorming were explained. Then, the documentation of ideas on concept sheets was explained. That introduction to theoretical aspects of Brainstorming was followed by the participants' application of the method to a problem of their choice. After that, the concept of Mindmapping after [START_REF] Buzan | Use your head[END_REF] was presented. After the introduction of different types of keywords as elements of a Mindmap, the advantages of that method such as visual support and stimulation of associations were explained.

Finally, the participants were asked to apply Mindmapping to a problem of their choice.

In contrast to Brainstorming and Mindmapping, which are currently used by designers [START_REF] Gonçalves | What inspires designers? Preferences on inspirational approaches during idea generation[END_REF], methods of the TD condition and particularly TRIZ are considered to be complex and thus to require much more time in order to be understood and successfully applied (e.g., [START_REF] Gundlach | Der Stellenwert der TRIZ-Methodik[END_REF][START_REF] Ilevbare | A review of TRIZ, and its benefits and challenges in practice[END_REF]. Therefore, a dedicated training was designed in order to provide the participants with the most important concepts in a shorter timeframe. At the end of the training in the TD condition, the participants obtained a sheet which synthesized the problem-solving process according to these methodologies.

All participants, in the TD as well as in the GT condition, were allowed to keep the printed training support for the following problem-solving sessions.

In order to foster methodological understanding and application, all groups where then asked to engage for two hours in an initial creative problem-solving task. They were told to follow a generic problemsolving meta-strategy consisting of problem definition; divergent idea generation; idea evaluation; convergent idea improvement; and solution generation. During this pedagogical case study, the participants had to generate propositions for the treatment of cancer using ionizing radiation without harming the patient's healthy tissue. This problem was derived from the so-called Duncker Radiation Problem [START_REF] Duncker | On problem solving[END_REF]. During this case study, phases of autonomous work were followed by phases during which the participants were provided with

| Problem to solve

After a short break, all participants had to engage the problem-solving task which was used for data collection. The task as well as the support provided to the participants is given in Table 1.

The problem was selected for the following reasons:

• The problem stems from a highly science and technology-based domain, that is, creativity and unorthodox approaches for problem solving are possible but must take into account complex causeand-effect relations.

• The initial and goal states are very ill-structured and a variety of problem analyses, problem statements, and solution strategies can be imagined, which classifies this problem as a design problem [START_REF] Goel | The structure of design problem spaces[END_REF][START_REF] Jonassen | Toward a design theory of problem solving[END_REF]. This makes the problem setting also open for engineering approaches and the application of engineering knowledge and know-how.

• However, the problem statement as well as the provided literature use codified language which is difficult to understand for problem solvers without a life science background, such as the engineering participants.

• There are existing solution propositions in the literature to which the participants' ideas can be compared.

In order to be able to prepare the task, the participants were provided with the problem description and the scientific literature some days before the problem-solving session.

| Data collection and analysis

Data collection was performed in three ways:

• After the pedagogical case study and the investigated problemsolving activity, the participants were asked to fill in a questionnaire on a seven-point Likert-type scale ranging from "not at all" to "completely". The questionnaire enquired into aspects like the participants' personal perception of the value of their knowledge with respect to the problem at hand (before the preparation of the problem and in general), perceived understanding of the methods taught during the training, personal motivation, and the value of the method for problem understanding, for problem solving and for communication (see Table 2).

• The participants were asked to document the results of each process step on dedicated sheets. In order not to privilege one of the two methodological approaches, i.e., the GT or TD condition, the sheets were designed following a generic creativity process [START_REF] Merrifield | The role of intellectual factors in problem solving[END_REF]. Initial reasoning and analysis of the problem was sought to be documented on "problem identification sheets" (PIS), problem statements and associated sub-problems were to be documented on "problem structuring sheets" (PSS), the results of the divergent idea generation processes should be filled into "concept sheets" (CS) and final solution propositions were sought to be noted in "solution sheets" (SS). In addition, the participants were asked to trace, whenever possible, links between the documentation sheets, e.g. to indicate what problem statement led to what concept and so on. In addition to this, the participants who had followed the TD training were required to note, whenever possible or applicable, the method or heuristic which led to a notation. For these indications, dedicated cases had previously been inserted into the sheets.

• The concepts (CS) and solutions (SS) generated by the participants were evaluated by two domain experts, i.e., by two experienced researchers in virology, on a seven-point Likert-type scale according to five independent creativity-related evaluation parameters [START_REF] Dean | Identifying quality, novel, and creative ideas: Constructs and scales for idea evaluation[END_REF], which are given in Table 3.

The output of the experiment, i.e. the replies on the two questionnaires as well as the creativity ratings attributed to the concept (CS) and solution sheets (SS), were analysed using analysis of variance (ANOVA), and the calculation of correlation parameters. Figure 2 First digits of the code: 1, question asked after the pedagogical case study; 2, question asked after the investigated problem-solving task.

provides an overview of the experimental protocol as well as on data collection and analysis.

5 | RESULTS

| Descriptive results

The 20 groups produced a total exploitable outcome of

• 83 problem identification sheets

• 62 problem structuring sheets

• 162 concept sheets

• 46 solution sheets of different types and degrees of detail. Figure 3 gives examples of concept and solution sheets.

The overall inter-rater reliability of the expert evaluation of the generated concepts and solution propositions amounts to a Cronbach's alpha of α = 0.728, which is considered an acceptable value. Three concepts and one solution proposition could not be evaluated due to ambiguous or indistinct documentation. Hence, the number of concepts which entered the statistical analysis totals 159 and the number of solution propositions amounts to 45.

The problem structuring sheets which had been generated by the groups in the TD condition were analysed and assigned to the TD tools which had been introduced during the training. The monodisciplinary teams of the LS condition used 3.5 TRIZ and USIT tools on average, whereas the multidisciplinary teams of the L2M condition used on average 5.4 tools. Moreover, two groups in the L2M conditions applied all proposed tools which were introduced during the training. In the LS condition, no group did so. Ideality (TRIZ) and the closed world method (USIT) were the most used concepts in the two conditions.

| Quantitative results

In this section the relevant quantitative statistical results will be presented, focusing on significant and marginal effects. For all other parameters, no significant effect could be detected or the effect was not related to the hypotheses. For an overview of the relevant significant and marginal effects, please see Tables 4 and5.

| Effects of disciplinary group composition and participant background

Both the participants' disciplinary background and disciplinary group composition were found to be related to the participants' evaluation of their personally held knowledge. Individuals with a life science The degree to which the idea applies to the stated problem

Effectiveness

The degree to which the idea will solve the problem Depth (Implicational explicitness and Completeness)

The degree to which there is a clear relationship between the recommended action and the expected outcome; the breadth of coverage with regard to who, what, where, when, why, and how; hence the degree of detail to which the idea is described

Originality

The degree to which the idea is not only rare but is also ingenious, imaginative, or surprising (especially with regard to already existing solutions) Moreover, disciplinary group composition seems to impact the evaluation of personally held knowledge (Figure 4). In monodisciplinary teams, the perceived value of the personally held knowledge of ME and LS participants with respect to the problem at hand was similar.

