Clément Tarantini

Philippe Brouqui

Rose Wilson

Karolina Griffiths

Philippe Patouraux

Patrick Peretti-Watel
email: patrick.peretti-watel@inserm.fr

Sociologist

Peretti -Watel

Health Care Workers' Attitudes towards Hand Hygiene Monitoring Technology

Keywords: Healthcare workers, Hand hygiene, Monitoring technology, Implementation process, Perceptions, Resistance

BACKGROUND: Automated Radio-Frequency Identification (RFID)-based hand hygiene monitoring technology has been implemented in an infectious disease department to study healthcare workers' (HCWs) practices and improve hand hygiene.

AIM: Assess HCWs' attitudes towards this innovative monitoring device in order to anticipate resistance to change and facilitate future implementation.

METHOD:

In-depth interviews and an ethnographic approach.

FINDINGS:

From the perspective of HCWs, while they recognise the usefulness of RFID technology to prevent the transmission of infections to patients, they expressed concerns about risks related to RFID electromagnetic waves, as well as control by their superiors. Overall, HCWs' opinions oscillate between positive feelings characterised by enthusiasm for the possibility of changing their practices using technologies and research, and negative feelings marked by strong criticisms of these technologies and research. These criticisms included blaming hand hygiene monitoring technology for decontextualising HCWs practices. They perceived the technologies through the prism of the local and national contexts in which they are embedded. From their point of view, technologies are primarily in the best interests of the project team. Thus, they affirm and maintain the different interests and objectives between themselves and the project team, crystallising a conflict of professional norms and values between these two groups. The forms of resistance taken by HCWs were practical as well as oral.

CONCLUSION: Innovative technologies should be developed to address HCWs' attitudes surrounding

RFIDs. It is crucial to inform HCWs about the nature of these technologies, although some criticisms about monitoring systems are based on more structural causes.

Introduction

Hospital-acquired infections (HAIs) have caused the largest epidemic of infectious disease worldwide in terms of patient morbidity and mortality, as well as cost [START_REF]WHO Guidelines on hand hygiene in health care: first global patient safety challenge clean care is safer care[END_REF]. Improving the observance of hand hygiene techniques by healthcare workers (HCWs), including the use of hydro-alcoholic solutions (HAS), is one of the most effective ways to reduce these infections [START_REF] Pittet | Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Infection Control Programme[END_REF]. The establishment of regular audits of healthcare facilities through direct or indirect observation is strongly advocated [START_REF] Sax | The World Health Organization hand hygiene observation method[END_REF][START_REF] Sax | My five moments for hand hygiene': a user-centred design approach to understand, train, monitor and report hand hygiene[END_REF]. The former, which is considered the gold standard, has several biases, the main one being the Hawthorne Effect [START_REF] Hagel | Quantifying the Hawthorne effect in hand hygiene compliance through comparing direct observation with automated hand hygiene monitoring[END_REF]. For this reason automated technologies are playing an increasingly important role in producing more accurate hand hygiene compliance data [START_REF] Boudjema | MediHandTrace®: a tool for measuring and understanding hand hygiene adherence[END_REF]. The infectious disease unit (IDU) of the Hôpital Nord in Marseille set up an automated RFID-based system called MediHandTrace® (MHT).

This system aims to monitor HCW hand hygiene and also generates quantitative data for scientific research [START_REF] Boudjema | MediHandTrace®: a tool for measuring and understanding hand hygiene adherence[END_REF][START_REF] Dufour | Evaluation of handhygiene compliance and associated factors with a radio-frequency-identification-based-real-time continuous automated monitoring system[END_REF]. A study using MHT data in this ward highlighted a compliance rate of 22.6% [START_REF] Dufour | Input of innovative technology for surveillance and improvement of hand hygiene: the Medihandtrace® contribution to hand disinfection monitoring and intervention[END_REF]. From the beginning of the research project, a team of social science researchers was involved in collecting qualitative data. One of their objectives was to investigate HCWs' opinions and attitudes toward the hand hygiene monitoring system, as well as the unforeseen consequences of its introduction. Indeed, monitoring systems can improve hand hygiene compliance [START_REF] Staats | Motivating process compliance through individual electronic monitoring: an empirical examination of hand hygiene in healthcare[END_REF] but human factors have an important role in this process [START_REF] Anderson | Using human factors engineering to improve the effectiveness of infection prevention and control[END_REF]. This is why it is crucial to take into account opinions and attitudes of HCWs toward these devices and to evaluate their acceptability in order to facilitate the future implementation of such technologies in routine practice [START_REF] Dawson | Assessing user acceptance towards automated and conventional sink use for hand decontamination using the technology acceptance model[END_REF]. We mobilise a broad definition of the notion of attitude strongly rooted in the field of social psychology: as a more or less sustainable judgement or evaluation of an object, an individual or a situation, according to a certain degree of favour or disadvantage [START_REF] Ajzen | Attitudes, Personality, and Behaviour[END_REF][START_REF] Eagly | The Psychology of Attitudes[END_REF]. It includes affective, cognitive and behavioural components [START_REF] Eagly | The Psychology of Attitudes[END_REF][START_REF] Katz | A Preliminary Statement to a Theory of Attitude Structure and Change[END_REF][START_REF] Rosenberg | Belief, Attitude, intention and behavior. An introduction to theory and research[END_REF]. The expression of an attitude can be verbal, in which case we can talk about opinion, or nonverbal [START_REF] Katz | The Functional Approach to the Study of Attitudes[END_REF].

Context

Focus on MHT technology

The MHT project is a consortium of private companies and public organisations that share a common objective: to reduce the risk of HAIs by improving HCWs' practices. The MHT technology consists of a combination of electronic chips (tags) inserted into HCWs' shoes and antennae which are glued to the floor of the patient's room and connected to an HAS dispenser by RFID, allowing the HCW to be identified when using the dispenser. A feedback screen is located in the HCWs' office and provides real-time hand disinfection rates by occupational group, also known as "scores".

A short demo video is available at the following link: https://www.youtube.com/watch?v=d1Oa7vNT_iQ

Focus on the implementation process

The implementation process was divided into three main phases between January 2012 and March 2015. Each of these phases corresponded to a particular moment in the chronology of the implementation of the monitoring technology (Figure 1); and to specific modalities for managing the issues related to this implementation process: nature of the meetings, actors involved and themes addressed (Table I). Phase two was also a period of technological testing, which resulted in some scientific publications [START_REF] Boudjema | MediHandTrace®: a tool for measuring and understanding hand hygiene adherence[END_REF].

Methodology

Among the professionals working in the unit, we distinguished between different groups: HCWs who included the so-called paramedical staff (nurses (N), nursing assistants (NA) hospital housekeepers (HHK), and students); physicians most often referred to as medical staff. This study focused on the HCWs group. Indeed, these categories performed the most care paths during a shift and had the lowest hand hygiene compliance rate in the unit compared to physicians [START_REF] Dufour | Input of innovative technology for surveillance and improvement of hand hygiene: the Medihandtrace® contribution to hand disinfection monitoring and intervention[END_REF][START_REF] Barrau | Hand antisepsis: evaluation of a sprayer system for alcohol distribution[END_REF]. As a result, these categories are both the most exposed to the MHT system and the most concerned with improving hand hygiene. Trainee students were excluded from our surveys to limit bias.

The interview survey

This study involved 24 semi-structured face-to-face interviews with HCWs (13 N, 6 NA, 4 HHK) using a topic guide (Table II) and undertaken by CT and PP between January 2014 and January 2015. One HHK explicitly refused to be interviewed because she was "not interested in the study". Some professionals asked to postpone their interview several times due to time constraints and were finally not interviewed.

The ethnographic survey

In order to limit social desirability bias and compare different kinds of data, an additional data collection method was added. This took the form of ethnographic fieldwork in the ward conducted by CT 2-3 days a week between July 2014 and January 2015. The purpose was to observe the professionals of the IDU unit during their work. Field observations and informal discussions related to the study objectives were recorded in a notebook. CT also attended nearly 25 meetings with the project team (steering, technical or scientific committees) from which he also drew ethnographic observations. The project team included the department head, researchers, product engineers, technicians and sales managers. In the project team, the role of interlocutor with the HCWs was usually assigned to the department head. Triangulation of data sources [START_REF] Denzin | The research act: a theoretical introduction to sociological methods[END_REF] confirmed that we had reached data saturation [START_REF] Guest | How many interviews are enough? An experiment with data saturation and variability[END_REF] (more details are available in Table III).

Data analysis

CT coded transcripts and ethnographic data independently using an inductive approach based on grounded theory [START_REF] Strauss | The hospital and its negotiated order[END_REF] identifying recurrent and salient themes. CT then met with PB and PPW to compare, discuss and adjust the codes (for additional information on the methodology see Table III).

In a second round, PB, RW, KG and PPW did critical revisions to the manuscript. We illustrated our study in quotes provided in Table IV and in the text next to the corresponding sentence using the symbol "Q" followed by quotation number.

Along the same lines, twelve interviewees (12/24) explained that "scores" on the feedback screen were biased because it did not reflect the reality of work in relation to the number of staff and tasks assigned to each professional category (Q16).

