M.D Jebrane Bouaoud
email: jebrane.bouaoud@gmail.com

C Bertolus

P Zrounba

P Saintigny

Digitalized healthcare for Head and Neck cancer patients 1 2

Keywords: Head and Neck cancer, Digitalized healthcare, eHealth, Telemedicine, Telemonitoring, 47 Digital therapeutics. 48

The ongoing shortage in healthcare services and the increasing cancer incidence, highlight the need for 30 new strategies to ensure optimal treatments, cares and follow-up for all patients. Digitalized healthcare, 31 which includes various concepts (digital health, telemedicine, telemonitoring and digital therapeutics), 32 are a promising option to meet these needs.

33

In this scoping review, we provide an overview of the recent available research evidence on digitalized 34 healthcare for HNC patients and caregivers.

35

Through the interrogation of PubMed and Cochrane Library databases, a total of 32 relevant articles 36 reporting the use of digitalized healthcare in different settings of HNC patients care management, were 37 analyzed.

38

Overall, HNC patients as well as caregivers were highly satisfied, especially because digitalized 39 healthcare allows the early detection of health disorders, improve patient s management, quality of life, 40 self-confidence and communication. Furthermore, digitalized healthcare were significantly time-and 41 cost-effective. While the benefits digitalized healthcare has been reported to be feasible and clinically 42 relevant, our future efforts should focus on the demonstration of their clinical utility in well-designed 43 clinical trials. It is tempting to anticipate that this approach will improve patients management and 44 quality of life and change the way patients interact with family and professional health care givers.

Introduction

49

Head and neck cancers (HNC) are ranked as the eight most common cancer worldwide with a worldwide 50 incidence exceeding 890,000 new cases annually [START_REF] Ferlay | Estimating 242 the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods[END_REF] and increasing in some anatomical sites 51 (oro/hypopharyngeal and lip/oral cavity) [START_REF] Aupérin | Epidemiology of head and neck cancers: an update[END_REF]. HNC treatment requires multimodal approaches including 52 surgery, chemoradiation [3 5] and more recently immunotherapy in recurrent/metastatic disease [6 8].

53

This management involves multiple caregivers (physicians, nurses, psychologists, physiotherapist, 54 speech therapists ) who should be coordinated. Moreover, treatments are associated with significant 55 morbidity that impact patients both physically and psychologically and can be associated with long-term 56 sequelae that need appropriate management. Finally, the active participation of the patient in his care 57 as well as his motivation are essential elements of management.

58

Digitalized healthcare refers to a variety of concepts including digital health, telemedicine, 59 telemonitoring and digital therapeutics [START_REF] Aapro | Digital health for 269 optimal supportive care in oncology: benefits, limits, and future perspectives[END_REF]. Digital health, also called eHealth or telehealth, refers to 60 using the digital technologies or telecommunications to provide healthcare services for prevention, 61 diagnosis, management, and patients follow-up. Telemedicine describes the provision of medical 62 services using telecommunications platforms. Telemonitoring allows to monitor patients using digital 63 technologies. Digital therapeutics aims at improving patients management through algorithms 64 continuously enriched by symptoms collection (patients reported outcomes) and evidence-based 65 medical guidelines integration.

66

In order to meet with patients as well as healthcare professionals and caregivers needs, several authors 67 have evaluated the feasibility and the benefits of digitalized healthcare, especially in oncology [START_REF] Aapro | Digital health for 269 optimal supportive care in oncology: benefits, limits, and future perspectives[END_REF][START_REF] Van Den Bosch | Oral & 272 Maxillofacial surgery is ready for patient-centred eHealth interventions the outcomes of a scoping 273 review[END_REF].

68

The purpose of this review is to provide an overview of the recent available research evidence on 69 digitalized healthcare for HNC patients and their caregivers.

76

Editorials, perspectives, seminars, letters to the editor, abstracts, case reports and small case series (less 77 than five patients) were excluded as well as ongoing clinical trials for which results were non-available.