However, in multidisciplinary teams, LS students tended to evaluate their knowledge to be more important than did ME participants (F(1/ 26) = 3.26; p = 0.084). Also, multidisciplinary groups produced solution propositions that were documented in significantly more depth (F(1/ 45) = 4.42; p = 0.042) than the solution propositions produced by monodisciplinary teams. In a similar realm, differences in view of personally held knowledge with regard to the problem at hand were found to moderately impact the depth in which solution propositions were documented (r(45) = 0.383; p = 0.009).

| Effects of methodological support

First of all, the type of methodological support seems to impact the participants' evaluation of their personally held knowledge with respect to the problem at hand. Individuals in the GT condition tended to report having possessed more relevant knowledge than did participants in the TD condition (F(1/57) = 3.67; p = 0.061). Second, the perceived methodological support for understanding the problem was evaluated to be significantly different. The participants in the TD condition evaluated their method significantly better compared to partici-

| Combined effects of disciplinary group composition and methodological support

Finally, several results relate to a combined effect of disciplinary group composition or participant background and the chosen methodological support. First, after the initial case study, among the participants in the TD condition, the participants of monodisciplinary groups judged the value of the methodological support for problem understanding higher than did participants in monodisciplinary teams (F(1/26) = 14.3; p = 0.001). Furthermore, with regard to the creativity-related evaluation of the creative outcome, one significant combined effect was detected.

With regard to the criterion Originality, the value of the methodological support-Brainstorming and Mindmapping or TRIZ and USITdepends on disciplinary group composition. Whereas monodisciplinary The results presented in the previous section allow a differentiated insight on the impact of disciplinary group composition and methodological support on the process of creative problem solving by groups in knowledge and technology-intensive domains.

| Discussion of results with respect to Hypothesis 1

Hypothesis 1 relates to the impact of heterogeneity in terms of disciplinary group composition on the creative problem-solving process in groups, its outcome and information processing during this process.

Hypothesis 1a suggests an impact of disciplinary group composition on the process of creative group problem solving. The increased depth of the solutions produced by the multidisciplinary (L2M) teams compared to monodisciplinary groups (LS/ME) is considered indirect evidence in favour of that hypothesis. Two explanations for that result can be offered. First, multidisciplinary group composition is likely to add several types of conflicts to group processes [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF][START_REF] Van Knippenberg | Work group diversity[END_REF]. Especially value conflicts, which relate to the desired outcome [START_REF] Gebert | Cross-functionality and innovation in new product development teams: A dilemmatic structure and its consequences for the management of diversity[END_REF], and task conflicts, which describe disagreements with regard to problem solving strategies [START_REF] Pelled | Exploring the black box: An analysis of work group diversity, conflict, and performance[END_REF], can be the result of disciplinary diversity.

Those conflicts, under certain conditions, have been found to improve the consideration of previously unshared knowledge within a group [START_REF] Brodbeck | The dissemination of critical, unshared information in decision-making groups: The effects of pre-discussion dissent[END_REF]. The integration of that knowledge during the discussion of a solution proposition is likely to improve the degree to which the solution is documented. A second, probably more trivial, explanation would be that the presence of team members with a different disciplinary background forces the others to describe their ideas in more detail. Once those explanations are given, they are also reflected in the documentation of the results.

The combined impact of disciplinary group composition and disciplinary background on the participants' evaluation of personally held knowledge is more directly related to Hypothesis 1a. One can argue that knowledge which is considered not valuable with respect to a problem by the knowledge owner has a higher risk of remaining unshared. Likewise, the excessive consideration of knowledge that is estimated to be superior by the majority of the group members risks dominating group problem-solving processes. In that sense, the result confirms the view of Nemeth et al. [START_REF] Nemeth | Differential contributions of majority and minority influence[END_REF][START_REF] Nemeth | Better than individuals?: The potential benefits of dissent and diversity for group creativity[END_REF], who argue that majority influence in groups leads to convergent thinking in both majority and minority individuals.

Hence, it provides evidence, albeit marginal, for the impact of disciplinary group composition on information sharing and thus information processing in groups. The fact that the result could not be reproduced after the investigated second case study can be explained by a learning effect among the participants. The experience that non-domain knowledge, which was considered by some a priori not relevant to the problem, can contribute to interesting results of problem-solving processes could have led to a re-evaluation of that knowledge with respect to the second problem by both ME and LS students. Hence, the more equal estimation of personally held knowledge with respect to the second problem can be interpreted as an indicator that exemplary case studies can help to reduce problems related to knowledge transfer in working groups [START_REF] Kane | Knowledge transfer between groups via personnel rotation: Effects of social identity and knowledge quality[END_REF].

Hypothesis 1b relates to the impact of disciplinary group composition on quantitative and qualitative aspects of the generated concepts and solution propositions. The finding that solutions generated by interdisciplinary L2M groups are described in more detail than the solutions produced by monodisciplinary LS and ME groups can be directly associated to that sub-hypothesis. In addition, the positive correlation between differences regarding the perceived value of personal knowledge among members of a group and the degree of detail to which solution propositions are described also confirms that hypothesis. Together, these results suggest that, due to individual differences in terms of possessed knowledge, multidisciplinary groups generate more deeply reflected creative outcomes than do monodisciplinary groups.

6.2 | Discussion of results with respect to Hypothesis 2

Hypothesis 2 states an impact of the methodological support on the creative problem-solving process in groups, its outcome and information processing during this process.

Hypothesis 2a, which suggests that the choice of the method used during the problem-solving process impacts the latter, was supported.

The fact that the participants in the TD condition evaluated the methodological support to be significantly more useful when it comes to problem understanding obviously exerts influence on the problemsolving process. The result experimentally confirms Ilevbare et al.'s (2013) empirical finding that the use of TRIZ leads to improved problem analysis in teams. Further, methodological impact is somewhat confirmed by the difference in the number of sub-problems and problem models that were identified and respectively generated in the two methodological conditions. Whereas the groups in the GT condition identified significantly more sub-problems, the teams in the TD condition produced significantly more problem structuring sheets. One possible interpretation of these results is that the value of TD for problem structuring and problem modelling, which translates into an increased number of problem models, also leads to more focused problem identification in TD groups. At the same time, due to a lack of methodological support for problem analysis and problem understanding, GT groups engage in a more extensive and divergent problem identification process. Those results are interesting if one takes into account the findings of [START_REF] Fricke | Successful individual approaches in engineering design[END_REF], who suggests that "balanced" strategies, which are characterized by reasonable expansion of the search space, are most likely to help designers to find quality solutions in limited timeframes. On the assumption of an extrapolation of Fricke's findings to group processes, the present findings suggest that the choice of the methodological support can help teams to adjust their meta-strategies for problem solving. In initial problem-solving phases, TRIZ and derived approaches seem to lead to a restriction of the problem space. In subsequent phases of deeper problem analysis, those approaches allow an enlargement of the search space compared to intuitive methods.