MHT and the professional context

Seven of the twenty-four interviewees reported negative perceptions of MHT technologies and verbal manifestations of resistance were often associated with problematic professional contexts, such as lack of human or material resources (Q17, Q18). Indeed, phase 3 of the implementation process began at a time when health care workers felt short of staff and equipment. In this context, HCWs did not understand why such significant funding was being allocated to research when they considered that the priority was to fund jobs and equipment (Q19). Although this topic is not a majority in the interview corpus, it was also frequently mentioned in informal discussions during observations (Q20). These sentiments were still evident even after the project team had explained, at information meetings, the nature of funding and the inability to use scientific funding to create jobs or purchase equipment. This type of discourse reduced when HCWs felt less distressed about team size and workload.

Distant relationships with the goals of the project team

Finally, some interviewees (5/24) perceived MHT technologies mainly as a tool to conduct scientific research and expressed their feelings of being used by the project team for scientific research and their feeling of a lack of recognition for their work and the difficulties they face (Q21). The interview data did not reflect the reality of these remarks because the observation revealed that they were very significant in the service. These comments highlighted the divisions that HCWs perceived with the research team, blaming them for their inability to understand the HCWs' work and the difficulties they faced because they were too busy doing their research (Q22). It was the same kind of criticisms when a HCW claimed that the implementation of the MHT system was primarily a way to access professional recognition within the scientific community by publishing in scientific journals (Q23).

From speeches to acts of resistance

Rejection of automated data feedback

The ethnography also revealed that the feedback screen had been disconnected several times. The HCWs admitted that one of them was responsible for this, but never identified the culprit or prevented them from doing so. This issue was raised several times during information meetings. The project team stressed the importance and usefulness of this device in improving patient care, its costs and the potential for disciplinary action against perpetrators. This behaviour continued throughout the entire investigation. HCWs never expressed the reasons for these acts to the project team and the anthropologist.

Discussion

In order to reduce HAIs, a number of innovative technologies have been developed to promote hand hygiene [START_REF] Ward | Automated and electronically assisted hand hygiene monitoring systems: a systematic review[END_REF][START_REF] Marra | New technologies to monitor healthcare worker hand hygiene[END_REF]. Few of these have been tested for accuracy or sensitivity, most are expensive, difficult to install and maintain, but their increasing use in hospitals is a key issue to improve hand hygiene [START_REF] Staats | Motivating process compliance through individual electronic monitoring: an empirical examination of hand hygiene in healthcare[END_REF][START_REF] Srigley | Hand hygiene monitoring technology: protocol for a systematic review[END_REF][START_REF] Larson | Monitoring hand hygiene: meaningless, harmful, or helpful?[END_REF]. Nevertheless, it is important to test these technologies in multiple and different settings to understand the factors that can positively or negatively influence their efficacy [START_REF] Srigley | Hand hygiene monitoring technology: a systematic review of efficacy[END_REF]. In the same way, it is also essential to investigate opinions and attitudes of HCWs toward these automated monitoring systems according to this variety of contexts [START_REF] Boscart | Acceptability of a wearable hand hygiene device with monitoring capabilities[END_REF]. Indeed, improving hand hygiene also requires adapting interventions, contexts and technologies for better acceptability [START_REF] Dawson | Assessing user acceptance towards automated and conventional sink use for hand decontamination using the technology acceptance model[END_REF][START_REF] Larson | Monitoring hand hygiene: meaningless, harmful, or helpful?[END_REF][START_REF] Ellingson | Healthcare personnel perceptions of hand hygiene monitoring technology[END_REF].

Our results reveal that HCWs attitudes towards the MHT system oscillate between enthusiasm and adherence on the one hand, and strong criticism or even acts of sabotage on the other. Positive remarks are in line with results of other studies reporting tolerance of HCWs toward these technologies, their desire to improve their practices or their adherence to the competitive game [START_REF] Ellingson | Healthcare personnel perceptions of hand hygiene monitoring technology[END_REF][START_REF] Marques | How can information systems provide support to nurses' hand hygiene performance? Using gamification and indoor location to improve hand hygiene awareness and reduce hospital infections[END_REF]. Nevertheless, competition is not necessarily well perceived. In this case, indifference, or at worst sabotage, may be a response to a tool considered biased or contrary to team spirit.

This study shows that, from the HCWs' point of view, technologies may introduce new types of health and social control risks. Other studies also reported that RFID systems give the impression of being controlling [START_REF] Fisher | Tracking the social dimensions of RFID systems in hospitals[END_REF] or raise concerns about potential punitive uses of the system and its inability to take into account the context and the possibilities or not in terms of hand hygiene [START_REF] Ellingson | Healthcare personnel perceptions of hand hygiene monitoring technology[END_REF]. The lack of information initially given to the HCWs is likely to play a role in their acceptance of the devices, especially regarding misconceptions about health effects and the fear of repressive use on HCWS.

Thus, our study also reveals that transparency and communication play a crucial role in acceptance [START_REF] Boscart | Acceptability of a wearable hand hygiene device with monitoring capabilities[END_REF][START_REF] Ellingson | Healthcare personnel perceptions of hand hygiene monitoring technology[END_REF][START_REF] Meng | Technological innovations in infection control: A rapid review of the acceptance of behavior monitoring systems and their contribution to the improvement of hand hygiene[END_REF].

Another of our results is supported by qualitative studies on this subject. This is the inability to assess the situational context of hand hygiene options [START_REF] Ellingson | Healthcare personnel perceptions of hand hygiene monitoring technology[END_REF]. These situations are also characterised by professional dilemmas -we can talk about conflicts of professional norms -that the system cannot take into account. For example, when a HCW prefers not to disinfect his or her hands to stay in contact with the patient.

Our study also reveals some original results. Indeed, HCWs perceive the MHT system through the prism of a broader and more global context, thus intertwining local and national contexts. The local context corresponds to the working conditions and professional experiences in this context. The system was set up at a time of difficulties that HCWs associated with a lack of human and material resources. A favourable or unfavourable professional context can influence HCWs perceptions toward monitoring technologies. In this perspective, the implementation of this tool is potentially a tool for HCWs to advocate and negotiate regarding their working conditions. The implementation of a project, that was seen to be disconnected from real care issues and mainly associated with the world of research, crystallised and strengthened these claims for HCWs. These perceptions correspond to the political context of national reforms of hospitals in France since the 1990s, inspired by the New Public Management paradigm, which contribute to intensifying the work of HCWs and have provoked protests from them, particularly in France over the past decade [START_REF] Belorgey | L'hôpital sous pression. Enquête sur le "nouveau management public[END_REF].

In addition, our findings show that HCWs rarely disassociate questions of monitoring technologies from those of scientific research. Most importantly, HCWs expressed differences in objectives and interests between their group and the project team, demonstrating that different social norms and values exist between them, in a context where they consider their identity and professional recognition threatened. This reflects the idea that the definition of risks and the priorities given to the means of reducing them differ according to whether it is a professional in charge of daily care tasks or an external actor seeking to manage patient safety through a direct approach [START_REF] Dixon-Woods | An ethnographic study of classifying and accounting for risk at the sharp end of medical wards[END_REF].

Limitations and strengths of the study

While the results of this study are very similar to those of other similar studies, they may not be more broadly relevant. Like all studies, the characteristics of the people interviewed also depended on its specific local context and the cultural, social, political and economic characteristics.

Nevertheless, there are still few qualitative studies on this subject, even though the challenges of hand hygiene are significant. Among these studies, few use several qualitative methods together: interviews and ethnography. Nevertheless, this study also shows the importance of questioning the singularities and characteristics of each context to understand caregivers' attitudes towards these technologies.

Conclusion

Although monitoring technologies are generally tolerated, they are always perceived from the context in which they are integrated.

Resistance and criticisms from HCWs towards MHT monitoring technologies have multiple causes. Some of these are the result of a simple lack of information and communication between HCWs and the project team. However, other causes are structural and depend on the coexistence of different professional cultures within the working environment.

A social and anthropological approach helped us to understand HCWs' perceptions and behaviour towards MHT. Through such an approach, resistance to these technologies can be anticipated; the benefits of which have been demonstrated with hand hygiene compliance [START_REF] Morgan | Automated hand hygiene count devices may better measure compliance than human observation[END_REF].

Finally, MHT technologies should be developed with the input of HCWs. They should be adapted to their routine practices taking into account the complex care environments in which they work, as well as the specific care constraints they face.

Acknowledgements

This anthropological research is a part of multidisciplinary research project funded by the European Regional Development Fund; the A*MIDEX project (ANR-11-IDEX-0001-02), APFR 2011 and FEDER 2007-2013 N°42171 MedihandTrace Oseo and the PACA Region; as well as the Fondation Mediterranée Infection.

This work was supported by the French Government under « Investissements d'avenir» by the Agence Nationale de la Recherche (ANR, fr: National Agency for Research), (reference: Méditerranée Infection 10-IAHU-03) TOTAL length: 3168, I, II, III and IV are included in the electronic supplementary material

data available at https://secure.urkund.

Ethics

All potential participants were informed of the MHT implementation project, its objectives and the option of refusing to participate. All participants provided their informed consent for both the interviews and the ethnography. Students were excluded from monitoring. Participants were guaranteed anonymity and confidentiality; any information that could identify participants was deleted from the tape-recording or field notes. The research was approved by the Ethics Review Board N° 2016-018.