78

Preliminary screening followed by full-text examination was done by one author (J.B) to ensure 79 eligibility. All selected publications as well as the flow diagrams were studied and reported according 80 to the PRISMA statement [START_REF] Moher | Preferred Reporting Items 275 for Systematic Reviews and Meta-Analyses: The PRISMA Statement[END_REF]. for the clinical follow-up of 99 HNC patients [START_REF] Lyu | Smartphone Application 294 WeChat for Clinical Follow-up of Discharged Patients with Head and Neck Tumors: A Randomized 295 Controlled Trial[END_REF]. WeChat application was found to be a viable option 111 for follow-up in discharged patient. Indeed, compared to the classic telephone follow-up, the WeChat 112 follow-up was found to be significantly time-effective, cost-effective, and convenient in 113 communication. This study reveals the potential of using available social media tools establish a good 114 physician-patient relationship by enhancing dynamic communications and providing individual health 115 instructions. Sosa et al., reported same conclusions using a similar approach (mobile texting, n=23 HNC 116 patients) [START_REF] Sosa | Improving patient 297 health engagement with mobile texting: A pilot study in the head and neck postoperative setting[END_REF]. Nevertheless, these options raise many privacy issues.

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To finish, care organization (appointment scheduling/reminders) and communication of some treatment 119 planning information using Telemedicine could be beneficial to both HNC patients and care givers [START_REF] Holderried | The potential 300 of eHealth in otorhinolaryngology head and neck surgery: patients perspectives[END_REF].

202

The ongoing shortage in oncology services linked to the increasing cancer incidence and treatments 203 options has highlighted the need for new strategies to ensure the provision of optimal treatments, cares 204 and follow-up for all patients [START_REF]The State of Cancer Care in America, 2016: A Report 369 by the American Society of Clinical Oncology[END_REF]. Digitalized healthcare is a cultural transformation of traditional 205 healthcare, and has the potential to meet this challenge [START_REF] Mesk | Digital health is a cultural 372 transformation of traditional healthcare[END_REF]. Indeed, a good illustration of this is the 206 ongoing COVID-19 crisis which has led to an unexpected increasing demand, forcing HNC specialists caregivers, to improve education of HNC patients and to help them in self-management [START_REF] Aapro | Digital health for 269 optimal supportive care in oncology: benefits, limits, and future perspectives[END_REF][START_REF] Buzzacchino | A mobile application supporting 391 outpatient treatment and follow-up[END_REF]. Early 225 evidence suggests that digitalized healthcare technologies are effective/cost-effective. However, 226 additional efforts are needed to improve implementation in daily practice [START_REF] Elbert | 393 Effectiveness and Cost-Effectiveness of eHealth Interventions in Somatic Diseases: A Systematic 394 Review of Systematic Reviews and Meta-Analyses[END_REF][START_REF] Ossebaard | eHealth and quality in health care: implementation 397 time[END_REF].

227

Implementation in real life is one of the identified limits of digitalized healthcare [START_REF] Ossebaard | eHealth and quality in health care: implementation 397 time[END_REF]. Several factors 228 may participate to this limit. Lower education level and non-working status may be barriers to accessing 229 interventions [START_REF] Aapro | Digital health for 269 optimal supportive care in oncology: benefits, limits, and future perspectives[END_REF]. Moreover, while patients studied in RCTs are carefully selected, many HNC in real-230 life may prefer more traditional sources of information compare to information technologies [START_REF] Lea | Survey of computer use for health topics by patients with head[END_REF].

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Furthermore, HNC survivors seem less likely to be eligible to digital healthcare interventions than 232 colorectal, breast and lymphoma cancer survivors [START_REF] Van Der Hout | Role of eHealth application Oncokompas in supporting self-management 323 of symptoms and health-related quality of life in cancer survivors: a randomised, controlled trial[END_REF]. To finish, patient confidentiality and compliance 233 with data privacy regulations could be a barrier to the implementation of these technologies. The Health Buddy® System (Robert Bosch Healthcare, Inc) Cost: using an existing program on the system for 1 month $45.00, more if the provider develops its own algorithm to be programmed Feasible, Well accepted, reassuring 98% no problems setting up 85% easy to use 84% better medical condition understanding 96% better medical condition managing 92% recommend the device to others

Head et al., 2011 [21]

RCTs To assess feasibility and acceptance among patients undergoing treatment for HNC N=44 patients newly diagnosed with HNC (mean age 59y)

Pfeifer et al., 2015 [22]

To evaluate the impact of the telehealth intervention on QoL and symptom burden N=80 patients (45 treatment, 35 control: standard of care) who had been diagnosed with HNC and were receiving 1 rea men modali ie . The d was conducted in the post treatment phase.