In addition, the measured correlations between the participants' evaluation of personally held knowledge and method value for problem understanding and group communication are of interest here.

They provide some insight into the influence of methodology on group The fact that participants in the TD condition, before the preparation of the problem, considered their knowledge with respect to the problem domain as sparser than did participants trained in the GT condition, can also be interpreted against an information processing background. One can argue that the use of methodology of the TD condition leads to the identification of aspects of the problem setting, of which the participants did not possess any knowledge, which, in turn, impacts the value perception of their knowledge. However, it should be noted that the discussed statistical effect is only marginal and that the explanation given here should be tested elsewhere.

An impact of the methodological support on quantitative aspects of the generated concepts and solutions was stated in Hypothesis 2b. That hypothesis could not be validated based on the experimental findings. For the majority of the creativity-related evaluation parameters outlined in Table 3, no significant relationship between method and outcome could be found. In this sense, the present experiment confirms the findings of [START_REF] Chulvi | Influence of type of idea-generation method on the creativity of solutions[END_REF], who could not detect significant differences in terms of usefulness between ideas that had been generated using TRIZ and those developed using intuitive creativity methods. The only experimental outcome that can be clearly related to Hypothesis 2b points to a significant positive relationship between the use of GT methods and the depth of generated concepts. One possible explanation for this phenomenon could be that participants of the GT condition stated they possessed more problem-relevant knowledge prior to the experimental procedure.

6.3 | Discussion of results with respect to Hypothesis 3

Hypothesis 3 suggests a mediating effect of disciplinary group composition regarding the impact of methodological support on the process (H3a) of creative problem solving in groups and its outcome (H3b).

With regard to Hypothesis 3a, not enough results supporting this hypothesis could be found in the replies to the questionnaires and from the evaluation of the creative output of the problem-solving groups. Either the results were of only marginal significance (p = 0.052; p = 0.069) or an effect was detected only after the initial case study and disappeared after the investigated one.

Concerning Hypothesis 3b, the link between disciplinary group composition, methodological support, and creative output originality is important. As mentioned previously, application of GT and TD exerts a significant influence on the originality of both generated concepts and solutions depending on whether the composition of the group is monodisciplinary (LS) or multidisciplinary (L2M). Whereas GT is advantageous when used by LS teams, the opposite is true for L2M groups.

Those findings are interesting for two main reasons. First, originality is considered one of the most important evaluation criteria for the output of creative problem-solving processes. Second, among the criteria introduced here, originality probably indicates best the extent to which new knowledge is applied in the generated creative products. In order to further investigate the combined impact of disciplinary group composition and methodological support on the type of generated output and the knowledge applied in the latter, a detailed qualitative analysis of that output would be necessary.

| Summary of results

The present experiment was designed to test three hypotheses. The first hypothesis suggested an impact of disciplinary group composition on the process of creative problem solving in groups in knowledgeintensive domains as well as on the output of that process. The increased depth with which multidisciplinary groups describe their solution propositions provides support for both aspects of the hypothesis. Hence both aspects of Hypothesis 1 obtain some support.

The polarizing impact of interdisciplinarity in groups on the-subjective -evaluation of personally held knowledge also point to the validation of a disciplinary impact on information processing during group problem solving. The reason is that potentially valuable extra-domain knowledge that is not shared-or sufficiently defended-due to a potential underestimation has no chance of being applied for problem solving.

The second hypothesis, analogously to the first, suggested an impact of the methodological support on the creative problem-solving process in groups and on its creative outcome. The analysis of the documentation of the problem-solving process and the evaluation of the participants' replies to the questionnaires confirm a method impact on the problem-solving process. Intuitive approaches seem to lead to broader definitions of sub-problems whereas analytical methodology stimulates more in-depth problem analysis. Furthermore, TRIZ and USIT, compared to Brainstorming and Mindmapping, feature an increased value for problem understanding. That value, contrary to that of intuitive approaches, does not depend on the participants' preparation of the problem at hand. However, the impact of the chosen methodological approach on the creative quality of the generated concepts and solutions could not be validated. Hypothesis 2 is thus only partially validated by the present experiment.

The third hypothesis relates to a mediating effect between disciplinary group composition and methodological support in terms of the problem-solving process in groups and its outcome. At least in terms of originality of the generated output, there seems to be a mediating effect between disciplinary group composition and methodological support. Whereas intuitive methods seem to be advantageous in monodisciplinary groups, the opposite is true for multidisciplinary teams. Hence, whereas Hypothesis 3a does not receive any support, Hypothesis 3b is supported by the experiment.

| Limitations

In the present experiment, a focus was put on quantitative data collection and analysis. That research strategy implies a certain number of qualitative limitations. First of all, students and not professional researchers or engineers were taken as participants. However, the domain experts in charge of evaluating the generated concepts certified a high quality and state-of-the-art output of the problem-solving session. Moreover, the detected differences regarding perceived value of personal knowledge between the "expert" and "non-expert" participants were significant. Thus, we believe that the generated experimental conditions reflect well the professional reality.

Second, both training time and the time that the participants were given to solve such a complex problem were very short. The time necessary to learn and successfully apply complex approaches like TRIZ is considered at least one order of magnitude higher. Taking into account the complexity of both this method and the problem to solve, there is a risk that the participants in the TD condition spent too much time and effort in understanding and correctly apply the methodological tools, thereby losing time for solution generation. Or the problem solvers simply did not have enough time for a proper application of TD models which could bias the evaluated creative performance of the TRIZ tools.

A means to counter this problem would be real-time data by video-or audio-recording and a subsequent analysis of the time spent for either method and problem-related activities.

This being said, it should be stressed that the conditions under which the participants were expected to apply the respective methods correspond-according to the authors' experience-well to the constraints of real-life industrial workshops and for interdisciplinary and inter-institutional workshops.

Finally, it could be argued that having chosen mechanical engineering as one of the disciplinary backgrounds of the participants could perhaps skew the general applicability of the results to interdisciplinary problem solving irrespective of the participating disciplines.

