Virtual Reality as a Promising Tool Supporting Oncological Treatment in Breast Cancer

Breast cancer (BC) treatment is associated with many physical and psychological symptoms. Psychological distress or physical dysfunction are one of the most common side effects of oncological treatment. Functional dysfunction and pain-related evasion of movement may increase disability in BC. Virtual reality (VR) can offer BC women a safe environment within which to carry out various rehabilitation interventions to patient support during medical procedures. The aim of this systematic review was to conduct an overview of the clinical studies that used VR therapy in BC. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines method: the initial search identified a total of 144 records, and 11 articles met the review criteria and were selected for the analysis. The results showed that VR seems to be a promising tool supporting oncological treatment in BC patients. VR can have a positive effect on mental and physical functions, such as relieving anxiety during oncotherapy, diminution pain syndrome, and increasing the range of motion and performance in daily activities.


Introduction
Breast cancer (BC) is the most commonly occurring cancer in women over the world [1,2]. It severely affects both physical and mental health. Psychological stress is the most common consequence of BC diagnosis [3] and treatment, and a frequent symptom of anxiety and depression [4]. Oncological treatment of BC involves choosing the right intervention based on a number of prognostic and predictive factors. The most important ones are the stage of clinical advancement, the presence of metastases, the histological type, the biological subtype, or the results of molecular tests. Standard cancer treatments include surgical treatment, chemotherapy, and radiation. These may lead to further life quality deterioration due to side effects they produce [4]. Additionally, pain may be accompanied by both physical fitness and mental health deterioration, regardless of disease stage [5].
Effective supportive therapies have the potential to reduce the negative effects of treatment and the cancer recurrence risk and mortality rate [6]. However, significant side effects and life quality deterioration are affected in these oncological treatments [7]. Currently, BC surgery may involve physical and pain symptoms of the posture and upper extremities [8,9]. Functional dysfunction and pain-related evasion of movement may increase the disability level in BC. Additionally, axillary radiotherapy is associated with increased risk of posture and upper limb impairment such as lymphedema, shoulder, and arm mobility dysfunction, and soft tissue thickening [8]. Other symptoms such as fatigue, pain, a decrease of muscle strength or range of motion (ROM), developed in the postoperative time result in daily living activity limitations [10]. Physical exercises, manual mobilisation and stretching involving a combination of physiotherapy technics are effective in postsurgical pain management and restoring limb functionality [11][12][13]. Next, the lymphedema of the upper limb is one of the most frequent morbidity causes Int. J. Environ. Res. Public Health 2021, 18, 8768 2 of 17 after mastectomies with axillary lymph node dissection and radiation [8,11,14]. This condition involves abnormal accumulation of fluids and proteins in the intercellular space, chronic inflammation, and oedema [14] which consequently causes upper limb functional impairment. Additionally, limitations in ROM following breast cancer treatment may be due to scar tissue formation at the incisional site, post-radiation fibrosis, protective forward shoulder posturing, post-mastectomy pain syndrome, and/or restriction of use upper extremity [8,14]. Limited shoulder ROM may restrict activities of daily living, e.g., tilting the head back while washing or combing hair, or arm movements involving shoulder elevation during, e.g., reaching for the item high on the shelf [15]. Traditional physiotherapy, the use of kinesiotherapy, and massage-using modalities concentrate on improving upper limb mobility, while task-oriented programs focus on BC patients' adaptability to daily life situations. They aim at shortening adaptation processes and gaining problem-solving processes of daily tasks by taming the dread of movement.
Task-oriented programs seem to be superior to exercises involving repetitive multiple movement patterns. Task-oriented training programs also improve patients' quality of life and functionality [16]. There is a rapid increase in the use of new technology in rehabilitation as tools that motivate patients to participate in usual care and standard programs. Virtual reality (VR) therapy seems to be as effective as conventional therapy in improving upper extremity function and basic activities of daily living [17]. These interventions are effective as patients focus on pleasant or interesting stimuli instead of focusing on unpleasant symptoms which are connected with the emotional sphere [18]. Supportive techniques using humour, relaxation, music, imagery, and VR are classified as distraction interventions, where symptoms such as pain, anxiety, nausea, fatigue, and stress may be relieved [19]. Distraction can also alleviate psychological symptoms [20].

