Ethical, legal, organizational and social issues related to the use of scalp cooling for the prevention of chemotherapy‐induced alopecia: A systematic review

Scalp cooling (SC) aims to prevent chemotherapy‐induced alopecia. The goal of this systematic review is to tackle ethical, legal, organizational and social issues related to SC.


| INTRODUCTION
Alopecia is one of the most common and visible adverse effects of chemotherapy, which affects approximately 65% of all patients undergoing chemotherapy. 1,2 Although chemotherapy-induced alopecia (CIA) is not lifethreatening and in most cases is reversible, it can have a significant impact on a patient's quality of life, especially in psychological and social terms. 3,4 While it has long been considered an acceptable side effect in the treatment of patients, the increasing number of cancer survivors and a better understanding of the associated psychological processes have led to a greater consideration of CIA as a relevant problem. 5 The negative psychosocial effects associated with CIA are strongly related to the diversity of sociocultural values and symbolic assignments attributed to hair. [6][7][8] As an essential element in personal identity, hair loss causes high levels of stress and anxiety, and makes it difficult to perform daily activities, especially those in social contexts. 9 The clear visibility of alopecia for patients and the people around them acts to identify the cancer and usually, when alopecia appears it becomes the moment of public recognition of the disease. 9,10 As a result, people with CIA may begin to perceive certain changes in the attitudes towards them of the people they relate to, ranging from sympathy to rejection. 11,12 Scalp cooling (SC) has been used since the late 1970s as a system to prevent CIA. 13 Reduction in scalp temperature induces vasoconstriction, which limits the arrival of chemotherapeutic agents to the scalp and also produces a reduction in metabolism in the cells present in hair follicles at the time of highest chemotherapeutic concentration in the blood plasma. This reduces their vulnerability to the antimitotic and antimetabolic effects of these drugs. 14 The scalp must attain a subcutaneous temperature (between 1 and 2 mm) below 22°C, 15 which is equivalent to an epicutaneous temperature of 19°C, 14 although greater preventive effects could be achieved with temperatures close to 15°C. 16 A correct adjustment of the SC system to the patient's head is essential to attain these temperatures consistently and homogeneously. 17,18 The SC activation should commence 5 and 30 min before the infusion of cytostatic drugs and continue until completion. 18 After completion of the infusion, the SC must remain for a more or less prolonged time depending on the pharmacokinetics of the chemotherapeutic agents used, with postinfusion cooling times varying from 15 min to 4 h. 18 In 2021, the Spanish Network of Agencies for Health Technology Assessment (HTA) and Services of the National Health System (RedETS) drew up an HTA report 19 commissioned by the Spanish Ministry of Health on the effectiveness, safety and cost-effectiveness of SC devices for the prevention of CIA. This Systematic Review (SR) was conducted as part of this HTA report. This report commissioned by the Ministry of Health of our country has the main objective of informing the political decision to include the technology in the common portfolio of health services of the National Health System, but it is also useful in decision-making for clinicians and patients. 20 Particularly, the ethical, legal, organizational and social issues are relevant when considering the equity in access, feasibility and acceptability of the technology, which are key elements to take into account for a successful implementation of the technology.

| Protocol and registration
The SR of the literature followed the methodologic guidelines drawn up by the Cochrane Collaboration 21 with reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The prespecified protocol for this review was registered in PROSPERO (registration number CRD42021268228). The PRISMA checklist is available in Supporting Information: File 1.

| Design and participation of stakeholders
In this SR, the representatives of patient associations such as the Spanish Association Against Cancer (AECC) and the Spanish Breast Cancer Federation (FECMA) participated in the review of the study protocol, as well as in the results, discussion and conclusions, having the opportunity to make their contributions. In addition, representatives of professional scientific societies related to the topic such as the Spanish Society of Medical Oncology (SEOM) were invited to participate. Although direct patient participation is not common in systematic reviews, we have integrated it into this study because we believe that the involvement of patients and other stakeholders in the research process is crucia. 22

| Selection criteria
Studies were eligible for inclusion if they fulfilled the criteria shown in Table 1.

| Study selection
Two reviewers independently screened and in duplicate the title and abstract of retrieved references to identify potentially eligible studies.
The full text of these references was then screened again in duplicate to confirm eligibility. Doubts and discrepancies between reviewers were resolved by discussion and, when no consensus was reached, a third reviewer was consulted.