Results

Positive opinions towards MHT devices

A tool for improvement

Half of the HCWs interviewed (12/24) expressed an opinion on the importance of HAIS prevention and believed in the role of the MHT system in achieving this goal. For example, they considered MHT technologies as a way to acquire in-depth knowledge about hand hygiene and good practice (Q1) and/or they mentioned the positive impact of evaluation in raising awareness of their practices and trying to improve them (Q2). Three of them stated that these devices could have a lasting impact on HCWs behaviours (Q3). Nevertheless, these kind of enthusiasm were always nuanced by different kinds of critical comments.

The feedback screen, from interest to indifference

Among the half of HCWs with positive comments, four of them also expressed particularly enthusiastic remarks on the usefulness of the feedback screen to change practice and stated that they had joined the competition as a game over time(Q4). Three other HCWs stated that they were interested and stimulated by the feedback screen at the very beginning of its installation, but that they gradually became completely disinterested in this device (Q5).

A risk free technology? Health risk and social control Some HCWs (5/24) had concerns regarding the possible impact of RFID waves (and their perceived carcinogenic potential) on their health (Q6).

In addition, some HCWs (8/24) also explained that the principle of being "tagged" promoted the feeling of being watched and controlled by their superiors (Q7). The project team addressed the concerns of HCWs at information meetings where the harmless nature of RFID waves, anonymisation of data, scientific objectives and the non-punitive nature of the project were discussed. This has had a reassuring effect on health care workers and they no longer express such apprehensions.

Criticisms according to HCWs

Indifference and inefficiency

The other half of the caregivers (12/24) expressed their indifference to this system (Q8), considered it ineffective, explaining that it did not change their behaviours (Q9), whether it was about the tags, the feedback screen or both (Q10, Q11). These remarks very often went hand in hand with more specific criticisms. One of these interviewees explicitly blamed the principle of competition between occupational categories (Q12)

The MHT system does not take context into account Just under half of the interviewees (10/24) claimed that the MHT technology and the scientific research relating to it did not take into account the complex context in which they operate and the reasons for their actions (Q13). For example, in discussing with these interviewees their opinion of these technologies, they discussed the difficulties of matching disinfection recommendations with gloves recommendations in practices (Q14), or the issue that disinfection recommendations created in the relationship with the patient (Q15).

Conflict of interest

Philippe Brouqui owns shares in the MediHandTrace® start-up.


K Drareni

A Dougkas

A Giboreau

M Laville

P J Souquet

Dr Moustafa Bensafi
email: moustafa.bensafi@cnrs.fr

Relationship between food behavior and taste and smell alterations in cancer patients undergoing chemotherapy: a structured review

Keywords: Cancer, Chemotherapy, Taste, Smell, Food intake, Food behavior

INTRODUCTION Taste and smell alteration is a frequent side effect of chemotherapy. However, little is known about their influence on patients' food behavior and the mechanisms underpinning their occurrence. This lack of clarity is likely due to a series of factors among which heterogeneity in chemotherapy-induced taste and smell modifications may play a prominent role. The present review provides a critical overview of the evidence on the association between taste and smell alterations and food behavior modifications in cancer patients undergoing chemotherapy.

DESIGN

The literature search was performed using PubMed and Google Scholar databases and restricted to literature for English-language articles published between 1990 and June 2018. Sensory related terms were combined with food behavior related terms to identify the studies that examined the association between these two terms. The retrieved studies were grouped based on the taste and smell assessment outcomes.

RESULTS

Thirteen eligible articles were included in the review. The studies varied in design, length, methodology of assessment, and studied population. The categorization of studies depending on taste and smell assessment outcomes allowed the definition of three patient profiles: unaltered, hypo-and hyper-chemosensation (taste and/or smell). Alterations were significantly correlated with patients' energy intake and macronutrient preferences suggesting that sensitivity of each patient to olfactory and gustatory stimuli is likely to play a role in food behavior modulation during cancer and chemotherapy.

CONCLUSION

The review summarizes and provides relevant associations between taste/smell alterations and food behavior while receiving chemotherapy considering existing individual variations. Given the sensory influence on food behavior modulation, a better characterization of smell and taste alterations before the launch of chemotherapy seems important for a better understanding and management of patients' food behavior trajectory over the treatment.

Introduction

Cancer patients treated with chemotherapy have reported adverse taste [START_REF] Bernhardson | Chemosensory changes experienced by patients undergoing cancer chemotherapy: a qualitative interview study[END_REF][START_REF] Jensen | Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients[END_REF][START_REF] Bernhardson | Reframing eating during chemotherapy in cancer patients with chemosensory alterations[END_REF][START_REF] Speck | Taste alteration in breast cancer patients treated with taxane chemotherapy: experience, effect, and coping strategies[END_REF], and smell modifications [START_REF] Yakirevitch | Olfactory function in oncologic hospice patients[END_REF][START_REF] Riga | Hyposmia: an underestimated and frequent adverse effect of chemotherapy[END_REF], associated with deterioration of some quality of life aspects such as loss of appetite, fatigue [START_REF] Gamper | Taste alterations in breast and gynaecological cancer patients receiving chemotherapy: prevalence, course of severity, and quality of life correlates[END_REF][START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF], nausea [START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF] and decrease in energy intake [START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF]. Systemic chemotherapy for cancer often lacks specificity [START_REF] Knowles | Introduction to the Cellular and Molecular Biology of Cancer[END_REF] and can cause distressing side effects such as alopecia [START_REF] Botchkarev | Molecular Mechanisms of Chemotherapy-Induced Hair Loss[END_REF], anemia [START_REF] Groopman | Chemotherapy-Induced Anemia in Adults: Incidence and Treatment[END_REF], and sensory impairments, especially to chemosensory systems, that rely on the perception of molecular properties of stimulus [START_REF] Roland | Odorat et goût: De la neurobiologie des sens chimiques aux applications[END_REF]. During the administration of cytotoxic chemotherapy the chemosensory systems is exposed to more changes than other sensory systems [START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF][START_REF] Yakirevitch | Effects of cisplatin on olfactory function in cancer patients[END_REF][START_REF] Steinbach | Effect of platinum-containing chemotherapy on olfactory, gustatory, and hearing function in ovarian cancer patients[END_REF]. This is possibly due to the short life span of gustatory and olfactory receptor cells and their frequent renewal [START_REF] Barlow | Developing and regenerating a sense of taste[END_REF], making them more vulnerable to cytotoxic chemotherapy drugs.

In addition to these physiological changes, cognition is also altered with patients exhibiting difficulties in gustatory and olfactory recognition [START_REF] Steinbach | Gustatory and olfactory function in breast cancer patients[END_REF] or overall hedonic appreciation [START_REF] Joussain | Cisplatin chemotherapy induces odor perception changes in bronchial cancer patients[END_REF][START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF]. However, at higher levels of integration, gustation and olfaction do not result in independent percepts; but instead, in combination with somatosensory inputs [START_REF] Small | Odor/taste integration and the perception of flavor[END_REF][START_REF] Cullen | DISORDERS OF SMELL AND TASTE[END_REF] including trigeminal nerve endings located in the oral and nasal cavities [START_REF] Spence | Multisensory flavour perception[END_REF], they lead to a unitary perception called flavor. This multisensory percept is considered to be a major determinant of food acceptance or rejection [START_REF] Nicklaus | Les perceptions gustatives chez l'enfant[END_REF]. A recurrent hypothesis in the fields of oncology and nutrition is that any alteration of taste and/or smell (during chemotherapy for instance) may have significant consequence on flavor perception and on the hedonic judgment of food. In cancer patients undergoing chemotherapy, that may be reflected in changes in food preferences [START_REF] Holmes | Food avoidance in patients undergoing cancer chemotherapy[END_REF][START_REF] Coa | The impact of cancer treatment on the diets and food preferences of patients receiving outpatient treatment[END_REF], development of aversions [START_REF] Schwartz | Role of nausea in the development of aversions to a beverage paired with chemotherapy treatment in cancer patients[END_REF][START_REF] Fontas | Perspective socio-anthropologique de la prise en charge de la dénutrition du malade cancéreux[END_REF], decrease in food enjoyment [START_REF] Cohen | Smell and Taste Disorders Resulting from Cancer and Chemotherapy[END_REF],

changes in dietary habits and loss of appetite [START_REF] Coa | The impact of cancer treatment on the diets and food preferences of patients receiving outpatient treatment[END_REF][START_REF] Mardas | Dietary habits changes and quality of life in patients undergoing chemotherapy for epithelial ovarian cancer[END_REF]. Although this assumption has been mentioned in various articles in the field [START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF][START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF][START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF], there is no structured review that summarizes how taste and smell alterations are specifically related to modifications in food behavior in cancer patients receiving chemotherapy.

