A systematic review to explore the effectiveness of physical health and psychosocial interventions on anxiety, depression and quality of life in people living with blood cancer

Abstract Problem identification Anxiety and depression are more prevalent in hematological cancer patients who experience unpredictable illness trajectories and aggressive treatments compared to solid tumor patients. Efficacy of psychosocial interventions targeted at blood cancer patients is relatively unknown. This systematic review examined trials of physical health and psychosocial interventions intending to improve levels of anxiety, depression, and/or quality of life in adults with hematological cancers. Literature search PubMed and CINAHL databases were used to perform a systematic review of literature using PRISMA guidelines. Data evaluation/synthesis Twenty-nine randomized controlled trials of 3232 participants were included. Thirteen studies were physical therapy, nine psychological, five complementary, one nutritional and one spiritual therapy interventions. Improvements were found in all therapy types except nutritional therapy. Conclusions Interventions that included personal contact with clinicians were more likely to be effective in improving mental health than those without. Implications for psychosocial oncology Various psychosocial interventions can be offered but interactive components appear crucial for generating long-standing improvements in quality of life, anxiety and depression.

the survival rates for many types of blood cancer have increased substantially over the past decade: leukemia and myeloma five-year survival rates are over 50%, Non-Hodgkin's lymphoma is 65.9% and Hodgkin's lymphoma is 82.3%. 39However, despite these increases in survival, the blood cancer patient pathway is frequently challenging, with treatment regimens for hematological malignancies often lengthy, aggressive, and an unpredictable illness trajectory compared to solid tumors, 2 with related widespread physical and psychological repercussions for patients. 53he psychological and social burden of a cancer diagnosis is considerable and can lead to patients experiencing higher levels of anxiety and depression than the general population. 31Occasionally, emotional and psychological distress following a cancer diagnosis can lead to outcomes such as suicide or cardiovascular fatalities 25 and the presence of depression and anxiety can adversely affect cancer treatment, recovery and survival outcomes. 56A number of studies have reported the prevalence of anxiety and depression of blood cancer patients as being higher than in patients with other forms of cancer. 1,18,28,35Depression and anxiety may be greater in blood cancer patients due to the uncertainty they face from living with a non-solid tumor. 53It may also be due to the significant impact on their quality of life.A systematic review of the impact of hematological malignancies on quality of life, identified deterioration in many areas of patients' lives including physical, psychological, social and even cognitive functioning. 5ematological cancer patients often undergo chemotherapy treatment, which requires patient to isolate.Not only are physical and mental wellbeing impacted by chemotherapy itself, but the experience of isolation also negatively impacts the quality of life, with patients often feeling lonely. 54Yet, a recent study identified considerable variation in the psychosocial support that patients receive and less than half of professionals agreed that their patients' psychosocial wellbeing were well supported. 13Moreover, 85% of doctors and 40% of nurses stated they had no received training in the assessment and management of psychological needs of blood cancer patients. 13ultiple meta-analyses and literature reviews have focused on the effectiveness of psychosocial interventions in reducing anxiety and depression and increasing quality of life in cancer patients.Barsevick et al. 9 systematically reviewed 36 studies and concluded that psychoeducational interventions, including behavioral therapy, reduced depression in cancer patients.Similarly, a meta-analysis of 37 published controlled outcome studies conducted by Rehse and Pukrop 43 found that psychosocial interventions of at least 12 wk in length improved the quality of life of cancer patients.However, these studies included in these reviews either solely focused on patients with solid tumors or the majority of the study sample population were patients with solid tumors.Bryant et al. 15 conducted a review on the psychosocial outcomes of individuals with hematological cancers, aiming to understand the proportion of measurement, descriptive and intervention study designs conducted in this area, as well as their efficacy in improving anxiety and depression.Few studies found improvements in psychosocial outcomes in blood cancer patients, with only five of the included studies being classed as randomized controlled trials (RCTs) and the methodological quality of these studies was described as variable. 15hus, despite widespread evidence of the positive benefits of psychosocial interventions in enhancing mental health and health-related quality of life in cancer patients with solid tumors, there remains a paucity of evidence relating to the effectiveness of these psychosocial interventions targeted specifically at blood cancer patients.From the differences in prognosis and treatment for hematological malignancies compared to solid tumors, it is logical to expect that the psychosocial impact will also vary, and therefore it is important to ascertain which interventions improve the well-being of blood cancer patients.
This systematic review aims to build upon previous reviews on this topic, with an updated literature search for RCTs.It also has a broader scope as the definition of psychological outcomes has been extended to include measures of health-related quality of life.Thus, the aim of this paper is to report on a systematic review of RCTs of physical health and psychosocial interventions that aimed to improve levels of anxiety, depression, and health-related quality of life in adults with blood cancer.