| Data extraction and quality assessment
Data were extracted from studies included by one reviewer and checked by a second reviewer using a piloted form in Excel format devised by the authors that included the following items: general information (authors, publication year, country and funding), study design, population, measures used, main findings, study limitations and conflict of interest.
Two reviewers independently and in duplicate assessed possible methodologic limitations of the studies included. We planned to assess quantitative, qualitative and mixed methods studies using the Mixed Methods Assessment Tool (MMAT). 23 The quality of systematic reviews and narrative reviews were assessed with the aid of the AMSTAR-2 24 and SANRA tools, 25 respectively. Descriptive studies, qualitative studies and mixed methods studies were then assessed using MMAT. 23 This tool permits to appraise the methodological quality of five categories of studies: qualitative research, randomized controlled trials, non-randomized studies, quantitative descriptive studies and mixed methods studies. For each relevant study, we used the corresponding criteria to appraise the study's quality, conduct the appraisal process and determined an overall quality score for each study. In the case of SANRA, used for the assessment of narrative articles, although the authors of the tool do not establish cut-offs for different grades of quality, we considered a score of ≤5 as low, 6-8 as moderate and 9-12 as high quality.

| Data synthesis
A narrative synthesis of the main themes found was performed, taking into account criteria of relevance (applicability to the context specified in the review question), coherence (how clear and well supported are the data from the primary studies and from the synthesized outcomes provided by reviews) and adequacy (the degree of richness and amount of data supporting a review conclusion). 23  The studies included in the review were synthesized according to their relevance, coherence and adequacy, and different standard tools were used to assess the quality of the studies, depending on their design ( Table 2). All the quality assessments of the studies are available in Supporting Information: File 3. We found that the quality of four of the five descriptive studies [29][30][31][32] was considered low, and only the study by Bitto et al. 28  low. The aspects assessed for qualitative studies were the adequacy of the qualitative approach, the method of data collection if the findings are adequately derived from the data, the appropriate interpretation of results and the coherence. Two mixed-methods studies were also found, 40,41 but the quality was rated as low, the same as the observational study included. 44 The aspects assessed were the adequacy of the rationale, the integration of the different components of the study, whether the outputs were adequately interpreted, the divergences and inconsistencies between quantitative and qualitative results, and if the quality criteria of each method were followed. The SANRA tool 25 was used to evaluate the quality of narrative reviews, and thus the four narrative reviews included were of a moderate-high quality. [33][34][35][36] With this tool aspects such as justification, explicit aims, 3.1 | Ethical aspects focused on equal access, gender equity and doctor-patient communication supported by PtDAs The main concern expressed by healthcare professionals was the patients' access to SC, as for many there can be a lack of equal access. 39 On the one hand, this problem is mainly related to the limited availability of devices that affects accessibility and patient expectations. 39 On the other hand, in the healthcare context, although a large percentage of professionals (85%) believe that both women and men need support to discuss their concerns about CIA, 40 there seems to be a tendency for nurses to recommend SC more to women than to men. 40 Thus, the availability of SC and adequate information provided to the patient to make a decision are two essential attributes to contributing to equal access and gender equity. 33,35 Communication between professionals and patients about how to cope with alopecia and available therapies to reduce it, such as SC, encourages evidence-based informed and shared decision-making.
According to the nursing professionals' point of view, patients are not sufficiently informed about the associated risks of SC. Moreover, most nurses consider that patients are discouraged due to the required long duration of its use. 40 Communicating SC characteristics on correct hair preservation, restoration, care and maintenance precautions (expected outcomes and appropriate, patient-adjusted expectations) can reduce concerns and distress about CIA. 34 However, according to individual characteristics, it is necessary to know the most appropriate timing of treatment to enhance a positive experience with SC. 35,37 A study highlighted that the nursing staff is one optimal profile to inform about SC to chemotherapy-treated patients', as medical staff tend to offer SC to a lesser degree. 36 The findings of a qualitative study conducted with patients treated with SC to reduce CIA indicate that information about the efficacy of SC provided by oncology staff was verbal and within the framework of professional experience. 38 Patients reported that the information received on the SC process in terms of tolerability and hair care preservation, during treatment, was insufficient. However, patients with CIA who did not undergo SC reported that they did not receive Shaw et al. 39 To qualitatively explore healthcare professionals' perceptions, barriers and facilitators to the implementation of SC in Australian cancer centres Qualitative study using telephone interviews Health professionals working in oncology (21)  Dougherty, 37 Roe, 35 Peterson et al. 34 Patient experiences influence oncology healthcare professionals' attitudes towards SC technology.
Shaw et al. 39 Online decision-making tools, scientific information and practical advice on CIA and SC have been developed, as well as a value clarification exercise. https://www.scalpcooling.org/ (last access 11 August 2021).
Van Den Hurk et al. 41 Patient perspective and acceptability Patients who undergo SC may have a mismatch between their expectations and their experience, as well as feel greater distress if their hair begins to fall out despite SC therapy, compared to those who do not undergo SC, since that for the latter, alopecia is an expected result of chemotherapy.
Breed et al., 33 Shaw et al. 38 Factors favoring acceptability are faster hair growth, the attitude of the nursing staff towards the SC.
Shaw et al., 38 Shaw et al. 39 Barriers to acceptability are the fact that the SC technology does not guarantee that the hair will be kept, having to spend more time in the hospital, the potential risk of skin metastases to the scalp, thinking that it may be too cold, inability to of tolerating the cold cap for 5 h, prioritizing hair colouring to mask grey, finding using colour powder for touch-ups too time-consuming or finding that washing hair only once a week was intolerable.
Peerbooms et al., 31 Van Den Hurk et al., 41 Heery et al. 43 Professional perspective and acceptability Health professionals should discuss SC with both men and women in a way that enables men to discuss their concerns. They should not assume that men do not have concerns about hair loss, as they may also want to keep their hair during chemotherapy.
Randall and Ream, 40 Breed et al., 33 Roe 35 Nursing staff may be charged with informing their patients about the SC to provide them with sufficient knowledge about the risks and benefits, to make an informed decision.