In particular, whereas some reviews have examined taste and smell modifications during cancer and/or chemotherapy [START_REF] Cohen | Smell and Taste Disorders Resulting from Cancer and Chemotherapy[END_REF][START_REF] Comeau | Taste and smell dysfunction in patients receiving chemotherapy: a review of current knowledge[END_REF][START_REF] Hong | Taste and odor abnormalities in cancer patients[END_REF][START_REF] Gamper | Coming to your senses: detecting taste and smell alterations in chemotherapy patients. A systematic review[END_REF][START_REF] Epstein | A systematic review of orofacial pain in patients receiving cancer therapy[END_REF][START_REF] Hovan | A systematic review of dysgeusia induced by cancer therapies[END_REF][START_REF] Thorne | A state-of-the-art review of the management and treatment of taste and smell alterations in adult oncology patients[END_REF][START_REF] Ijpma | Metallic taste in cancer patients treated with chemotherapy[END_REF][START_REF] Boltong | The influence of chemotherapy on taste perception and food hedonics: a systematic review[END_REF][START_REF] Altundag | Chemical Senses in Cancer Patients[END_REF][START_REF] Ravasco | Aspects of taste and compliance in patients with cancer[END_REF][START_REF] Wismer | Assessing alterations in taste and their impact on cancer care[END_REF][START_REF] Van Der Werf | Insight in taste alterations during treatment with protein kinase inhibitors[END_REF] and others explored the effect of cancer and/or chemotherapy on food behavior and nutrition, none explored potential associations between the taste/smell modifications and food behavior. Understanding the relationship between chemosensory alterations during chemotherapy (mainly taste and smell) and modification of food behavior is important at two levels: 1/ at a fundamental level, it allows a better understanding of the sensory and cognitive mechanisms that connect the sensory systems to neural network involved in the process of food intake; 2/ at a clinical level, this may contribute to the improvement in the care of patients, considering the impact of taste and smell alterations throughout the treatment on food intake and eating enjoyment.

The main aim of the present review is to discuss scientific and clinical findings from studies investigating the link between taste and smell alterations and food behavior modifications in cancer patients undergoing chemotherapy. For a better understanding of the chemosensory perception and its importance in daily life, this review first introduces the sensory systems involved in flavor perception (i.e. gustation, olfaction, trigeminal sensitivity).

Secondly, we define the concept of food behavior and its determinants. Thirdly, we review the existing literature exploring both taste and smell alterations and food behavior changes during chemotherapy. We further examine whether a homogeneous profile of chemosensory alterations exists or whether chemotherapy and/or cancer have differential impact on patients' chemosensory capabilities (i.e. hyposensitivity, hypersensitivity, mixed profiles, no change, etc.). In addition, the relationship between these sensory change profiles and food behavior alterations in this population is discussed. The review concludes by opening future perspectives that consider early evaluation of alterations in taste and smell (at the individual level) for better management of the future food behavior alterations of the patient.

Chemo-sensation: definition and underlying sensory systems

The chemosensory processes involve the olfactory, gustatory and trigeminal systems and enable the detection and recognition of external chemical signals. These fundamental sensory modalities are shared by most multicellular organisms and significantly impact their behavior [START_REF] Md | Chemoreception in human behaviour: experimental analysis of the social effects of fragrances[END_REF]. For instance, environmental chemical signals allow the detection of food, reproductive partners, prey and predators. In the following section, we present an overview of the functioning of each chemosensory system.

The gustatory system

At the periphery, the gustatory system includes an array of taste buds in the oral and pharyngeal cavities. Taste buds are located around small structures known as papillae, which are found mainly on the upper surface of the tongue (but also on the soft palate, upper esophagus, cheek and epiglottis). There are four known types of papillae: foliate, cirumvallate, fungiform and filiform, distributed on different zones of the surface of the tongue (Figure 1) [START_REF] Epstein | Understanding the impact of taste changes in oncology care[END_REF]. Taste perception is the result of an interaction between sapid molecules and taste receptors in specialized epithelial gustatory cells present in taste buds [START_REF] Sugita | Taste perception and coding in the periphery[END_REF]. Taste buds are located on the tongue and have a lifespan of 5-20 days [START_REF] Barlow | Developing and regenerating a sense of taste[END_REF].

On a functional level, the gustatory system works as a nutrient sensing system. It enables the detection, recognition and discrimination of the five basic tastes -sweet, bitter, umami, sour and salty, which can be combined to form more elaborate taste sensations [START_REF] Breslin | Mammalian taste perception[END_REF].

Salty and sour tastes are detected through ion channels (Na+ for salt and intracellular proton concentration for sour) [START_REF] Heck | Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway[END_REF][START_REF] Liu | Mechanism of fat taste perception: Association with diet and obesity[END_REF]. Sweet, bitter and umami tastes are mediated by G protein coupled receptors (GPCRs) [START_REF] Sugita | Taste perception and coding in the periphery[END_REF]. The proteins called T1R1, T1R2 and T1R3 detect sweet and umami tastants, while T2Rs is specific to bitter. The combination of these receptors with their specific ligand (contained in the sapid molecule) triggers a series of intracellular reactions [START_REF] Epstein | A systematic review of orofacial pain in patients receiving cancer therapy[END_REF][START_REF] Nelson | Mammalian sweet taste receptors[END_REF]. The sensory information is transmitted to the primary taste cortex via three cranial nerves that carry taste sensations from different areas: the facial nerve (VII) from the anterior two thirds of the tongue; the glossopharyngeal nerve (IX), from the posterior one third of the tongue; and the vagus nerve (X) from the back of the oral cavity. These sensations are then transmitted to secondary or associative cortical areas common to olfactory and gustatory sensations (Figure 1) [START_REF] Roland | Odorat et goût: De la neurobiologie des sens chimiques aux applications[END_REF][START_REF] Epstein | Understanding the impact of taste changes in oncology care[END_REF].

An important factor that plays a fundamental role in gustatory perception is saliva.

Saliva is the first digestive fluid in the food canal. It is secreted by the salivary glands and poured directly into the oral cavity [START_REF] Proctor | The physiology of salivary secretion[END_REF]. Saliva helps in chewing food, forming and swallowing the food bolus, and digesting starch (amylase) [START_REF] Mandel | The functions of saliva[END_REF]. Saliva also serves as the solvent of sapid molecules, which need to be dissolved in order to be detected by the taste receptor cells. By detecting these molecules, the gustatory system provides qualitative information of the ingested food. It is estimated that about 2 ml of saliva are secreted every 15 to 20 minutes. A decrease in salivary flow leads to xerostomia (mouth dryness), which makes the detection of sapid molecules more difficult, complicates the action of mastication and swallowing and may cause oral problems such as mucositis or candidiasis [START_REF]Salivary secretion, taste and hyposalivation -MESE[END_REF].

The olfactory system

At the periphery, the human olfactory system is characterized by the large number and the diversity of its sensory receptors (between 350 and 400), which are G-protein coupled receptors that enable the detection and discrimination of a very large number of odorants [START_REF] Bushdid | Humans can Discriminate more than one Trillion Olfactory Stimuli[END_REF].

The neurons of the olfactory receptors are in direct contact with the environment, which facilitates the detection of environmental chemical molecules [START_REF] Mcewen | Olfactory cilia: our direct neuronal connection to the external world[END_REF]. These neurons are located in the olfactory epithelium, a specialized tissue of about 2.5 to 10 cm² in surface area located on the roof of the nasal cavity. The neurons are bipolar cells with several cilia, which contain the olfactory receptors on their surface projecting into the nasal mucosa. The mucus moistens the nasal cavity but also plays an important role in olfactory perception, as it is involved in the dissolution of some hydrophobic odorant molecules, their transport to receptor sites, and the degradation and the removal of the excess odorants [START_REF] Nagashima | Enzymatic conversion of odorants in nasal mucus affects olfactory glomerular activation patterns and odor perception[END_REF].

There are two ways of transporting odorous molecules towards the nasal epithelium:

(i) the ortho-nasal pathway ensures the detection of volatile odorous molecules by the olfactory receptors following their passage through the nasal cavity, (ii) the retro-nasal pathway enables the detection of aromas contained in the food. The later path is triggered by the action of chewing food, which induces the release of its flavors [START_REF] Masaoka | Expiration: the moment we experience retronasal olfaction in flavor[END_REF]. It is suggested that ortho-nasal and retro-nasal olfaction may be sustained by distinct neural processes [START_REF] Landis | Differences Between Orthonasal and Retronasal Olfactory Functions in Patients With Loss of the Sense of Smell[END_REF].

Whether via the ortho-nasal or retro-nasal route, once the interaction between the odorous molecule and receptor is established, the sensory information is then transmitted via the olfactory nerve (I: olfactory) to a central structure called the olfactory bulb (Figure 1). The olfactory bulb is composed of excitatory and glutaminergic mitral cells and is located in the cranial chamber in both hemispheres. Thereafter, the olfactory tract connects the olfactory bulbs to the brain areas involved in the perception and identification of odors including (among others) the primary olfactory cortex (piriform cortex, part of the amygdala) and both the orbito-frontal cortex and insula, which play a role in hedonic and associative treatment with other sensory modalities (Figure 1) [START_REF] Önerci | Nasal Physiology and Pathophysiology of Nasal Disorders[END_REF]. The sense of smell is therefore closely related to other senses, especially the gustatory and trigeminal systems, as well as to emotion and memory [START_REF] Zald | Emotion, olfaction, and the human amygdala: Amygdala activation during aversive olfactory stimulation[END_REF]. In both, the olfactory and the gustatory systems, high-order information is sent and processed to associative brain areas including the orbito frontal cortex (OFC) and the insula via the thalamus (THAL) for gustation.