Even though the participants with ME background reported not to have had any experience in this regard, the fact that TRIZ and USIT were developed in mechanical engineering could have given them a certain advantage over the life science students. However, a better understanding of the training content by ME participants could only be detected after the initial case study. Therefore, we consider the methodological advantage of the participants with an ME background during the investigated case study to be negligible.

| Implications

The results presented in this paper have managerial, theoretical as well as pedagogical implications.

From a management perspective, the findings indicate that the choice of the methodology to support creative problem solving in groups in knowledge-intensive and high-technology domains should depend on several aspects. Disciplinary group composition, perceived average problem-related expert knowledge as well as differences with respect to that knowledge within a multidisciplinary group are important factors to take into account. Moreover, the application of intuitive deliberate creativity methods on the one hand and more logical analytical methods on the other can effectively influence a group's metastrategy [START_REF] Fricke | Successful individual approaches in engineering design[END_REF] for problem solving. Even though it must be confirmed by further research, the finding that disciplinary group composition influences the participants' evaluation of personally held knowledge, also bears important implications for knowledge management in organizations. The processing and the integration of extradomain knowledge into a given domain-specific problem setting require support. That support can be in the form of quantitative adjustments of the group composition in order to profit from majority/ minority influence [START_REF] Brodbeck | The dissemination of critical, unshared information in decision-making groups: The effects of pre-discussion dissent[END_REF][START_REF] Nemeth | Better than individuals?: The potential benefits of dissent and diversity for group creativity[END_REF] effects. It might also be possible to favour the integration of extra-domain knowledge by combining approaches presented here with progressive methods [START_REF] Shah | Evaluation of idea generation methods for conceptual design: Effectiveness metrics and design of experiments[END_REF]. Gallery Method [START_REF] Van Gundy | Techniques of structured problem solving[END_REF] or Method 635 [START_REF] Rohrbach | Kreativ nach Regeln-Methode 635, eine neue Technik zum Lösen von Problemen[END_REF] are techniques which allow every participant to provide her/his contribution without group pressure. Finally, against the background of an ever-increasing application of Open Innovation processes and structures, the differences with regard to the creative outcome as a combined effect of group compo- With regard to theoretical aspects of problem solving, the following implications were identified. First, disciplinary diversity in problem-solving groups promotes the detailed description of solution propositions. We argue that this increased degree of detail points towards an increased discussion of ideas during the problem-solving process. Second, from the evaluation of the questionnaires, it seems at first sight that the value of logical analytical approaches is higher for problem identification and problem analysis than it is for the generation of solution propositions. Whether this result is due to the fact that problem-solving heuristics only indirectly lead to the generation of ideas-as reported elsewhere [START_REF] Howard | Reuse of ideas and concepts for creative stimuli in engineering design[END_REF])-could not be tested with the current research methodology.

A confirmation of these findings and-to some degree-a response to open questions like the impact of group composition and methodological support on the development of ideas and solutions as well as on the type of generated creative outcome requires more qualitative approaches. Such approaches could, for example, use audio-and video-recording for the analysis of the problem-solving groups in order to map the dynamics of problem statements and ideas during the problem-solving process. In a similar realm, a more thorough documentation of the generated concepts and solutions and finally a mapping of these onto a "knowledge map" of some sort could provide interesting insight into the question of how to integrate knowledge from specific domains into the creative problem-solving process.

Finally, the experimental results indicate a sound use of TRIZ and USIT tools by the participants. From a pedagogical perspective, these findings are interesting insofar as they point to the potential of these methods to improve creative thinking in teams even after a short period of training.

  found to engender several types of conflicts. Carefully managed and embedded into a shared team mental model, those conflicts-much like conceptual conflicts in individual reasoning-have the potential to increase a group's problem-solving performance. Methodological approaches known for their capacity to induce and overcome conceptual conflicts are tools of the TRIZ complex. To the best of the authors' knowledge, the value of TRIZ methodology for mono-and interdisciplinary creative problem solving in a scientific-knowledge based domain has not yet been tested. From that the following research question can be formulated: What is the impact of problem relevant disciplinary group composition and the applied problem-solving methodology on creative problem solving in knowledge-intensive domains, and are these impacts-to some extent-interdependent? This question leads to the following three hypotheses: Hypothesis 1. Heterogeneous group composition in terms of disciplinary background and the resulting problem-relevant knowledge and perspective diversity impact the process (H1a) and outputs (H1b) of creative problem solving of groups in knowledge-intensive domains.

  divided into two groups. Half of the participants (23 with LS background and seven with ME background) took part in 4.5-hour training in Brainstorming and Mindmapping, which are both instances of intuitive general creativity techniques (GT). The other half of the participants (22 with LS background and eight with ME background) took part in 4.5-hour training in basic concepts of TRIZ and its derivatives as rational creativity methods (TD).

FIGURE 1

 1 FIGURE 1 Group classification along two dimensions-disciplinary group composition and methodological support

FIGURE 2

 2 FIGURE 2 Experimental protocol, data collection, and data analysis

  pants in the GT condition (F(1/54) = 4.7; p = 0.035). Taking into account the quantity of identified sub-problems and of generated problem models, the following was detected. The teams in the GT condition identified more sub-problems (F(1/18) = 10.0; p = 0.005) but generated fewer problem models (F(1/18) = 22.62; p = 0.001) than did the groups in the TD condition. Regarding the creativity-related attributes of the process outcome, only the degree to which the products were described in detail (Depth) was impacted by the methodological support. The initial ideas generated by the groups in the GT condition were evaluated to be documented in more depth than the ideas in the TD condition (F(1/59) = 11.77; p = 0.001). The calculation of correlation parameters yielded the following results. In the GT condition, the degree to which the participants had prepared the problem to solve (e.g., reading the provided literature) was positively correlated to the participants' perception of method value for problem understanding (r(79) = 0.304; p = 0.006), problem solving (r(79) = 0.424; p = 0.001), and intra-group communication (r(79) = 0.530; p = 0.001). In the TD condition, the correlations were either less strong or non-existent (r(72) = 0.228; p = 0.054; r(72) = 0.040; p = 0.738; r(72) = 0.332; p = 0.004). Finally, a strong positive correlation of differences with respect to problem-related knowledge among the members of a group and the perceived value of methods in the GT condition for intra-group communication was detected. The correlation was found to be strong for both problem-related knowledge before the preparation of the problem to solve (r(79) = 0.435; p = 0.001) and in general (r(79) = 0.453; p = 0.001). For TRIZ and USIT, both correlations were negative (r(72) = -0.295; p = 0.012; r(72) = -0.339; p = 0.004).