Improved some aspects of post treatment QoL and symptom burden.

Peltola et al., 2015 [23]

Pilot study To assess the suitability of Kaiku®, for collecting PROs on early adverse effects of RT and on health related QoL and also to gain insight into how the patient experienced the system N=5 patients, treated for a HNC, used Kaiku® during and one month after RT Kaiku® is an internet-based electronic application which enables real-time, online collection of PROs (https://kaikuhealth.com/)

Seems to improve follow-up and communication between the patient and the care team

Duman-Lubberding et al., 2015 [24]

Feasibility study

To in e iga e heal h care profe ional perspectives toward follow-up care and Clinician assessments indicated a high degree of satisfaction with the ease of using the CYCORE system and the resulting ability to monitor their patients remotely.

domains using a suite of home-based and mobile sensors.

Sterba et al., 2017 [30]

Pilot This study provides elements to improve the ease of use and usefulness of HN-STAR

Manne et al., 2020 [39]

Pilot study

To assess the development, feasibility, and pilot testing of a web-based selfmanagemen ool called Empo ered S r i or N= 66 patients diagnosed with a first primary oral or oropharyngeal cancer between 1 and 3 years ago; currently cancer-free (but could experience a recurrence)

Empo ered S r i or : interactive web-based application (computer, mobile phone)

Significant beneficial impact on self-management selfefficacy, preparedness for survivorship care, and QoL.

Improved engagement in oral self-exams and head and neck strengthening exercises, Improved ability to address barriers, and decreased information and support needs

  literature related to digitalized healthcare for HNSCC patients, MEDLINE Public Library 72 of Medicine (PubMed) and Cochrane Library databases were searched for full text articles using the 73 following search string (head [Title/Abstract]) AND (digital health [Title/Abstract] OR telehealth 74 [Title/Abstract] OR eHealth [Title/Abstract]). Inclusion criteria were publications in English language, 75 published from December 1, 2002 to August 30, 2020 and reporting a minimum of five patients. All

  89 studies were primarily identified from PubMed and Cochrane Library databases. After 84 removing one duplicate, n=88 potentially relevant studies were screened (Figure1). Fifty-six studies 85 were excluded because they were out of the HNC scope (n=43) or because they did not report 86 available/robust results on digitalized healthcare interventions in the population of interest, i.e. HNC 87 patients, HNC patients families and caregivers (n=13). Finally, n=32 full-text relevant articles were 88 included in this review. Briefly, reported digitalized healthcare were studied in different settings of HNC 89 patients management, from care organization through post-treatment supportive care. evaluated the impact of consultation using telemedicine.Beswick et al., have 94 recently reported a telemedicine model integrating tissue diagnosis and imaging, data review for HNC95 patients during preoperative (n=15) and post-operative (n=24) teleconsultations [12]. This model 96 enabled timely access to surgical care and allowed considerable savings (about $900/patient) among 97 HNC patients. Similar results and an overall high level of satisfaction were observed by Hamilton et al., 98 who proposed TeleHealth for radiation oncology consultations to geographically distant HNC patients 99 (n=32) [13]. Stalfors et al., have evaluated the use of telemedicine at a multidisciplinary tumor meeting 100 among n=45 HNC patients [14]. Compare to the classic face-to-face multidisciplinary tumor meeting, 101 telemedicine seemed to bring to HNC patients better consideration feelings and higher satisfaction. 102 103 Telemonitoring has also been evaluated for HNC patients follow-up. Rimmer et al., reported 104 telemonitoring to be safe for the postoperative follow-up in a large population of patients (n=255) [15]. 105 Indeed, telemonitoring enabled early detection of the occurrence of health problems (pain, speech, 106 swallowing, tracheostomy canula ) requiring direct intervention by different stakeholders (n=36 HNC 107 patients, n=24 caregivers/patricians) [16]. 108 109 Interestingly, Lyu et al., recently investigated the feasibility and benefits of the WeChat application,