PLEASE BE SURE TO PROVIDE US THE MOST ORIGINAL VERSION OF THIS FIGURE THAT YOU HAVE AND IF THIS IS FROM ANOTHER SOURCE PLEASE CITE THAT SOURCE AND IMMEDIATELY OBTAIN PERMISSION FOR ITS USE

The trigeminal system

With gustation and olfaction, the trigeminal system is the third chemosensory system that contributes to flavor perception. Trigeminal sensitivity (both proprioceptive and kinesthetic) of the face and associated cavities (i.e. oral and nasal) is transmitted via the three branchesthe ophthalmic, maxillary and mandibular -of the fifth cranial nerve also called the trigeminal nerve [START_REF] Small | Odor/taste integration and the perception of flavor[END_REF] (Figure 1). The trigeminal nerve endings in the nasal and oral cavities are sensitive to tactile and thermic information and to several molecules known to be pungent, tingling, irritating or astringent [START_REF] Purves | Trigeminal Chemoreception[END_REF]. Thus, the spiciness of pepper, the burning of ginger, the sparkling of carbonated drinks, and the astringency of red wines, are potential stimulants of the trigeminal system. Psychophysical and neurobiological investigations have revealed that interactions between the trigeminal and the olfactory system may occur at both peripheral (trigeminal fibers were identified in the nasal epithelium [START_REF] Schaefer | Trigeminal collaterals in the nasal epithelium and olfactory bulb: a potential route for direct modulation of olfactory information by trigeminal stimuli[END_REF]) and central levels [START_REF] Bensafi | Neural coding of stimulus concentration in the human olfactory and intranasal trigeminal systems[END_REF], although compared to pure olfactory stimuli, intranasal trigeminal stimuli show specific neural activations [START_REF] Iannilli | Trigeminal activation using chemical, electrical, and mechanical stimuli[END_REF] .

Food behavior: definition and determinants

Food behavior represents food beliefs and practices linked to food choice, preparation, cooking and consumption and encompasses both nutrition and food safety knowledge, attitudes, perceptions and beliefs in the selection and handling of food [START_REF] Tepper | Understanding food choice in adult men: Influence of nutrition knowledge, food beliefs and dietary restraint[END_REF]. Although there are several influences on food behavior related to an individual's cultural and social environment, as well as personal and food nature or food risk factors that interact these are almost impossible to disentangle [67], and most of the research linked with food behavior in pathological states is in the areas of food preferences and food intake. Food/energy intake, and food preferences and hedonics (which include choices, motives and habits) characterize not only healthy eating practices but also eating-related pathologic behaviors such as obesity, eating disorders (e.g. anorexia) and malnutrition [START_REF] Lacaille | Eating Behavior[END_REF]. "Food/energy intake", is considered adequate when food consumption meets the energy requirements of the individual, a state known as energy balance. The regulation of food intake is based on complex neuro-hormonal mechanisms that allow the maintenance of the energetic balance [START_REF] Luquet | Régulation de la prise alimentaire[END_REF] and is mainly driven within the hypothalamus, and specifically the arcuate nucleus, which plays a major role in the integration of hunger/satiety signals [START_REF] Luquet | Régulation de la prise alimentaire[END_REF]. Food intake is regulated by a series of homeostatic and non-homeostatic factors [START_REF] Levine | Why Do We Eat? A Neural Systems Approach[END_REF][START_REF] Berthoud | Homeostatic and non-homeostatic pathways involved in the control of food intake and energy balance[END_REF]. Hunger and appetite [START_REF] Fromentin | Peripheral and central mechanisms involved in the control of food intake by dietary amino acids and proteins[END_REF] are prominent regulatory factors of energy balance since they modulate the energy intake side of the equation. Hunger is the sensation of needing food, expressed at the physiological level by a complex interaction between vagal signals, secretion of orexigenic hormones (ghrelin, orexin), decrease in plasma concentration of leptin, and a low level of circulating glucose (hypoglycemia) [START_REF] Sanger | The Hungry Stomach: Physiology, Disease, and Drug Development Opportunities[END_REF], [START_REF] Amin | Hunger and Satiety Mechanisms and Their Potential Exploitation in the Regulation of Food Intake[END_REF]. The term appetite covers the whole process of food intake, including food selection, motivation to eat, and individual preferences and is generally described as the desire to consume certain foods [START_REF] Sanger | The Hungry Stomach: Physiology, Disease, and Drug Development Opportunities[END_REF]. The sensory and external environmental stimulation of appetite and thus food intake has drawn attention to the hedonic dimension of appetite without underestimating the importance of internal homeostatic system (energy needs) [START_REF] Blundell | Appetite control: methodological aspects of the evaluation of foods[END_REF]. Food preferences and hedonics despite being a process driven by deficits in energy, contribute to the pivotal role of pleasure during an eating experience [START_REF] Luquet | Régulation de la prise alimentaire[END_REF][START_REF] Levine | Why Do We Eat? A Neural Systems Approach[END_REF][START_REF] Lutter | Homeostatic and Hedonic Signals Interact in the Regulation of Food Intake[END_REF]. The sensory properties of food such as palatability, appearance, taste, smell and texture influence hedonic expectations, and contribute to the decision of food consumption: food intake is increased if food is perceived as palatable, and decreased if the sensory experience is unpleasant [START_REF] Hurling | Eating with your eyes: effect of appearance on expectations of liking[END_REF][START_REF] Sørensen | Effect of sensory perception of foods on appetite and food intake: a review of studies on humans[END_REF]. Beside these two dimensions, a pleasantness-based phenomenon called sensory specific satiety plays a major role in the regulation of food intake [START_REF] Hetherington | Sensory-specific satiety and its importance in meal termination[END_REF]. Sensory specific satiety is defined as the decline of liking of a specific food over the course of eating, leading to termination of its consumption, in contrast to food with a different sensory profile [START_REF] Rolls | Sensory-specific satiety[END_REF][START_REF] Brondel | Variety enhances food intake in humans: role of sensory-specific satiety[END_REF]. Overall, it is noticeable that food behavior is strongly modulated by sensory inputs [START_REF] Sørensen | Effect of sensory perception of foods on appetite and food intake: a review of studies on humans[END_REF][START_REF] Rolls | How sensory properties of foods affect human feeding behavior[END_REF], and especially chemosensory signals [START_REF] Ramaekers | Odors: appetizing or satiating? Development of appetite during odor exposure over time[END_REF][START_REF] Gaillet | Priming effects of an olfactory food cue on subsequent food-related behaviour[END_REF].

Research methodology

Data search and selection criteria strategy

The literature search was performed using PubMed and Google Scholar databases and restricted to literature for English-language articles published up to June 2018. As we aimed to understand the specific impact of cytotoxic chemotherapy on taste and smell perception and food behavior, sensory related terms were combined with food behavior related terms to identify the studies that examined the association between these two arms. The key words included 1) for the sensory arm: taste, gustatory, smell, olfactory, trigeminal sensitivity, flavor and 2) for the food behavior arm: food/energy intake, hunger, appetite, satiety, food preferences, food hedonics/liking/enjoyment. The selection of food related terms focused on the biological and hedonic determinants of food behavior, excluding other aspects such as economic, physical and social determinants. The terms chemotherapy and cancer were added to the search. Articles were eligible for inclusion if both sensory changes (including taste and smell) and food behavior determinants modifications were investigated as an explicit side effect of chemotherapy. Studies on patients with head and neck tumors, which are known to be strongly associated with taste and smell alterations, and studies on patients having any other treatment than chemotherapy were excluded. Article database was augmented by a manual search in reference lists of identified published articles, as well as previous relevant systematic and narrative reviews for citation of further eligible studies. Using these selection criteria, a total of 19 articles that cover both the sensory and the food behavior dimensions were identified. Finally, 13 eligible articles were included in this review after removing those studies that did not provide quantitative data of the variables of interest (Table 1).

Data extraction and processing

The relevant information extracted from each study is related to the study characteristics, methodological characteristics and main outcomes as described in Table 1.

Those study characteristics and outcomes are described as follows: (i) "Reference" (Authors and date of the studies), (ii) "Study type" (cross-sectional, longitudinal, following patients for a period varying from 6 weeks [START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF] to 1 year after the chemotherapy induction [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF]), (iii)

"Groups" characteristics (number of patients, mean age), (iv) "Cancer type and chemotherapy regimen", (v) the tools used for "Sensory assessment" and the type of "Approach" used to assess taste and smell ("Objective" methods that include psychophysical tests; "Subjective" methods based on self-reported description of sensory capabilities [START_REF] Spotten | Subjective and objective taste and smell changes in cancer[END_REF]), (vi) the "Food behavior measure", (vii) the "Main effects of chemotherapy on gustatory and olfactory perceptions" from the sensory measures, (viii) the "Main effects of chemotherapy on food behavior", and finally (ix) the results of the interaction between sensory and food dimensions ("Sensory/food interaction"). To the best of our knowledge, alterations of the trigeminal system due to chemotherapy treatments have not been reported.