Virtual Reality
Recent years have seen a real change in the world due to advances in rehabilitation technology. A great variety of user-friendly pieces of equipment with multiple settings or/and functions has been developed. The use of modern technology in the health field is a source of new knowledge and offers significant advantages.
In 1989, Jaron Lanier first used the term virtual reality (VR). Then, the definitions of VR referred to a specific technological system, which typically includes a computer capable of real-time animation controlled by wired gloves or other controllers and a position tracker, as well as a head-mounted display for visual yield [21]. Many different definitions of VR are available in the literature. One of a recent [22], defines VR as 'an artificial environment that is experienced through sensory stimuli such as images and sounds provided by a computer and in which our actions partially determine what happens in the environment'.
VR systems are divided into two categories: immersive and non-immersive [23]. Immersive VR is defined by filled immersion, which can affect users' attention. A wholeimmersive experience is achieved through a head-mounted exhibition that obscures users' view of the real world and presents patients with a computer-generated view instead. The head-mounted display and headphones exclude access to light and sound from the outside. Thus, patients can be personally isolated from the hospital-medical milieu. This is what helps patients to focus on enjoyable stimuli and reduce unfavourable emotions [24]. Jennett et al. [25] defined immersion as a 'lack of awareness of time, a loss of it'. A key driver of distraction in VR is its capability to simultaneously involve various senses, delivering synthetic stimuli such as visual images, spatial sound, or tactile and olfactory feedback [19].
The non-immersive VR is characterised by a computer screen, where the user is joined to the virtual world but can still communicate with the external environment. This technology offers patients a safe environment, where it is possible to carry out a variety of interventions including lifestyle changes [26], rehabilitation at home, or providing support to hospitalised patients undergoing various medical treatments. VR is emerging as a promising device to support cancer patients and monitor neurophysiological changes and medical feedback during interventions [23]. The aim of this systematic review was to conduct an overview of the clinical studies where researchers used VR intervention in BC patients as a tool in cancer rehabilitation of this patients' group.

Materials and Methods
The guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [27] were used to conduct the review. Ethics Committee approval for this type of retrospective study was not required. This review was registered in Research Registry (reviewregistry1152).

Search Strategy
The identified keywords and Medical Subject Headings (MeSH) were combined using the following combinations of terms with the Boolean operator 'AND': 'virtual reality', 'VR' AND 'breast cancer' was used to find relevant publications. This systematic review was conducted by querying PubMed, Web of Science, PEDro, and Cochrane Library databases were searched from the establishment of the database to 1 March 2021.
A search for additional articles was also carried out by browsing through the reference lists. The authors (EZ and AP) conducted an independent search.

Primary Outcome
The primary outcome was the analysis of using VR systems on the physical functions of BC patients.

Secondary Outcome Measure
The secondary outcome measure was the analysis of VR treatment on the mental sphere and the pain level in BC patients.

Data Collection and Analysis
An independent review and analysis of the articles were undertaken by the authors (E.Z. and A.P.), who removed duplicates and then checked for compliance with the inclusion and exclusion criteria. The following data were extracted from the articles: first author, year of publication, study population characteristics, study design, inclusion/exclusion criteria, intervention characteristics, assessment of the outcome, and results.

Inclusion and Exclusion Criteria for the Articles
The inclusion criteria for the reports were as follows: published in English in a journal with a review process; original research study with a control group or/and presentation of results of comparative pre-and post-therapy involving VR in BC; clearly defined inclusion and exclusion criteria for the study groups.
The following articles were excluded: studies on populations including other patients than BC; animal studies; studies examining the effect of robotic intervention; studies lacking the approval of local ethics committee or with incomplete outcome data; studies of undetermined type, and pilot studies or conference proceedings.

Quality Assessment
The quality of the included studies was assessed using the Quality Assessment Tool for Quantitative Studies (QATQS) [28] by the authors (E.Z. and A.P.). Possible conflicts were discussed and resolved by the other author (K.H.). The following sections were assessed: selection bias; study design; confounders; blinding; data collection methods, withdrawals and dropouts; intervention integrity; and analysis, classifying them as 'weak', 'moderate' or 'strong', according to a reviewer's key. The rating of one section as 'weak' results in the evaluation of the entire study as 'moderate'. If more than one rating is 'weak', the survey will automatically determine 'weak'. Lack of the 'weak' rating in individual sections allows the evaluation of the entire study as 'strong'.

Evaluation of the Study
In total, 137 records were identified from searches in all databases, and 9 additional records were identified after the reference list search; a total of 11 entries [29][30][31][32][33][34][35][36][37][38][39] were included in the study. The PRISMA flowchart of the search process is presented in Figure 1.
assessed: selection bias; study design; confounders; blinding; data collection methods, withdrawals and dropouts; intervention integrity; and analysis, classifying them as 'weak', 'moderate' or 'strong', according to a reviewer's key. The rating of one section as 'weak' results in the evaluation of the entire study as 'moderate'. If more than one rating is 'weak', the survey will automatically determine 'weak'. Lack of the 'weak' rating in individual sections allows the evaluation of the entire study as 'strong'.