  110

Australia

  to improve patient s management through algorithms continuously enriched 124 by symptoms collection (patients reported outcomes[PROs]) and evidence-based medical reported the use of digital therapeutics in HNC patients cohorts (Table1). Among 128 the different digital solutions, The Health Buddy® System was among the most studied [20 22]. It is a 129 simple telehealth messaging device which requires any available land phone line. Symptom 130 management algorithms are programmed in this device, allowing also daily patients feedbacks. After a 131 pilot study demonstrating the feasibility, use, and acceptance of this digital therapeutic solution in 42 132 patients newly diagnosed with HNC [20], Head et al. performed a randomized clinical trial (RCTs) 133 comparing the telehealth intervention to the standard of care to assess feasibility and acceptance of this 134 approach during treatment [21]. They showed that the Health Buddy® System was feasible, well 135 accepted, and regularly used by HNC patients even when they experienced extreme symptoms burden 136 and declining quality of life (QoL) during treatment. Moreover, Pfeifer et al., have demonstrated in 137 another RCT including 80 patients with HNC previously treated (post-treatment trial) that the Health 138 Buddy® System improved some aspects of posttreatment QoL and symptom burden measured using the 139 Functional Assessment of Cancer Therapy-Head & Neck Scale [FACT-HN] and the Memorial 140 Symptom Assessment Scale [MSAS] respectively [22]. 141 Kaiku® (https://kaikuhealth.com/) is an internet-based electronic application which enables real-time, 142 online collection of PROs such as treatment side effects and also QoL. In their pilot study (n=5 HNC 143 patients using Kaiku® during and one month after radiotherapy), Peltola et al., 2015 reported that this 144 digital solution improved follow-up and communication between HNC patients and the caregivers [23]. 145 OncoKompas® (https://www.oncokompas.nl/) is a web-based application that supports survivors in 146 self-management by monitoring QoL and symptoms (Measure) and obtaining tailored feedback (Learn) 147 with a personalized overview of supportive care options (Act). While feasible and allowing satisfaction 148 (n=56 HNC survivors and n=13 health care professionals), the structure of OncoKompas® seems 149 complex and needs further improvements [24,25]. In a non-blinded RCT including 185 HNC survivors 150 (3 months to 5 years after treatment with curative intent, all treatment modalities), van der Hout et al., 151 evaluated the reach, usage as intended, and efficacy of OncoKompas® to improve knowledge, skills, 152 and confidence for self-management among cancer survivors [26]. They found that OncoKompas® did 153 not improve the amount of knowledge, skills, and confidence for self-management in HNC survivors. 154 Nevertheless, the course of mouth pain, social eating, swallowing, coughing disorders and trismus were 155 significantly reduced over time (secondary outcomes). Of note, a RCT is ongoing (NTR 7636) to 156 evaluate an OncoKompas® dedicated version to support patients with incurable cancer and their 157 partners in finding and obtaining optimal supportive cares [27]. 158 In a pilot study, Badr et al., showed that the web-based intervention system CARES , meaning 159 Computer-Assisted oral cancer REhabilitation and Support, was interesting and usable for both HNC 160 survivors and their family caregivers to improve QoL [28]. 