FIGURE 3

 3 FIGURE 3 Examples of concept sheets (left) and solution sheets (right) generated during the experiment [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

 4 FIGURE 4 Combined effect of disciplinary group composition and participant background on perceived value of personally held knowledge [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

 5 FIGURE 5 Impact of methodological support on originality of generated solutions depending on disciplinary group composition [Colour figure can be viewed at wileyonlinelibrary.com]

  information processing during group problem solving. The results suggest that GT methods-Brainstorming and Mindmapping-are more suitable to foster the processing of recently acquired information within groups. Probably most important in view of interdisciplinary group problem solving are the significant differences between the methodological approaches regarding the support of group communication when perceived knowledge differences among the team members are high. Whereas the capacity of methods of the GT condition to foster group communication is strongly positively related to perceived differences in terms of expertise in groups, the correlation is moderately negative in the TD condition. These results reflect only the subjective perception of the participants and somewhat contrast other findings (see below). However, they point towards some potential drawbacks of TRIZ and USIT in respect to the facilitation of problem solving in interdisciplinary teams. Together with other results presented here, those findings may provide help for the choice of methodological support for the facilitation of group problem solving processes. Logical creativity-enhancing methodology, compared to intuitive methods, seems to have overall advantages in terms of support for problem understanding. Perhaps more obviously, when it comes to the facilitation of solution generation, the methodological support of both approaches seems to decrease with increased problem-related knowledge. That means that domain novices are more likely than experts to require methodological support for the generation of solution propositions to a given knowledge-intensive problem. Furthermore, independently from general domain knowledge, Brainstorming and Mindmapping should be used only when team members have well prepared the problem to be solved, whereas the support of TRIZ and derived methods does not depend on such constraints.

  sition and methodological support seem important. Based on these findings one can argue for an increased use of problem structuring and problem modelling methods of TRIZ and USIT when problems are shared with extra-domain problem solvers, be it in the case of Innovation Networks or collaborative workshops of any sort.

TABLE 1

 1 Problem-solving task to be engaged during the experiment

		The problem solvers are members of a team in
		the domain of medicine who have total freedom
		to propose new research projects and all types
	Scenario	of treatment
	Problem	Propose creative solutions to the problem of
		opportunistic adenovirus infections of children
		which are in an immunosuppressed state due to
		hematopoietic stem cell transplantation

Fictional resources Sufficient financial, scientific, and technological resources

Real resources

Internet; scientific databases; scientific publications in order to give an overview on the problem and existing solution strategies

TABLE 2

 2 Questionnaire questions

	Code a	Question
	2Q1	I have prepared the problem at hand (adenovirus
		infection) (by reading the provided papers,
		internet inquiry, etc.) before the treatment
		of the problem.
	1/2Q2	Before the preparation of the problem at hand,
		I possessed a certain amount of knowledge
		in the problem domain (adenovirus infection).
	1/2Q3	My knowledge about the problem seemed
		adequate for the treatment of the problem.
	1/2Q4	I believe to have understood the content of
		the training which preceded the case study.
	1/2Q5	I was motivated to treat the problem (adenovirus
		infection).
	1/2Q6	The methods acquired during the training helped
		me to better understand the problem.
	1/2Q7	The methods acquired during the training helped
		me during the generation of solutions.
	1/2Q8	The methods acquired during the training helped
		my group to better communicate.

a

TABLE 3

 3 Creativity-related evaluation parameters for creative process output

	Criterion	Explanation
	Feasibility (Acceptability)	The degree to which the idea is socially,
		legally, or politically acceptable and
		technically feasible
	Pertinence (Applicability)

TABLE 4

 4 Relevant ANOVA results

Habilitation here in 1996. His field of research is the optimization of design and innovation processes. In particular, he is interested in the integration of new professions and skills and in the formalization of individual and collective design processes. He has published more than 62 articles in international journals, 12 international books and more than 151 contributions to international conferences. He is also reviewer for several international journals. He has directed 36 PhDs and coordinated many national and international projects.

Giacomo


MD Ludovic Jovenaux

MD Jennifer Cautela

Noémie Resseguier

MD Michele Pibarot

MD Myriam Taouqi

MD Morgane Orabona

MD Johan Pinto

MD Michael Peyrol

MD Jeremie Barraud

MD Marc Laine

MD Noemie Resseguier

MD Laurent Bonello

MD, PhD Franck Paganelli

MD Fabrice Barlesi

MD Franck Thuny
email: franck.thuny@gmail.com

Prof Franck Thuny

Practices in management of cancer treatment-related cardiovascular toxicity: A cardio-oncology survey

Keywords: cardiotoxicity, cardio-oncology, cancer therapy, prevention, heart failure

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

ABSTRACT

Background: Cardiovascular toxicity has become a challenging issue during cancer therapy.

Nonetheless, there is a lack of consensual guidelines for their management. We aimed to determine the current practices of oncologists regarding cardiovascular toxicity related to anthracyclines, trastuzumab and angiogenic inhibitors and to gather their opinions on the development of cardio-oncology programs.

Methods:

A cross-sectional declarative study was submitted to French oncologists in the form of an individual, structured questionnaire.

Results: A total of 303 oncologists responded to the survey. Ninety-nine percent of oncologists prescribed cardiotoxic therapies, including anthracyclines (83%), trastuzumab (51%) and other angiogenic inhibitors (64%). The method adopted for managing cardiovascular toxicity was based on guidelines from expert oncology societies for only 35% of oncologists. None was aware of recommendations from expert cardiology societies.

Prescription of pre-, peri-and post-therapy cardiovascular assessment was inconsistent and significantly less frequent for all classes of angiogenic inhibitors than for anthracyclines and trastuzumab (P<0.0001). Relative to pre-therapy assessment, post-therapy assessment was prescribed significantly less often for all cancer therapies (P<0.0001). Attitudes regarding the onset of left ventricular dysfunction were much more inconsistent when angiogenic inhibitors were involved. Additionally, the management of hypertension and QT prolongation was also inconsistent. Finally, 88% of oncologists supported projects of cardiooncology programs development.

Conclusions: Practices of oncologists are disparate in the field of cardiovascular toxicity. This finding underlines the complexity of managing many different situations and the need for distribution of formal guidelines from oncology and cardiology expert societies. The development of personalized cardio-oncology programs seems essential.

INTRODUCTION

Cancer and cardiovascular diseases are the two leading causes of death in the United States and Europe, where they are responsible for almost 50% of overall mortality [START_REF] Kochanek | Mortality in the United States, 2013[END_REF].

Cancer therapies are being rapidly developed and have improved the prognosis of many patients [START_REF] Goldhirsch | 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial[END_REF]. Nevertheless, the improvements in survival due to new cancer therapies bring a cost because these treatments can have deleterious effects on the cardiovascular system [START_REF] Cautela | Management and research in cancer treatment-related cardiovascular toxicity: Challenges and perspectives[END_REF].