Evaluation of the Study
In total, 137 records were identified from searches in all databases, and 9 additional records were identified after the reference list search; a total of 11 entries [29][30][31][32][33][34][35][36][37][38][39] were included in the study. The PRISMA flowchart of the search process is presented in Figure  1.

Methodological Quality
The methodological quality of all included studies was presented in Table 1. Seven studies were considered as 'strong' [29][30][31][33][34][35]39], and four were considered 'weak' [32,[36][37][38]. The highest-rated section was data collection, and the worst sections were blinding and selection bias. studies on populations including other patients than breast cancer (n = 3) studies that do not evaluate the effect of VR-based treatment in women with breast cancer (n = 11)

Characteristics of study participants.
The total number of participants in the analysed studies was 619. In four studies [29][30][31]34], participants were assigned to a control group (CG) and an intervention group (IG). Three studies did not include CG [32,33,35], and the remaining four [36][37][38][39] used a crossstudy type design where the same patients constituted CG and IG. All women were diagnosed with BC. Participants' characteristics of the included studies are presented in Table  2. Table 2. Characteristics of the participants of the included studies.

Characteristics of Study Participants
The total number of participants in the analysed studies was 619. In four studies [29][30][31]34], participants were assigned to a control group (CG) and an intervention group (IG). Three studies did not include CG [32,33,35], and the remaining four [36][37][38][39] used a cross-study type design where the same patients constituted CG and IG. All women were diagnosed with BC. Participants' characteristics of the included studies are presented in Table 2.   Three of the studies also included patients with BC and other types of cancers such as gynaecological cancer [33], colon, or lung cancer [38,39]. In four studies [29,31,32,35], VR-based therapy was used as an adjunctive treatment after surgical removal of breast tumours, and in six [30,33,[36][37][38][39] during chemotherapy.
Atef et al. [29] compared VR therapy (using video games of tennis, triceps extension, and rhythmic boxing) and the PNF method in the treatment of lymphedema and improving upper limb functionality. Their results indicate a statistically significant improvement in both study variables after the VR intervention. Feyzioglu et al. [31] also used sports games (darts, bowling, boxing, beach volleyball, table tennis) for therapy to compare their effectiveness with standard physiotherapy. The authors examined shoulder range of motion, arm and handgrip strength, upper extremity functionality, fear of movement, and pain intensity. House et al. [32] conducted motor training in VR, but also emotive and cognitive training. They used the BrightArm Duo Rehabilitation System consisting of a robotic rehabilitation table, computerised forearm supports, a display, a laptop computer for the therapist, a remote clinical server, and a library of custom integrative rehabilitation games. Plejko et al. [35] used VR for exercises in patients after mastectomy, assessing their influence on static and dynamic postural control. Non-immersive VR was used in the interventions aiming at improving motor functions in patients.
The remaining articles analysed used immersive VR. In five studies [30,[36][37][38][39], VR technology was used in patients during chemotherapy by intravenous infusions. Chirico et al. [30] compared the effects of VR and music therapy on the anxiety level and mood states. Patients had a controller to interact with the virtual environment, which consisted of relaxing landscapes. For example, they were exploring walking through a forest, an island, observing different animals, swimming in the sea, and climbing a mountain. Schneider et al. [36][37][38][39], on the other hand, in their four studies offered patients VR sessions consisting of diving in the deep sea, walking over an art museum, or solving a mystery, while testing for levels of anxiety, stress, and fatigue associated with chemotherapy.