161 Interestingly, using the software CYCORE (CYberinfrastructure for COmparative effectiveness 162 REsearch) which allows collection and analyses of data from multiple domains using a suite of home-163 based and mobile sensors, Peterson et al., have shown the feasibility of using digital therapeutics for 164 early identification of dehydration risk in 48 HNC patients during radiation therapy [29]. 165 Sterba et al., have developed and tested a survivorship needs assessment planning (SNAP) tool to 166 systematically assess needs in post-treatment HNC survivors (n=42) and their primary caregivers (n=39) 167 and generate tailored care plans [30,31]. Beside the high satisfaction, this web-based interface has 168 allowed to decrease depression and unmet needs while the survivorship knowledge increased. 169 170 Swallowing, speech and nutrition disorders are a field in which this type of digital therapeutics have 171 been widely evaluated. Recent reviews, highlight the existing evidence for this type of symptom 172 management and care optimization in order to improve HNC patients pre-habilitation as well as post 173 treatment QoL [32,33]. Firstly, Wall et al., have evaluated the accuracy of ScreenIT , a web-based 174 screening tool capturing PROs, to detect swallowing, nutrition and distress status in 100 HNC patients 175 receiving chemo/radiotherapy and facilitate appropriate referrals for multimodality treatment 176 management [34]. ScreenIT was effective and efficient for disorders monitoring and facilitated 177 clinically appropriate prioritization of supportive cares. Focusing on swallowing disorders, the same 178 team have developed and evaluated SwallowIT , a tool designed to support HNC patients to remotely 179 complete intensive swallowing therapy during curative chemoradiotherapy [35,36] (pilot study, and 180 RCT included n=15 and n=79 HNC patients, respectively). SwallowIT provided clinically equivalent 181 outcomes to traditional service models delivering prophylactic swallowing therapy. Overall, these 182 digital therapeutics allowing interventions into patients homes regarding swallowing, speech and 183 nutrition disorders, have shown to be satisfactory and to significantly reduce costs by decreasing the 184 number and duration of appointments as well as travelling costs, especially in big countries such 185 Neck Survivorship Tool: Assessment and Recommendations (HN-STAR, https://hn-188 star.org/) is an electronic platform allowing PROs collection and giving automatically access to a clinical 189 decision support tool to improve care coordination and to facilitate late-effects management among 190 HNC survivors. HN-STAR was evaluated in a pilot study (n=5 Human-computer interaction experts, 191 n=10 nurse practitioners, and n=10 HNC survivors more than 3 years from treatment) to provide 192 elements allowing the improvement of HN-STAR use and usefulness [38]. Of note, a RCT is ongoing 193 to assess the implementation and effectiveness of HN-STAR compared to the standard care in a cohort 194 of HNC patients who have completed chemotherapy and/or radiation therapy less than 6 months prior 195 to enrollment (NCT04208490). 196 Another digital therapeutics has been recently tested in HNC survivors. Indeed, the Empowered 197 Survivor interactive web-based application (computer, mobile phone) was evaluated in a pilot study 198 including 66 HNC patients diagnosed with a first primary oral or oropharyngeal cancer one to 3 years 199 ago and currently cancer-free [39]. Interestingly, s a positive impact on self-management and QoL has 200 been reported. 201 Discussion