These include myocardial dysfunction, systemic hypertension, QT prolongation, arrhythmias, myocardial ischemia, pulmonary hypertension, thrombo-embolic events, accelerated atherosclerosis, pericardial and valvular heart diseases [START_REF] Curigliano | Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management[END_REF]. This toxicity can be observed very early or many years after the use of "old" classes of cytotoxic chemotherapy drugs or the most recent targeted therapies [START_REF] Cautela | Management and research in cancer treatment-related cardiovascular toxicity: Challenges and perspectives[END_REF][START_REF] Moslehi | Cardiovascular Toxic Effects of Targeted Cancer Therapies[END_REF][START_REF] Cardinale | Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy[END_REF][START_REF] Ewer | Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events[END_REF]. Furthermore, as a consequence of the aging population, cancer and cardiovascular diseases frequently co-exist, sometimes in an unknown manner [START_REF] Koene | Shared Risk Factors in Cardiovascular Disease and Cancer[END_REF][START_REF] Hasin | Heart Failure After Myocardial Infarction Is Associated With Increased Risk of Cancer[END_REF]. Thus, cardiovascular toxicity management has become challenging because it could significantly influence global survival [START_REF] Yeh | Oncocardiology-Past, Present, and Future: A Review[END_REF]. International guidelines on cardiovascular monitoring during and after cancer treatment lack consensus and are not based on substantial evidence, in particular for the novel targeted cancer therapies [START_REF] Armenian | Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group[END_REF][START_REF] Lancellotti | Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography[END_REF][START_REF] Curigliano | Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines[END_REF][START_REF] Plana | Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF][START_REF] Zamorano | ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)[END_REF][START_REF] Armenian | Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline[END_REF].

Additionally, the current practices regarding management of cardiovascular toxicity remain unknown.

Accordingly, we designed a national survey of French oncologists. The purpose of the study was to [START_REF] Kochanek | Mortality in the United States, 2013[END_REF] analyze their professional practices in the field of prevention, screening, and treatment of cancer-therapy-related cardiovascular toxicity and (2) solicit their opinions on cardio-oncology programs that have recently emerged to manage cardiovascular diseases related to cancer treatments [START_REF] Yeh | Oncocardiology-Past, Present, and Future: A Review[END_REF][17][18][START_REF] Parent | The Cardio-oncology Program: A Multidisciplinary Approach to the Care of Cancer Patients With Cardiovascular Disease[END_REF].

METHODS

Study Design and Sample

Between August 2015 and August 2016, we conducted a cross-sectional declarative survey in the form of an individual, structured questionnaire that was submitted to the 918 French medical oncologists working in teaching and non-teaching hospitals, cancer centres and private healthcare facilities in France (data from the French National Medical Council). The oncologists were invited to participate via regional oncology networks. The oncologists were first contacted by phone or e-mail to agree on a date for an interview, either in person or by phone, during which the answers to the survey questions were collected. They also had the opportunity to complete the questionnaire via an online version that was created for this purpose. For both paper-and web-based formats, we used an established method for questionnaire distribution to maximize response rates that involved a preliminary notice, an invitation letter with a questionnaire and up to 2 reminders, and another copy of the survey for non-responders. We merged all study data into a secure central database for analysis.

Survey Instrument

The questionnaire was composed of items written by four oncologists and four cardiologists specializing in cardio-oncology. The survey was arranged into three distinct sections, covering successively the following topics (Supplementary-file1):

Section (i): The profile of the oncologist and the organization of cardiovascular monitoring and management within their healthcare facility. This profile included specialization of the practitioner, fields of competence, place of work, professional experience and prescription of drugs with potential cardiovascular toxicity. It also discussed the physical presence within the structure of a cardiologist, a cardiology department, a cardiology care unit or a cardio-oncology unit, and the access within the structure of performing transthoracic echocardiography (TTE) studies. Our survey was focused on the most commonly used drugs with potential cardiovascular toxicity including anthracyclines, trastuzumab, vascular endothelium growth factor pathway (VSP) monoclonal antibodies and other angiogenic inhibitors.

Section (ii): The practice of the oncologist in the field of cardiovascular toxicity. Questions covered awareness of the existence of guidelines from expert societies and, in particular, the recommendations of the European Society of Medical Oncology (ESMO) [START_REF] Curigliano | Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines[END_REF] and the consensus of experts from the American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) [START_REF] Plana | Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]. It also covered awareness of cardiovascular toxicity regarding the drugs prescribed, knowledge of screening methods and definitions of toxicity. Furthermore, it requested the cardiologist to estimate the number of patients who have presented with proven cardiovascular toxicity in association with a cancer therapy, the number of patients rejected from optimal cancer treatment because of a previous cardiovascular disease or risk factors and types of cardiovascular toxicity leading to interruption of cancer therapy. Finally, it covered modalities for pre-, peri-and post-therapy cardiovascular assessment, approaches to left ventricular dysfunction and prolongation of the QTc interval or hypertension. Section (iii): Personal opinions regarding cardio-oncology programs; whether cardiooncology is of any value, openness to the opinion of a specialized cardiologist, the level of cardio-oncology expertise of the cardiologists with whom he or she works and whether there are obstacles to the creation or development of cardio-oncology programs.

Information indicating that participation was voluntary and ensuring confidentiality was provided. Responding to the survey implied that the oncologists had given their consent to participate in the study.

Statistical Analysis

Categorical variables are described as counts and percentages with their 95% confidence intervals. The answers to the questions were expressed using a 5-or 6-category Likert scale.

To facilitate presentation, certain responses were grouped together to form three categories. χ2 tests were used to compare the different groups. Statistical significance was defined as P<0.05. All tests were 2-sided. Analyses were conducted using SPSS Statistics Software, version 20.0 (IBM Inc., New York, USA).

RESULTS

Oncologists Profiles and Cardiovascular Management Organizations

Of the 918 oncologists working in France, 303 responded to the survey. All regions of France were represented (Supplementary-file2). The profiles of oncologists and the organizations of cardiovascular management are summarized in Table 1. Three hundred and one oncologists (99%) had prescribed potentially cardiotoxic cancer therapies, including anthracyclines (83%), trastuzumab (51%), VSP antibodies (63%) and other angiogenic inhibitors (66%). Eighty-three percent of the oncologists worked with cardiologists in the same healthcare facility. To assess left ventricular function, 283 oncologists (93%) had used TTE, 156 (51%) had used isotopic ventriculography, and 75 (25%) had used cardiac MRI.