Results

Modification in cancer patients' taste and smell in during chemotherapy

Eleven of the 13 studies listed in Table 1 showed an effect of chemotherapy treatment on perceptions (including taste and smell). In studies that used subjective methods of chemosensory assessment, there was high heterogeneity in chemosensory outcomes for patients not only between the studies but also within the same study (Table 1, Section A). For example, Marinho et al. [START_REF] Marinho E Da | Impact of chemotherapy on perceptions related to food intake in women with[END_REF] showed that 64% of the patients reported taste changes during the chemotherapy treatment with no sensory modifications in 36%. to taste and smell (section D); These 3 types of profiles are described below.

The "Unaltered taste and smell" profile

This profile characterizes patients exhibiting no changes in their olfactory and gustatory functions (Table 1, Section B). Two studies using an objective method of assessment showed no effect of chemotherapy on the taste and smell perception of cancer patients [START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF][START_REF] Ovesen | Food intake, eating-related complaints, and smell and taste sensations in patients with cancer of the lung, ovary and breast undergoing chemotherapy[END_REF]. Ovesen et al. [START_REF] Ovesen | Food intake, eating-related complaints, and smell and taste sensations in patients with cancer of the lung, ovary and breast undergoing chemotherapy[END_REF] reported on 52 patients with a diagnosis of cancer, including 25 lung, 21 ovarian, and 6 breast cancer. In a longitudinal study, they performed 3 time-points for assessments including a baseline (T0), a first follow up before the second cycle of chemotherapy (T1) and a second follow up three weeks after the third cycle of chemotherapy (T2). The results showed no significant difference in olfactory threshold of patients between the three time points. However, the gustatory assessment revealed a decrease in taste threshold, but only in the patients with a diagnosis of lung cancer. Similarly, in a longitudinal study by De Vries et al. [START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF] using both objective and subjective methods of assessment, there was no modification of gustatory and olfactory sensitivity after 2 cycles of chemotherapy on a small but homogeneous group of patients with diagnosis of esophagogastric cancer.

The "Hyposensitivity to tastes and/or smells" profile

This profile identifies patients who experience decreased gustatory and/or olfactory function (Table 1, Section C). Three studies showed a decrease in both olfactory and gustatory perceptions [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF][START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF][START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF], and two reported a reduced ability to identify gustatory stimuli [START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF][START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF]. In a longitudinal study, IJpma et al. [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF] assessed the olfactory and gustatory capabilities in 21 patients with a diagnosis of testicular cancer undergoing cisplatin chemotherapy. The results showed a transient decrease of subjective taste and smell perception, associated with a decrease in sensitivity for salty taste. This effect was prominent during the first week of each chemotherapy cycle. Similarly, De Vries et al. [START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF] assessed the olfactory and gustatory functions in 28 women with a diagnosis of breast cancer, during, and 6 months after the completion of chemotherapy. Patients reported their taste and smell functions as lower during chemotherapy and shortly after chemotherapy, yet improved 6 months after the completion of chemotherapy. In the same study, objective psychophysical tests showed a lower olfactory and gustatory sensitivity during chemotherapy, especially for salty taste. The decrease of subjective taste and/or smell perception was also found in a larger group including 117 women with breast cancer [START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF].

Besides sensitivity, Boltong et al. [START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF] showed a reduced ability to identify salty, sour and umami tastes in women with breast cancer between their first and their final cycle of chemotherapy, as well as a decrease in sweet taste liking. A difficulty recognizing tastes was also reported in a cross-sectional study by Lara-Sanchez et al. [START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF], who compared patients with different cancer diagnoses and healthy controls. After 2 cycles of chemotherapy, an increase in complaints about gustatory perceptions was associated with a decreased ability to identify bitter taste in patients.

The "Hyper-sensitivity to tastes and smells" profile

Only one study reported a significantly higher gustatory sensitivity for bitter and umami tastes, assessed by a Rinsing Mouth Test (RMT), in 40 patients with a diagnosis of lung cancer receiving platinum-based chemotherapy (Table 1, Section D). Interestingly, the increase in gustatory sensitivity was accompanied by a decrease ability to identify taste (umami). These findings suggest that a hyper gustatory sensitivity may alter taste representation and thus taste identification, which may significantly impact food recognition.

In sum, there is a high incidence of alterations in chemosensation while cancer chemotherapy is administered, as well as at times high inter-individual variability between patients and likely across treatments and cancer types. The observed heterogeneity is supported by the findings of several studies, which reported unaltered [START_REF] Joussain | Cisplatin chemotherapy induces odor perception changes in bronchial cancer patients[END_REF], decreased [START_REF] Steinbach | Gustatory and olfactory function in breast cancer patients[END_REF][START_REF] Berteretche | Decreased taste sensitivity in cancer patients under chemotherapy[END_REF][START_REF] Bernhardson | Self-reported taste and smell changes during cancer chemotherapy[END_REF][START_REF] Steinbach | Qualitative and quantitative assessment of taste and smell changes in patients undergoing chemotherapy for breast cancer or gynecologic malignancies[END_REF][START_REF] Riga | Hyposmia: an underestimated and frequent adverse effect of chemotherapy[END_REF][START_REF] Walliczek-Dworschak | Testicular cancer patients undergoing cisplatin based chemotherapy exhibit temporary olfactory threshold scores changes[END_REF], or intensified gustatory and/or olfactory capabilities in patients who were treated with chemotherapy [START_REF] Yakirevitch | Effects of cisplatin on olfactory function in cancer patients[END_REF][START_REF] Bossola | Taste intensity and hedonic responses to simple beverages in gastrointestinal cancer patients[END_REF][START_REF] Bernhardson | Olfactory changes among patients receiving chemotherapy[END_REF]. This inter-individual variability with regards to the effect of chemotherapy on the taste and smell perception of cancer patients could be attributable to a number of putative factors as discussed in the section below.

Putative factors modulating taste and smell profiles

At the methodological level, study design, method of assessment, variable of interest, or stage of chemotherapy at the time point of assessment may influence the results and explain the lack of consistency between studies. For instance, we observed variability in study design, with 3 cross sectional studies and 10 longitudinal studies that followed patients for a period from 6 weeks [START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF] (2 chemotherapy cycles) to 1 year after the initiation of chemotherapy [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF]. There was also heterogeneity in the populations studied. Eight of the selected studies had a homogeneous group of patients in terms of cancer histology, however in some, patients received different chemotherapy regimens which may have influenced the reported effects. We also noted that only five studies enrolled a control group, enabling one to examine whether the observed effect is a consequence of the pathology and/or the treatment, or if it deviates from normal fluctuations over time.

Other factors are related to the disease and treatment such as histology and chemotherapy regimen. Considering histology, studies reported a varying percentage of patients with taste and/or smell alterations: 76% of patients with breast and gynecological cancers [START_REF] Gamper | Taste alterations in breast and gynaecological cancer patients receiving chemotherapy: prevalence, course of severity, and quality of life correlates[END_REF]; 41.4% of patients with a diagnosis of lung cancer [START_REF] Bernhardson | Self-reported taste and smell changes during cancer chemotherapy[END_REF]; 68% of those with a gastrointestinal cancer [START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF]; and 31% of those with pancreatic cancer [START_REF] Bernhardson | Self-reported taste and smell changes during cancer chemotherapy[END_REF]. This factor is closely related to the type of chemotherapy used, given that certain treatment regimens are more likely to induce chemosensory impairment. For example, Zabbernig et al. [START_REF] Zabernigg | Taste alterations in cancer patients receiving chemotherapy: a neglected side effect?[END_REF] showed that irinocetan, a drug commonly in the management of colorectal cancer, induces more taste disorders than other drugs such as gemcitabine, commonly used for pancreatic cancer. [START_REF] Zabernigg | Taste alterations in cancer patients receiving chemotherapy: a neglected side effect?[END_REF].

Furthermore, the same study reported a maximal occurrence of taste dysfunction with epirubicin, docetaxel and capecitabine as neoadjuvant treatment of patients with early breast cancers.

In addition to the disease-related factors enumerated above, individual differences may be explained by intrinsic physiological factors that vary from one individual to another regardless of the cancer's histology [Table 2]. The gustatory and olfactory perception process operates at several levels, and each level is likely to present individual differences. For instance, the perception of gustatory stimuli is based on releasing sapid molecules in contact with saliva, and their interaction with gustatory receptors located in taste buds that are held in papillae. The quantification of papillae density and more specifically fungiform papillae density allows one to detect individual variation in the number of papillae on the surface of the human tongue [START_REF] Miller | Variations in human taste bud density and taste intensity perception[END_REF]. A high density of fungiform papillae corresponds to a higher number of taste buds, and so a higher number of taste receptors, which corresponds to a higher taste intensity perception. Thus, this physiological difference may play a role in the heterogeneity of chemotherapy-induced sensory alterations.

Another contributing factor to the observed variability is genetic variation such as the perception of bitterness [START_REF] Kim | Genetics of individual differences in bitter taste perception: lessons from the PTC gene[END_REF][START_REF] Bufe | The Molecular Basis of Individual Differences in Phenylthiocarbamide and Propylthiouracil Bitterness Perception[END_REF][START_REF] Mennella | Genetic and Environmental Determinants of Bitter Perception and Sweet Preferences[END_REF]: the ability to (hypo or hyper) perceive specific molecules (phenylthiocarbamide and 6-n-propylthiouracil) depends on the expression of gustatory receptors. Therefore, without considering cancer histology or treatment, the status of patients (hypo vs. hypersensitive) towards bitterness perception is inherently different. This genetic/phenotypic status may result in differential chemotherapy effects on taste perception explaining the reported complaints of patients about sensitivity to bitterness [START_REF] Hong | Taste and odor abnormalities in cancer patients[END_REF][START_REF] Dewys | Abnormalities of taste sensation in cancer patients[END_REF].