McGarvey et al. [33] investigated whether VR technology could reduce the level of stress associated with hair loss in women after chemotherapy. Through the use of VR, patients were able to see themselves with a bald head, various wigs, and hair styles.
In three publications [31,32,34], the authors assessed the influence of VR therapy on patients' pain levels using the VAS [31,34] or NRS [32] scale. In each case, VR therapy was effective in relieving pain. Bani Mohammad et al. [34] showed that the combination of VR therapy with morphine administration provides a better analgesic effect than pharmacotherapy alone.
The results of all the studies analysed showed the effectiveness of VR-based therapy in reducing lymphoedema, improving dynamic balance and upper extremity functionality, reducing the level of stress, anxiety, and fatigue associated with chemotherapy, reducing stress levels related to hair loss after chemotherapy, and alleviating pain. Table 3 presents the type of interventions, characteristics of measures, and results of the included studies. -Lymphedema: circumferential method: The excess arm volume (EAV) = VL − VH, where VL refers to the lymphoedematous limb's volume, and VH refers to the healthy extremity's volume.
-Function: QuickDASH-9 scale -In the VR group was a greater improvement in lymphedema and upper limb function than in the PNF group.
-No statistically significant differences were found between EAVs and QuickDASH-9 scores between these groups. The results before and after therapy with the use of VR improved EAVs (p = 0.001) and QuickDASH-9 scores (p = 0.001) Chirico 2019 [30] Effectiveness and comparison of the effects of therapy with the use of VR and MT in alleviating the psychological stress associated with CHT in BC patients Immersive and interactive VR. The VR equipment: head-mounted glasses (Vuzix Wrap 1200 VR) with a head motion tracking system. Relaxing images virtual surroundings created on the Second Life ® platform (Linden Lab), e.g., being on an island, walking through a forest, observing animals, climbing a mountain, and swimming in the sea. VR therapy turned out to be more effective than MT. The anxiety decreased significantly in the CG group and was statistically insignificant in IG. Cybersickness symptoms occurred at a frequency of less than 20% (except for difficulty concentrating).   -One session of the immersive VR plus morphine made a significant reduction in pain and anxiety self-reported scores, compared with morphine alone, in BC patients.
-The independent-sample t-test showed a significant difference post intervention between the two groups' pain scores.
-The paired t-test showed a significant difference in the means of pain scores at the pre-and post-test in IG and the CG.
-Regarding the anxiety testing, the independent sample t-test showed a significant difference post intervention between the two groups. The IG mean was lower than in the CG (p < 0.001).
Piejko 2020 [35] Impact of medical resort treatment extended with modern feedback exercises using VR to improve postural control in BC survivors.
-Individual exercises were conducted using feedback based on VR and were aimed at improving motor coordination and body balance. Exercises on Alfa and Gamma stabilometric platforms and exercises of motor coordination of lower limbs with elastic resistance were used using the Telko device. Rehab software enabling feedback based on VR and collecting data on the type of tasks ordered to patients and the accuracy of their performance by patients.
3 weeks (6 d/wk, for 45 min./d) -Static postural control was assessed in a Romberg test -Dynamic postural control was evaluated in the dynamic test, during which the patient's task was to move the centre of gravity of the body in different directions in a targeted and controlled manner in accordance with the task displayed on the monitor screen.
-In the assessment of dynamic postural control, the length of the centre of foot pressure (COP) movement path before the treatment and after treatment was statistically significant (p = 0.0083) shortened.
In the assessment of static postural control, no statistically significant differences were found between the length of the COP pathway before treatment compared to the condition before treatment (p > 0.05).