Young and Arif 36
Although oncology professionals consider the implementation of SC technology in their chemotherapy unit acceptable, they do not consider it feasible for patients to remain in the ward 90 min after the chemotherapy session to end the SC therapy. Lemieux et al. 29 Approximately 50% of oncology professionals consider the implementation of SC technology in their chemotherapy unit to be acceptable. Lemieux et al. 29 Some facilitators for the acceptability of the professionals include considering it as a service for their patients, the fact that patients actively request it, the participation of personnel in the decisionmaking for implementation and the commitment between the medical and nursing staff. Attitudes towards the need for intervention on alopecia and towards SC influenced professionals to defend the technology within their centres and offer the treatment to their patients.
Peerbooms et al., 31 Shaw et al. 39 Some barriers are the lack of evidence on efficacy and safety, little evidence about the risk of metastases to the scalp skin, logistic difficulties and lack of organizational support.
Peerbooms et al., 31 Shaw et al., 39 Fischer-Cartlidge et al. 42 Professionals perceive that SC supposes an increased workload of the nursing staff. The development of protocols and records for the evaluation of results in daily practice in hospitals that use SC technology is recommended. Planning to manage changes to your workflow is an important precursor to implementation.
Breed et al., 33 Shaw et al. 39 Organizational aspects focused on accessibility and feasibility Equal access of patients to SC is a concern for the group of professionals since the number of patients exceeds the availability of machines, which can lead to unequal access to care in a universal health system.

Shaw et al. 39
The subsequent cooling time of the SC is added to the treatment time, so the chemotherapy session space is not available to another/patient. It is necessary to ensure that patients, regardless of whether or not they use SC technology, do not exceed waiting times for treatment.

| Patients' perspective and acceptability
The acceptability of SC among patients was high when applied in cases where this therapy has shown good results. In the pilot study by Dougherty, 37 50% of participants deemed that SC was worthwhile, and 50% also reported that they would use SC again. In another study, 82.22% of participants who obtained positive results with SC would recommend its use compared to 11.11% of those who obtained negative results. 28 A factor affecting the acceptability of SC is the need for information before, during and after SC treatment. 41

Studies that contribute to the findings
To address accessibility issues, it has been proposed: (a) to match the postcooling period with the administration of cytostatic agents that do not produce alopecia, when those are prescribed, (b) provide an additional room to which the patient can move with SC technology during the postcooling period and (c) assess using SC technology to enable two patients to be treated at once in open rooms.
Fischer-Cartlidge et al. 42 For successful implementation, the support of the organization is necessary. Organizational support includes both increased funding for nursing time and provision of additional space to accommodate increased treatment time, as well as SC therapy-free spaces to reduce expectations of access for patients whom cannot receive this. Regarding the implementation of SC systems, it is necessary to consider the need for an interprofessional team, working with facility teams, training, taking into account medical resources and legal considerations, integrating technology into documentation, records and orders and good planning. The oncology nursing team could conduct patient education and reinforce adherence, which may positively affect their outcomes with SC technology.