Global Practices in the Field of Cardiovascular Toxicity

The method adopted by oncologists for managing the cardiovascular toxicity of cancer therapies was based essentially (52%) on data obtained from the clinical trials conducted for each drug. Only 105 oncologists (35%) declared that they used the guidelines of expert societies of oncology. None was aware of recommendations published by expert societies of cardiology in this field.

All the oncologists were aware that anthracyclines and trastuzumab could cause left ventricular dysfunction and heart failure. However, this toxicity was known to only 55% of oncologists for the VSP antibodies and 68% for the other angiogenic inhibitors. For these two types of angiogenic inhibitors, the main types of cardiovascular toxicity cited were hypertension (cited by 90% and 74% of the oncologists, respectively) and venous thromboembolic events (83% and 51% of the oncologists, respectively).

One hundred and fifteen oncologists (38%) were unaware of the existence of early screening methods for left ventricular dysfunction. Using biomarkers such as troponin for this purpose or assessing global longitudinal strain in TTE were known methodologies to only 30% and 32% of oncologists, respectively. Seventy-five oncologists (25%) were familiar with the use of cardiac MRI for this purpose. The upper limit of the QTc interval was unknown by 128 oncologists (42%), and 180 (60%) of them stated that they knew how to calculate it.

Two hundred and seventy-nine oncologists (92%) reported that they had been confronted at least once by proven cardiovascular toxicity associated with cancer therapy. Estimates of the annual incidence of the onset of this type of toxicity were 5% to 20% for 17% of the oncologists, and less than 5% for 75% of them. The most commonly cited forms of cardiovascular toxicity responsible for terminating a cancer therapy were left ventricular dysfunction with or without heart failure (84%), venous thromboembolic events (56%), coronary artery disease (35%), hypertension (37%) and QTc interval prolongation (18%).

Most of the respondents (93%) had previously rejected a patient from a cancer therapy judged to be optimal because of a history of cardiovascular disease or risk factors.

Cardiovascular Assessment

The monitoring strategies according to the type of anti-cancer drug used are detailed in Table 2. A pre-therapy cardiovascular assessment (including cardiologic consultation and/or TTE) was prescribed systematically before use of anthracyclines and trastuzumab for 96% and 99% of oncologists, respectively. This pre-therapy assessment was significantly less frequent (P<0.0001) for VSP antibodies (43%) and other antiangiogenic drugs (70%) (Figure 1A). A per-therapy cardiovascular assessment was prescribed systematically for trastuzumab by 95% of oncologists and significantly less often (P<0.0001) for anthracyclines (54%), VSP antibodies (28%) and the other angiogenic inhibitors (42%) (Figure 1B). When using anthracyclines, troponin serum level assessment was used by only 7% of oncologists.

The post-therapy cardiovascular assessment (at the end of the treatment and thereafter) was prescribed systematically more often for anthracyclines (49%) and trastuzumab (59%) than for VSP antibodies (14%) and the other angiogenic inhibitors (28%) (P< .0001) (Figure 1C). Relative to pre-therapy cardiovascular assessment, post-therapy assessment was prescribed significantly less often for all therapies, including anthracyclines (96% versus 49%, P<0.0001), trastuzumab (99% versus 59%, P< .0001), VSP antibodies (43% versus 14%, P<0.0001), and the other angiogenic inhibitors (70% versus 28%, P<0.0001).

Management of Left Ventricular Dysfunction

The approach to the onset of left ventricular dysfunction (a decrease in LVEF) in relation to the type of cancer therapy used is described in Figure 2. For anthracyclines, management was inconsistent for asymptomatic patients with an LVEF between 40 and 50% and relatively consistent in all other cases (Figure 2A).

For trastuzumab, the management was inconsistent for all cases unless for asymptomatic patients with an LVEF between 40% and 50% (Figure 2B).

For VSP antibodies and other angiogenic inhibitors, management was inconsistent in all cases of left ventricular dysfunction (Figure 2C and Figure 2D).

Management of Hypertension and QT Prolongation

In case of hypertension under all angiogenic inhibitors, excluding cases of hypertensive emergency, 82% of oncologists performed systematic screening for proteinuria, and 44% chose to introduce an antihypertensive treatment themselves. Additionally, only 27% of oncologists maintained the cancer therapy, while 40% opted for a temporary interruption while waiting for a cardiology consultation. One third of the oncologists stated that they were unfamiliar with the approach to this situation.

When confronted with a >500 msec QTc interval prolongation or >60 msec progression, 45% of oncologists declared that they did not know how to manage the situation. In all the cases, the opinion of a cardiologist was requested.

Cardio-Oncology Programs

Sixty-four percent of oncologists believed that with regard to the cardiovascular toxicity of cancer therapies, the level of knowledge of the cardiologists with whom they worked could be improved, and 26% believed that this knowledge was insufficient. Most of the oncologists (88%) supported the idea that the presence within their healthcare facilities of a cardiooncology unit or using a cardiologist specialized in this field could improve their management of the cardiovascular adverse events. The primary obstacle to the creation or extension of cardio-oncology programs within their establishments was of a financial nature for 61% of oncologists. Limitations in terms of insufficient infrastructure were mentioned in 22% of cases, while 27% of the oncologists feared that the interest provoked by the creation of this program would be insufficient, particularly for the cardiologists with whom they work.

Finally, 22% of the oncologists believed that no real obstacle existed.

DISCUSSION

This study is the first to analyze the current practices of oncologists in the challenging field of cancer-treatment-related cardiovascular toxicity. In the context of lack of consensual guidelines [START_REF] Armenian | Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group[END_REF][START_REF] Lancellotti | Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography[END_REF][START_REF] Curigliano | Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines[END_REF][START_REF] Plana | Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF][START_REF] Zamorano | ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)[END_REF][START_REF] Armenian | Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline[END_REF], this survey showed that the assessment and management of the cardiovascular status of cancer patients is often inconsistent between oncologists before, during and after cancer therapy administration. While the great majority of respondents prescribed potentially cardiotoxic drugs, their attitude was particularly disparate toward the use of angiogenic inhibitors in comparison with "older" chemotherapy drugs such as anthracyclines. Finally, their opinion was favorable regarding the development of cardiooncology programs.

Regarding the cardiac monitoring in relation to prescribed treatments, we observed that the management was relatively consistent when anthracyclines or trastuzumab were used, whereas it was notably inconsistent with the use of angiogenic inhibitors. This result can be explained by a better overall knowledge of the incidence and the mechanisms of adverse cardiac side effects that may occur during the use of anthracyclines or trastuzumab. In fact, the results of numerous clinical trials have led to the standardization of monitoring during use of these treatments [START_REF] Goldhirsch | 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial[END_REF][START_REF] Curigliano | Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines[END_REF][START_REF] Tan-Chiu | Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31[END_REF]. Instead, the different responses collected for monitoring under angiogenic inhibitors can be explained by much more disparate data regarding the incidence of life-threatening cardiac adverse effects such as heart failure [START_REF] Ewer | Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events[END_REF][START_REF] Chu | Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib[END_REF]. Recently, the guidelines from the American Society of Clinical Oncology (ASCO) estimated that there is insufficient evidence to recommend a specific cardiac monitoring for patients treated by these drugs [START_REF] Armenian | Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline[END_REF] whereas the European Society of Cardiology considers reasonable to perform TTE every 6 months until stability in LVEF values is achieved [START_REF] Zamorano | ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)[END_REF].