  207 to better organize themselves to manage HNC patients, especially using digital health technologies [evaluation of complex interventions such as digitalized health care should follow some 211 fundamentals steps as defined by the UK s Medical Research Council (MRC) framework [45]. The 212 preclinical or theoretical Phase 0 should respond to the following question why should this 213 intervention work? . After the modelling of the intervention (Phase 1, how does it work? ), pilot trials 214 (Phase 2, optimizing trial measures) allow to explore the perceptions, potential interests and challenges 215 from all stakeholders perspectives. Definitive RCTs are required (Phase 3) before implementation in 216 the routine care (Phase 4). Gemert-Pijnen et al., have recently proposed a Holistic Framework, called 217 the ceHRes Roadmap to improve the development of eHealth technologies [46]. This framework is 218 based on several key concepts: i) digitalized healthcare technologies development is a participatory 219 process, ii) it involves continuous evaluation cycles (feedback), iii) are intertwined with implementation, 220 iv) is changing the organization of health care, v) should involve persuasive design techniques and vi) 221 needs innovative methods to assess its impact. 222 223 Digitalized healthcare technologies seem to improve communication between HNC patients and health 224

234 235Future

 234 Figure and Table legend

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Figure 1 .

 1 Figure 1. Study flow diagram according to the PRISMA statement for systematic review analysis.

  (a) face-to-face therapy (b) eleprac ice herap ia S allo IT (c) patient self-directed therapy Swallowing, nutritional, and functional status were compared at baseline, 6weeks, and 3-months post-(C)RT.SwallowIT provided clinically equivalent outcomes to traditional service models.The high levels of therapy support provided by SwallowIT was strongly appreciatedCollins et al., 2017 [37]Feasibility trial To determine the feasibility of a homebased telehealth model for speech pathology and nutrition and dietetics reviews, to provide patients with more convenient access to these appointments N=30 patients post HNC curative treatment (CRT): N=15 supported via the standard model of care, and N=15 via the home-based telehealth model of care Software-based telehealth service allo ing in er en ion in o pa ien homes (computer/smart phone/tablet device with camera and microphone) Reduced number and duration of appointments until discharge Significant patient cost savings Easy to use; good audio/visual quality; high satisfaction Salz et al., 2018 [38] Pilot study To refine HN-STAR b elici ing and incorporating feedback on its ease of use and usefulness, from different stakeholders N=5 Human-computer interaction experts, N=10 nurse practitioners, and N=10 HNC r i or ( 3 ear from treatment) Head and Neck Survivorship Tool: Assessment and Recommendations (HN-STAR): is an electronic platform that incorporates PROs into a clinical decision support tool for use at a survivorship visit. (https://hn-star.org/).

Table 1 .

 1 Description of digital therapeutics technologies which have been studied in Head and Neck 406 cancer cohorts. (HNC: head and neck cancer; RCT: randomized clinical trials; PROs: patient reported

	407
	outcomes; RT: radiotherapy; CRT: chemo/radiotherapy)

van der Hout et al., 2020 [26]

						N=11 Health care professionals involved	OncoKompas is a web-based	Complexity of the navigation structure
						in HNC care			eHealth application that supports
			OncoKompas in follow-up cancer care				survivors in self-management by
									monitoring health-related QoL and
	Duman-Lubberding et al.,		To investigate the feasibility of the online	N=56 HNC survivors (patients treated	cancer-generic and tumor-specific	Feasible but has to be further improved
	2016 [25]		self-management		application	with curative intent with a maximum of 2	symptoms (Measure) and obtaining
			OncoKompas among cancer survivors	years prior)			tailored feedback (Learn) with a	High adoption, usage, and satisfaction
									personalized overview of supportive
		non-blinded RCT	To evaluate the reach, usage as intended, and efficacy of Oncokompas to improve	N= 185 HNC survivors (3 months to 5 years after treatment with curative intent,	care options (Act). (https://www.oncokompas.nl/)	No improvement of knowledge, skills, and confidence for self-management
			knowledge, skills, and confidence for	all treatment modalities) including n=99
			self-management	among	cancer	intervention	group	(access	to	The course of the symptoms pain in the mouth, social
			survivors			Oncokompas) and n=86 control group	eating, swallowing, coughing, and trismus were
						(access to Oncokompas after 6 months).	significantly reduced
	Badr et al., 2016 [28]	Pilot study	To develop and evaluate a dyadic, web-	N=13 HNC survivors and N=12	Computer-Assisted oral cancer	HNC survivors and family caregivers were interested in
			based intervention to improve survivor	caregivers to discern information and	REhabilitation	and	Support	using this online program to improve QoL
			self-management and survivor/caregiver	support needs as well as preferences	(CARES): web-based intervention
			QoL			regarding website features and tools.
						N=6 HNC survivors and N=5 caregivers
						for the usability tests
	Peterson et al., 2013 [29]	Feasibility study	To evaluate the feasibility of using	N=48 HNC patients treated by	CYCORE (CYberinfrastructure for	> 90% easy to use, satisfaction and suitability
			CYCORE to address early at-home	radiotherapy			COmparative	effectiveness
			identification of dehydration risk in HNC				REsearch) is a software-based
			patients undergoing radiation therapy				prototype for a user-friendly
									cyberinfrastructure supporting the
									comprehensive	collection	and
									analyses of data from multiple

-Fondation Nuovo Soldati 2019 (J Bouaoud)

-ITMO Cancer