Regarding the other taste modalities, a previous study showed a genetic variation in umami taste receptor that affected umami taste sensitivity [START_REF] Shigemura | Genetic and Molecular Basis of Individual Differences in Human Umami Taste Perception[END_REF]. Finally, considering the oral cavity, saliva, which varies in terms of flow and composition across people, may explain individual variations in the effect of chemotherapy on taste perception [START_REF] Mirlohi | Analysis of salivary fluid and chemosensory functions in patients treated for primary malignant brain tumors[END_REF][START_REF] Munoz | Inter-individual differences in human saliva composition affect the partition of food and beverages aroma compounds[END_REF][START_REF] Neyraud | Variability of human saliva composition: Possible relationships with fat perception and liking[END_REF].

Olfactory function also exhibits inter-individual variation in a non-pathologic state, and this may explain the different olfactory phenotypes during cancer and chemotherapy.

Prevalent genetic variations in olfactory receptors leads to differences in odor perception [START_REF] Keller | Genetic variation in a human odorant receptor alters odour perception[END_REF]. Moreover, human oral physiology and food oral processing, which determine the amount of released aroma in the nasal cavity are not similar across people [START_REF] Flaherty | Individual Differences in Retronasal Odor Responsiveness: Effects of Aging and Concurrent Taste[END_REF][START_REF] Hasin-Brumshtein | Human olfaction: from genomic variation to phenotypic diversity[END_REF].

Finally, other physiologic factors that may explain the variability in chemosensory profile are intrinsic to patients and include gender [START_REF] Koelega | Some Experiments on Sex Differences in Odor Perception[END_REF] and importantly age [START_REF] Doty | The influences of age on olfaction: a review[END_REF][START_REF] Sergi | Taste loss in the elderly: Possible implications for dietary habits[END_REF]. For example, during chemotherapy treatment, women were found to have a higher sensitivity in sweetness, bitterness perception than men [START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF] and younger patients showed less taste and/or smell impairments than older patients [START_REF] Steinbach | Qualitative and quantitative assessment of taste and smell changes in patients undergoing chemotherapy for breast cancer or gynecologic malignancies[END_REF].

Food behavior as a function of taste and smell profiles

Of the 13 studies listed in Table 1, nine studies examined patients' food intake (energy or macronutrients intake), and three studies assessed food or macronutrients preferences. Surprisingly, most of these studies did not report difference in patients' energy and macronutrients intake: three studies showed no effect of chemotherapy on food intake [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF][START_REF] Ovesen | Food intake, eating-related complaints, and smell and taste sensations in patients with cancer of the lung, ovary and breast undergoing chemotherapy[END_REF][START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF], and four studies did not mention the results related to food intake at the group level [START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF][START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF][START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF][START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF]. Four studies reported a decrease in food intake but only when the group was stratified following the severity of chemosensory complaints [START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF][START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF][START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF][START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF]. The more severe were the sensory complaints (hypo or hyper sensitivity), the lower was the energy intake of patients. The 3 sub-sections that follow summarize the effects of chemotherapy on food behavior as a function of sensory profiles (unaltered, hypo, hyper) in patients with a diagnosis of cancer.

The "unaltered taste and smell" profile Using a 3-day diet diary, Ovesen et al. [START_REF] Ovesen | Food intake, eating-related complaints, and smell and taste sensations in patients with cancer of the lung, ovary and breast undergoing chemotherapy[END_REF] assessed food intake in patients with a diagnosis of cancer of the lung, ovary, or breast cancer but did not find a significant difference in food intake between baseline and follow-up at cycle 3. Also, there were no within group differences when nutritional data were analyzed as a function of diagnostic group [START_REF] Ovesen | Food intake, eating-related complaints, and smell and taste sensations in patients with cancer of the lung, ovary and breast undergoing chemotherapy[END_REF]. These authors argued that the mean values of the group concealed the wide range of intake at the individual level, noting that about one-third of the patients consumed less energy than they should have consumed. Considering food preferences, De Vries et al. [START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF] showed that patients had a higher preference toward high protein than high carbohydrate or low energy products, but there was no difference in macronutrient preference between baseline and after 2 cycles of treatment. No difference was observed in preferences for sweet food and savory food [START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF]. In sum, the unaltered taste and smell profile is unlikely to present significant alterations in food behavior at a group level.

The "hyposensitivity to tastes and/or smells" profile

Studies showing a decrease in patients' taste and/or smell function reported either an unchanged [START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF][START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF] or a decreased energy intake [START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF] throughout the treatment. IJpma et al. [START_REF] Ijpma | Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy[END_REF] showed that food intake assessed by the Food Frequency Questionnaire in 21 men with a diagnosis of testicular cancer remained stable over time. Lara-Sanchez et al. [START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF] showed that nutrient intake assessed with the SNUT program [START_REF] Hernández-Avila | Validity and reproducibility of a food frequency questionnaire to assess dietary intake of women living in Mexico City[END_REF] of patients after 2 cycles of chemotherapy and controls were similar. However, a positive correlation between modification in sweet threshold/bitter recognition score and food intake was highlighted in some patient groups. While De Vries et al. [START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF] using a 24-h dietary recall reported a significantly lower energy, protein, and fat intake in 117 women with a diagnosis of breast cancer compared to 88 healthy controls [START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF]. This decrease in food intake was significantly correlated with a reduced self-reported taste function. Similarly, Boltong et al. [START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF] reported reduced energy intake in accordance with a reduced ability to identify tastes.

Regarding food and macronutrients preferences, DeVries et al. [START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF] noted a decreased liking for high fat and high protein products and an increased liking for savory food 1 to 3 weeks after chemotherapy in women with a diagnosis of breast cancer [START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF]. Furthermore, De Vries et al. [START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF] observed that a higher subjective rating of taste function was correlated with a higher liking of high protein, low energy, savory and sweet products, whereas a higher rating of subjective smell function was significantly correlated with a higher liking for low energy and sweet products only. This suggests that the olfactory and the gustatory impairments affect food preferences and likings differently.

Overall, these results indicate that when considered as a group, patients with a profile of hypo-sensitivity to tastes and/or smells do not exhibit modifications in food intake.

However, once the strength of the sensory alteration within this group is considered, a decrease in food intake and liking of certain food is apparent suggesting the more taste and smell are altered, the more food intake and liking is decreased.

The "hypersensitivity to taste and smell" profile

Only one study showed an increase in gustatory sensitivity using RMT [START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF]. This study assessed food intake of 40 patients with a diagnosis of lung cancer and showed a negative correlation between the sweet detection threshold and protein intake, which means that patients with higher sensitivity to sweet taste consumed less proteins, and specifically animal proteins. The difference in protein intake was not observed between patients with increased or decreased umami or bitter taste. This is in agreement with three studies, which used a subjective assessment of chemosensory function and linked significantly self-reported taste and/or smell complaints with a lower food consumption [START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF][START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF][START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF]. Hutton et al. [START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF], Brisbois et al. [START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF] and McGreevy et al. [START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF] adapted the "Taste and Smell Survey" questionnaire (initially designed for patients infected with the HIV [START_REF] Heald | Taste and smell complaints in HIV-infected patients[END_REF] to cancer patients and showed a strong correlation between the severity of patients' chemosensory complaints and the decrease of energy intake.

Interestingly, using the same assessment tools these three studies came to the same conclusions although the size of patient groups and cancer histology were different.

In summary, results suggest a negative impact of taste and/or smell changes (hyper or hypo profile) on energy intake [START_REF] Turcott | Value: Changes in the Detection and Recognition Thresholds of Three Basic Tastes in Lung Cancer Patients Receiving Cisplatin and Paclitaxel and Its Association with Nutritional and Quality of Life Parameters[END_REF][START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF][START_REF] Boltong | A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes[END_REF][START_REF] Hutton | Chemosensory Dysfunction Is a Primary Factor in the Evolution of Declining Nutritional Status and Quality of Life in Patients With Advanced Cancer[END_REF][START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF][START_REF] Sánchez-Lara | Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy[END_REF] and food preferences [START_REF] De Vries | Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy[END_REF][START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF][START_REF] De Vries | Altered food preferences and chemosensory perception during chemotherapy in breast cancer patients: A longitudinal comparison with healthy controls[END_REF][START_REF] Marinho E Da | Impact of chemotherapy on perceptions related to food intake in women with breast cancer: A prospective study[END_REF].

Conclusions and perspectives

In conclusion, the available scientific literature provides no evidence for a systematic and unvarying/consistent impact of chemotherapy on gustatory and olfactory functions in patients with a diagnosis of cancer. Additionally, the existence of different sensitivities in taste and smell profiles is highlighted in various studies, which used subjective and objective methods and showed unchanged, increased or decreased sensitivity to tastes and smells in various cancers. This diversity in the chemosensory profiles of patients may be attributable to various factors including those related to methodology and those that are inherent to the physiological state of the patient (structural and functional aspects of the olfactory and the gustatory systems, saliva composition, etc).