Although global longitudinal strain measurement and biomarkers such as serum troponin have shown promise as potential early biomarkers of cardiac dysfunction [START_REF] Cardinale | Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy[END_REF][START_REF] Sawaya | Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab[END_REF], the respondents seemed unfamiliar with these tools. Their advantages have been reported in many recent recommendations but without strong level of evidence [START_REF] Cardinale | Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy[END_REF][START_REF] Sawaya | Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab[END_REF][START_REF] Cardinale | Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition[END_REF][START_REF] Kang | Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy[END_REF].

Regarding the approach to left ventricular dysfunction, we found differences between anthracyclines and trastuzumab on the one hand and angiogenic inhibitors on the other hand. The disparity of the approaches when using angiogenic inhibitors can be explained by the same arguments as those cited above for patient monitoring. Nevertheless, different responses to the approach to left ventricular dysfunction were also observed when using anthracyclines and trastuzumab, particularly in difficult cases where the patient is asymptomatic with LVEF between 40% and 50%. In this case, the ESMO recommends holding anthracyclines but continuing trastuzumab [START_REF] Curigliano | Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines[END_REF]. In the survey, only 38% of oncologists using anthracyclines and 21% using trastuzumab adopted this recommended approach. However, guidelines oversimplify what is always a complex decision. Decisions regarding continuing, holding, or discontinuing cancer therapy should be made based on a risk-benefit balance weighing how significant the cancer treatment is to the patient (benefit) versus the totality of the risks. For example, one would be willing to tolerate mild cardiac toxicity in a patient with cancer therapy effective for a metastatic tumor, whereas one would be likely to tolerate much less toxicity for an adjuvant oncology treatment with relatively modest benefit. Thus, the ASCO guidelines recently stated that no recommendations could be made regarding continuation or discontinuation of cancer therapy in individuals with evidence of cardiac dysfunction. The disparate responses in difficult cases illustrate the need for close collaboration between oncologists and cardiologists to ensure the most appropriate treatment decisions for each patient.

Systemic hypertension represents the most common cardiovascular complication associated with angiogenic inhibitors [START_REF] Li | Vascular and Metabolic Implications of Novel Targeted Cancer Therapies: Focus on Kinase Inhibitors[END_REF]. This outcome can be linked to glomerular disease and renal thrombotic microangiopathy, thus justifying proteinuria screening and follow-up of the glomerular filtration rate. In our survey, this complication was well known to most of the respondents. Thus, the systematic search for proteinuria was routine in the vast majority of cases. However, regarding the continuation or cessation of angiogenic inhibitors, most oncologists (73%) did not have a prepared response or interrupted treatment pending cardiology consultation. Indeed, as reported by The Cardiovascular Toxicities Panel of the National Cancer Institute, there is no single algorithm to follow in managing hypertension induced by angiogenic inhibitors and treatment needs to be individualized for each patient.

Again, this is an expert opinion based on consensus rather than on clinical outcome data [START_REF] Maitland | Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors[END_REF].

Most of the respondents supported the idea that a cardio-oncology unit or the presence of a specialized cardio-oncologist in their healthcare facilities could improve their management of adverse cardiovascular events related to cancer therapies. Similar opinion was recently reported among cardiologists [START_REF] Barac | Cardiovascular Health of Patients With Cancer and Cancer Survivors: A Roadmap to the Next Level[END_REF]. Actually, in response to the challenging management of cardiovascular toxicity, the development of the cardio-oncology sub-specialty might be considered a helpful solution. Through a multidisciplinary approach, this specialty aims to provide optimal care for patients with cardiovascular diseases or relevant risk factors from the time of cancer diagnosis and throughout their lives, even after the completion of treatment. The oncologists' opinions toward the development of cardio-oncology programs seemed to be favorable, particularly because most of them believed that access to cardiologists was not always possible and that their level of knowledge in cardiovascular adverse events could be improved. Over the past few years, medical centers in the United States, Canada, and Europe have developed cardio-oncology programs [START_REF] Cautela | Management and research in cancer treatment-related cardiovascular toxicity: Challenges and perspectives[END_REF][START_REF] Parent | The Cardio-oncology Program: A Multidisciplinary Approach to the Care of Cancer Patients With Cardiovascular Disease[END_REF][START_REF] Okwuosa | Building a cardiooncology program in a small-to medium-sized, nonprimary cancer center, academic hospital in the USA: challenges and pitfalls[END_REF]. This development has allowed for better coordination in the management of patients because of easier access to comprehensive cardiovascular assessment by specialized cardiologists and better assessment of the therapeutic benefit-to-risk ratio of cancer treatments by closer communication between cardiologists and oncologists. This partnership has been supported by action from different professional scientific societies [START_REF] Zamorano | ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)[END_REF]30].

The results of our survey should be regarded in light of potential study limitations. We could not compare the profiles of respondents versus those of non-respondents. Moreover, this was a declarative survey, and the nature of the topics explored may have led to response bias, including a difference between declared practice and actual practice, and underreporting of negative opinions on the development of cardio-oncology programs. To minimize this potential bias, we provided full assurances of confidentiality. Furthermore, proposed answers sometimes were not appropriated in all clinical situations encountered in practice. For example, the answers would have been different according to the oncological or the cardiologic profiles of patients. Finally, this survey was performed in a single European country and may not reflect the practices elsewhere.

This study presents an overview of oncologists' practices regarding the challenging field of cancer treatment-related cardiovascular toxicity. It shows major disparities in the approaches underlining the complexity of management of many different situations and the need for distribution of consensual guidelines involving both oncology and cardiology expert societies. Finally, the management of cancer patients might be improved by a multidisciplinary approach and equal access to innovative and personalized cardio-oncology programs.

FIGURES LEGENDS

Figure 1 .

 1 Figure 1. Pre-(A), Per-(B), and Post-Therapy (C) Cardiovascular Assessment According to

Figure 2 .

 2 Figure 2. Approach to the Onset of Left Ventricular Dysfunction in Relation to its Severity

The totals may reach a figure of less than 303 because of the lack of response to certain items. VSP, vascular endothelium growth factor signal pathway.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abbreviations