| Professional perspective and acceptability
The acceptability of SC for healthcare professionals seems to be moderate. Although for most (85%) oncology healthcare professionals, SC is known to prevent CIA; only 50% consider its implementation in the chemotherapy unit acceptable. 29 On the one hand, the main facilitators for professionals' acceptability of SC are: seeing SC as a patient service 31 ; responding to patient requests for access 39 ; patient satisfaction with the experience 39 and professionals' personal attitudes towards the need for alopecia intervention and personal attitudes towards SC. 39 On the other hand, limited evidence on the efficacy and safety of SC mainly on the risk of scalp skin metastases, are the most important reasons for medical staff not supporting its use. 31,39,42 In addition, logistic difficulties in the hospital are the main reasons precluding nursing staff from supporting SC. 31 The nonavailability of SC in facilities on a routine basis, as well as the additional time and professional effort required by nursing staff, and limited access to SC were identified as the main barriers by healthcare professionals (not only nurses). 39 The lack of knowledge about which patient profiles benefit most from SC, 39 as well as difficulty identifying billing costs and processes without a similar intervention 42 have also been pointed out as barriers. Regarding the lack of knowledge, Peerbooms et al. 31 reported that 60% of nursing staff sought information about SC in scientific resources and exchanged knowledge with other professionals; 16% claimed the need for frequent SC training. 31 Finally, Lemieux et al. 29 reported that 88% of oncology healthcare staff believed that clinical trials on SC were necessary, and consequently, 85% would recommend their patients start a clinical trial on SC.

| Organizational aspects focused on accessibility and feasibility
Feasibility seems to be one of the main problems from healthcare professionals' perspectives. Thus, 72% of healthcare professionals do not consider it feasible to extend patients' stay in the treatment room to receive SC after the chemotherapy session has finished. 29 In terms of workload, limitations in trained nursing staff were considered an impediment to the routine use of SC. 39  First, the review has pointed out the necessity to avoid the possibility of gender inequity when implementing the SC system. Thus, to avoid gender inequity, SC therapy should be offered equally to men and women, which avoids the assumption that men care less than women about maintaining their hair. In this regard, having clear protocols on which population to offer this therapy to and how to offer it can help minimize the influence of professionals' attitudes towards both CIA and SC. 31 From an organizational point of view, patient access to SC should be ensured in circumstances where the demand exceeds the availability of devices to minimize access inequalities. 39 For this reason, the number of devices that each centre will require, the increase in nursing staff required, as well as the adequacy of additional space, must be carefully analysed and managed. 42 The possibility of using machines that enable two patients to be treated at the same time in open rooms, as well as optimizing the use of SC machines is another factor that may help reduce the nursing workload. 42 Regarding the implementation of SC, the literature points out some aspects worth highlighting. A crucial element for the successful implementation of this technology is planning ahead to manage changes in the workflow of the healthcare system. Healthcare managers should design an implementation plan with the help of the centre's interprofessional team, which could increase the acceptability of SC technology by professionals once it is implemented. 39 Good planning should also include the recording systems to be introduced, which will enable the technology's impact to be assessed. 33 Increased workload of the nursing staff can be reduced by strategies such as involving patients in the hair loss registry, preferably online. 33 Moreover, Nangia 45  And finally, it also might be interesting for the industry to better understand the main concerns that healthcare professionals find regarding the feasibility of the technology.

| Strengths and limitations of the review
This study has some strengths and offers valuable information for patients, healthcare professionals, managers and policymakers.
Despite the recent publication of an SR on the efficacy and safety of SC, 13

| CONCLUSIONS
This SR provides important learning points relevant to patient care, decision making and organizational policy. When ethical, legal, organizational and social issues related to the use of SC for the prevention of CIA were examined, the importance of equal access, which includes the need to offer SC to everybody, without assuming gender differences, to address concerns about hair loss and impaired perception of body selfimage was revealed. From a communication and educational perspective, the PtDa was found to be relevant to assist patients in clarifying their values and preferences, as well as the need for good communication with the healthcare staff team to adjust patients' prior expectations to reduce the potential distress associated with hair loss during SC use. This is important because the SR revealed that even when patients have