The sensitivity of each patient to olfactory and gustatory stimuli is likely to modulate patients' food behavior and preferences by modifying the representation of foods (from sensitivity, to recognition and preferences). This may lead to an individual "food trajectory" that differs between patients and throughout the treatment. Interestingly, when patients are admitted in clinical departments for chemotherapy treatments, their "food" trajectory during and after the treatment is unpredictable. Thus, an important challenge in the oncology field is to develop strategies to help health practitioners predict potential food behavior changes of patients by being more vigilant and provide appropriate dietary and culinary solutions tailored to each patient in order to maintain a healthy relationship with food and improve quality of life.

Exploiting the relationship between taste and smell alterations and changes in eating behavior could be part of the developed strategies. For example, by systematically screening patients' senses of smell and taste at arrival at the clinic, and after the first cycles of chemotherapy, it is possible to categorize patients according to the aforementioned chemosensory profiles and therefore describe, anticipate or predict a subsequent development of changes in eating behavior.

It is notable that relationships between taste and smell alterations and changes in food behavior have already been demonstrated in physiological and/or pathological conditions other than cancer. For instance, odor hedonic perception is altered in patients suffering from Alzheimer's disease [START_REF] Joussain | Altered Affective Evaluations of Smells in Alzheimer's Disease[END_REF][START_REF] Pouyet | Influence of flavour enhancement on food liking and consumption in older adults with poor, moderate or high cognitive status[END_REF], elderly individuals [START_REF] Joussain | Relationship Between Psychophysiological Responses to Aversive Odors and Nutritional Status During Normal Aging[END_REF], and children with autism [START_REF] Luisier | Odor Perception in Children with Autism Spectrum Disorder and its Relationship to Food Neophobia[END_REF].

Interestingly, patients with a diagnosis of Alzheimer's disease who perceived smells as less intense showed a tendency towards a decreased nutritional status [START_REF] Joussain | Altered Affective Evaluations of Smells in Alzheimer's Disease[END_REF], and elderly individuals who did not properly categorize smells exhibited a significant decrease in nutritional score [START_REF] Joussain | Relationship Between Psychophysiological Responses to Aversive Odors and Nutritional Status During Normal Aging[END_REF]. Moreover, altered hedonic discrimination of odors in children with autism was associated with a higher level of food neophobia defined as refusal to consume novel foods [START_REF] Luisier | Odor Perception in Children with Autism Spectrum Disorder and its Relationship to Food Neophobia[END_REF]. Finally, individuals with no oncological or neurological pathologies but presenting olfactory alterations (dysosmic patients), also exhibit significant modifications in food behavior reflected in a reduced attraction towards novel foods, a tendency to experience less pleasure when eating, and a significantly higher use of condiments such as sugar, mayonnaise, or sour cream to make their dishes tasty [START_REF] Manesse | Dysosmia-Associated Changes in Eating Behavior[END_REF].

Although the present review highlights a clear relationship between the occurrence of taste and smell alterations with the energy intake of patients with a diagnosis of cancer, experimental studies are still needed. Once validated in patients with cancer, such descriptive (or predictive) models relating olfactory and/or gustatory alterations and future modifications in food behavior may be applied in clinical settings by developing rapid and sensitive chemosensory assessments combined with efficient measures of food behavior. Such screening approaches and the resulting recommendations should be done using a patientcentered intervention approach rather than a group approach in order to meet the needs of each patient.

cancer: A prospective study.

Figure 1 .

 1 Figure 1. Chemosensory systems involved in flavor perception. The trigeminal system is composed of three branches: ophthalmic, maxillary and mandibular. In olfaction, odorant molecules are first detected in the olfactory epithelium (OE), and neural information is then transmitted to the olfactory bulb (OB) andother central structures such as the piriform cortex (PC) and the amygdala (Amyg). In gustation, sapid molecules are first treated within the different papillae on the tongue (there exist other receptor sites in the palate and esophagus), and the signal is then sent to the nucleus tractus solitarius (NTS) via different cranial nerves (VII: facial nerve (chorda tympani); IX: glossopharyngeal nerve (lingual branch); X: vagus nerve (laryngeal branch). In both, the olfactory and the gustatory systems, high-order information is sent

  Hutton et al. showed that 86% of the patients reported sensory abnormalities, of which 30% described only taste abnormalities, and 5% only smell. The prevalence of olfactory and gustatory changes in patients was 60% in Brisbois et al.[START_REF] Brisbois | Characterization of chemosensory alterations in advanced cancer reveals specific chemosensory phenotypes impacting dietary intake and quality of life[END_REF] but the sensory phenotype varied according to the participants: 42% declared a stronger sensation, 18% a weaker sensation, 14% a mixed sensation, and 26% no change in sensation. In accordance, Mc Greevy et al.[START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF] showed a large variability across patients, with a prominent effect of gender -for example, whereas 10% of the men vs. 37% of the women declared stronger sensation, 20% of the men vs. 6% of the women declared sensation was weaker. Finally, 73% of patients in the study byBelqaid et al.[START_REF] Belqaid | A longitudinal study of changing characteristics of self-reported taste and smell alterations in patients treated for lung cancer[END_REF] declared sensory alterations with a variation in sensory phenotypes throughout the

treatment -from weaker sensation to stronger sensation or no effect. Such heterogeneity in self-reported taste and smell modifications is confirmed by psychophysical studies based on objective methods of sensory assessment. Following patients' sensory capacities, three types of profiles were extracted from the papers listed in Table

1:

(1) patients exhibiting unaltered taste and smell (section B); (2) patients exhibiting reduced sensitivity or hyposensitivity to taste and smell (section C); (3) patients exhibiting a increased sensitivity or hypersensitivity

Declarations of interest: none

Funding: A funding contribution was provided by Elior, Apicil, Region Rhone-Alpes (ARC1 call), and Métropole de Lyon/Region Rhone-Alpes/Cancéropôle Lyon Auvergne Rhône-Alpes (CANUT project). The funding sources were not involved in the writing and the publication of this review.

Authors' contributions: K.D. prepared and analysed the database. K.D., A.D., A.G. and M.B. drafted the manuscript. All authors contributed to, and approved, the final version of the manuscript. • Chemotherapy (CT) regimen

Ethics approval and consent to participate: Not applicable

Chemosensory assessment and approach

Food behavior measure

Main effects of chemotherapy on gustatory and olfactory perceptions

Main effects of chemotherapy on food behavior

Chemosensory/Food interaction

Section A: Heterogeneous chemosensory outcomes • Women (36) --------------------------- Gustatory and olfactory functions:

• Habitual intake before CT:

Gustation and Olfaction:

• Lower self-reported • Appetite: Lower self-reported

• Self-reported taste perception ability VS. [START_REF] De Vries | Differences in dietary intake during chemotherapy in breast cancer patients compared to women without cancer[END_REF] assessment= random days during the full cycle of CT

• Women (117) ------------------ Genetic variations in the expression of gustatory receptors lead to individual differences in both bitterness perception [START_REF] Kim | Genetics of individual differences in bitter taste perception: lessons from the PTC gene[END_REF][START_REF] Bufe | The Molecular Basis of Individual Differences in Phenylthiocarbamide and Propylthiouracil Bitterness Perception[END_REF][START_REF] Mennella | Genetic and Environmental Determinants of Bitter Perception and Sweet Preferences[END_REF] umami perception [START_REF] Shigemura | Genetic and Molecular Basis of Individual Differences in Human Umami Taste Perception[END_REF] Genetic variation in olfaction Genetic variations in the expression of olfactory receptors lead to differences in odor perception [START_REF] Keller | Genetic variation in a human odorant receptor alters odour perception[END_REF] Density of fungiform papillae High density of fungiform papillae is associated to a higher number of taste buds, and so a higher number of taste receptors, resulting in a higher taste intensity perception [START_REF] Miller | Variations in human taste bud density and taste intensity perception[END_REF] Saliva Flow and composition of saliva influence chemosensory perception [START_REF] Mirlohi | Analysis of salivary fluid and chemosensory functions in patients treated for primary malignant brain tumors[END_REF][START_REF] Munoz | Inter-individual differences in human saliva composition affect the partition of food and beverages aroma compounds[END_REF][START_REF] Neyraud | Variability of human saliva composition: Possible relationships with fat perception and liking[END_REF]

Oral physiology

Differences in human oral physiology and food oral processing can determine the amount of released aroma in the nasal cavity [START_REF] Flaherty | Individual Differences in Retronasal Odor Responsiveness: Effects of Aging and Concurrent Taste[END_REF][START_REF] Hasin-Brumshtein | Human olfaction: from genomic variation to phenotypic diversity[END_REF]

Gender

Women exhibit a higher sweetness/bitterness perception than men [START_REF] Mcgreevy | Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer[END_REF][START_REF] Koelega | Some Experiments on Sex Differences in Odor Perception[END_REF]

Age

Young individuals show less taste and/or smell impairments than older individuals [START_REF] Steinbach | Qualitative and quantitative assessment of taste and smell changes in patients undergoing chemotherapy for breast cancer or gynecologic malignancies[END_REF][START_REF] Doty | The influences of age on olfaction: a review[END_REF][START_REF] Sergi | Taste loss in the elderly: Possible implications for dietary habits[END_REF]