Schneider 2003 [36]
Answer the questions: -Is VR an effective distraction intervention for reducing CHT-related symptom distress levels in older women with BC? -Does VR have a lasting effect?
-The individual wears an 8-oz head-mounted device, which projects an image with the corresponding sounds. The sense of touch is involved through the use of a computer mouse that allows for the manipulation of the image.  Abbreviations: VR-virtual reality; IG-intervention group; CG-control group; MT-music therapy; CHT-chemotherapy, MT-music therapy; IV-intravenous; ADL-activities of daily living; VAS-visual analogue scale.

Discussion
This systematic review presented an overview of the clinical studies in which researchers used VR intervention in BC patients. Despite the interpretability of the findings, this review is limited by the inclusion of a small number of trials given the novelty of this approach, generally small sample sizes, and diverse design of trials (including data from single-arm studies). Seven studies included in the present systematic review had a good level of evidence (low risk of bias). Additionally, some of the revised studies did not include information about the characteristics of VR rehabilitation protocols, reducing the possibility of replication by next studies.
Over the past two decades, new technologies such as VR, in which users to be immersed into a three-dimensional world in the computer, have found various applications in health care [19], offering both immersive and non-immersive experiences.
Numerous research studies have shown that a sitting lifestyle is now one of the considerable health problems associated with many diseases, including hypertension, cardiac diseases, metabolic disorders, cancer, and mental illness. Although the WHO recommends engaging in physical activity, a very large number of patients lead a sedentary lifestyle despite knowing about the benefits of regular exercise on general health. One of the factors contributing to this occurrence is the motivation deficiency in people as a barrier for intending to start changes in health habits. New alternatives to exercise such as VR can help patients lead healthier lifestyles [40].
The semi-immersive system is also used in the rehabilitation of various patient groups. The studies by De Luca et al. [41,42] show a positive effect of the exercises using semiimmersive VR in patients after stroke and after brain injury. The main advantage of VR is creating a motivating environment, with interactive and multisensory stimulation [43,44]. Specifically, this system is made up of computerised software, several tagless sensors, a video camera, and a projector connected to a screen. This installation allows an individual to perform different exercises; the participant exercises in a virtual context to inspire many cognitive spheres through a screen interface that responds to the patient's movements with audio-visual feedback. In practice, the patient's movements are monitored by an imaging camera that reinforces the information to the PC program, allowing the screenplay to be changed. In addition, this enables a greater consciousness of movements and performance and allows for sensory involvement with effects on rehabilitation outcomes [45].
As previous research shows [23], immersive VR is particularly recommended as a distraction instrument in relieving pain, stress, and other side emotional effects during different medical procedures, including chemotherapy in cancer patients. Emotional instability may be one of the factors that may increase the length of stay at the hospital during the treatment procedure or increase the quantity of sedation required during a painful procedure. Moreover, a stressed patient does not cope with treatment very well and may have difficulties in cooperation with the health service, thus making it difficult to carry out the procedure [46]. The authors of this review [23] suggested that immersive VR supports promise as an effective abstraction intervention in the treatment of pain and anxiety amongst patients with BC. Exertions that may reduce treatment-related stress or anxiety should intensify a person's capability to muddle through the disease, not merely by eliminating a stressor but possibly also helping to create a feeling of being in control of the disease. Another factor that can cause various problems during cancer treatment is hospitalisation. It can be considered a stressful state itself because it results from a shift in health and may also entail stressful conditions, such as a lack of intimacy and feelings of uncertainly. Espinoza et al. [47] have demonstrated the effectiveness of VR as a therapeutic tool to deal with a variety of problems and patient needs. Successful disease management can lead to improved adherence to treatment systems due to improvement of patients' survival time and their daily quality of life [36].
In the presented research, non-immersive VR was shown as more applicable in the rehabilitation treatment of BC patients. A study conducted by Feyziogli et al. [31] shown VR exercises using the Xbox Kinect™ console as more efficient than standard physical therapy in treating upper limb dysfunction after BC surgical treatment. Xbox Kinect™ video games are able to provide fun, inexpensive, and motivating exercise programs. Those authors [31] suggested that Kinect-based VR rehabilitation programs should be added to standard physical therapy or recommended as a substitute for traditional physical exercises for BC patients especially with severe levels of anxiety or pain about movement following surgery [31,32,34]. A study by Atef et al. [29] indicated VR as a beneficial tool in reducing lymphedema after mastectomy, which may be used as an exercise-based technique in BC patients as it motivates and provides visual feedback to them.
Exercises using non-immersive VR, which may stimulate the brain and effectuate motor and cognitive responses at the same time, require activation of the cortical and subcortical circuits [48]. Thanks to technological progress, new games are created, especially interactive games, which have the ability to improve patients' balance [49], physical fitness, and speed processing, and executive functions [50]. Changes in motor functions [51] may be related to the reorganisation of the cerebral cortex [52]. This was shown by previous studies on stroke patients who were treated with this technology [52].
Cancer rehabilitation is a relevant part of cancer patient care, which is becoming more and more essential with the growing quantity of cancer survivors, and highly documented rates of disability [53]. For example, the COVID-19 pandemic has required a modification from personal contact during rehabilitation to virtual care using telephone visits or the application of new technologies including VR [54]. However, this alteration has largely been made without sufficient evidence of best medical practice. Rehabilitation using VR may improve access for geographically scattered patients [55]. VR has emerged as an effective new approach to rehab treatment in various health areas [36], in the promotion of emotional well-being in hospitalised patients [56], diagnostics [57], surgical training [58], as well as in mental health treatment.
The limitations found in the revised studies indicate that despite the increased use of VR technology in cancer rehabilitation, it is not possible to draw strong conclusions about VR-based rehabilitation for BC patients because of the overall lack of methodological quality and statistical power observed in the current literature. Future research should avoid methodological limitations and use and report adequate statistical results so as to identify the effects of VR training and assure robustness for proper quantitative data analysis.

Conclusions
The review showed that VR seems to be one of the promising tools supporting oncological treatment in BC patients. VR can have a positive effect on mental and physical functions, such as relieving anxiety during oncotherapy, reducing pain syndrome, lymphoedema, and improving the range of motion and performance in daily activities. Rehabilitation with the use of this equipment may be supporting in cancer rehabilitation and probably suggested for this BC group who have a problem reaching routine rehabilitation services (e.g., due to lack of transport). Additionally, it is advisable to undertake randomised, controlled trials in a large group of BC patients with the use of VR therapy during and after oncological treatment.