Methods
The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. 37The protocol for this systematic review was registered on PROSPERO, the international prospective register of systematic reviews (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209492) in November 2020.

Procedure
The search strategy was limited to human studies published in peer reviewed journals between the years 2000 -2021 that were written in the English Language.Systematic searches of PubMed and CINAHL were undertaken between June 2020 and December 2021.The keywords and index terms in Table 1 were used to search for relevant studies.The reference lists of all studies included in the review were also checked for relevant studies, as well as any related systematic reviews and literature reviews in this area.Grey literature was included in the search strategy but did not yield any results.

Eligibility
To be eligible for inclusion in the review, specific criteria were outlined.Studies needed to have utilized an RCT design.To be eligible for inclusion in the review, specific criteria were outlined.Studies needed to have utilized an RCT design.This review chose to only include RCT studies because this study design is the gold standard for testing the efficacy of interventions, as it reduces the bias inherently present in other study designs.This was a key consideration when designing this systematic review, as a previous review by Bryant et al. 15 included a variety of study designs and thus the papers included varied in quality and limited the conclusions that could be drawn.Study primary and/or secondary outcome measures included anxiety, depression or health related quality of life (HRQoL).Participants were aged 18 years or over and studies were only included if the majority of the study population sampled (>66%) had a diagnosis of blood cancer.Additionally, all included RCTs tested the effectiveness of a psychosocial intervention for blood cancer patients implemented in any setting.In accordance with previous reviews 15,50 a psychosocial intervention was considered an intervention that was designed to lead to psychological change or behavioral change.Studies that combined any psychosocial intervention with pharmacological or physical treatments were included.There were no restrictions on blood cancer stage or type of treatment undertaken.

Study selection
Once the database searches were completed, duplicates were removed.Titles and abstracts of identified citations were screened for eligibility according to the predefined Patient, Intervention, Comparison, Context, Outcome (PICCO) criteria listed below (Table 2).The remaining full text papers were collated and screened for inclusion.Three reviewers undertook the screening process to ensure that a rigorous and comprehensive process was adhered to.Any discrepancies relating to whether a paper should be included in the review were discussed by the reviewers (VA, AF, MA, PD, FW).If no agreement could be achieved, then this was discussed at team meetings by the entire team until consensus was reached.

Data extraction
Data were independently extracted from each included paper by two authors (VA, AF, JB, MA and FW), utilizing a data extraction form developed from a Cochrane Collaboration template. 34Any discrepancies in the data extraction process were resolved by a third researcher.The following information was systematically extracted from all the included articles: study authors, date of publication, study population and participant characteristics (sample size, age, gender, country of origin, type of cancer, study methodology, setting and duration), method of outcome measurement, study outcomes and results.Where possible, data on experimental conditions, including the number of study arms, name and description of intervention(s) and comparator(s) groups were also extracted.

Quality appraisal
The quality of the included studies and the risk of bias were independently assessed by at least two authors, using the Critical Appraisal Skills Programme checklist for Randomized Controlled Trials. 21

Data analysis
Due to heterogeneity of the studies included in the review, meta-analysis was not conducted.However, all data were analyzed thematically to generate a descriptive and narrative synthesis. 41For the purposes of the analysis, the included studies' data was split into primary and secondary

Included studies
The database searches returned 7522 articles to be assessed for eligibility.A total of 249 duplicates were removed, leaving 7273 for inclusion.After screening the titles and abstracts of these studies, 7070 were deemed to not meet the eligibility criteria for the review, leaving 203 abstracts remaining.On further inspection of the abstracts, an additional 157 were excluded.46 of these remaining papers were reviewed by two authors.Upon examination, 17 studies were deemed to not meet the inclusion criteria.The main reasons for papers being excluded at the full text screening stage were as follows: wrong study design (n = 10); using the same study data as other included papers (n = 3); over one third of participants not being blood cancer patients (n = 1); not having access to the full text paper (n = 2); and not being explicit about the outcome measures used (n = 1).Therefore, twenty-nine studies were included in this review (Figure 1).

Quality of included studies
All included studies were RCTs and were deemed to be of adequate to good quality according to the Critical Appraisal Skills Programme Checklist. 21The risk of bias of studies included in the review is summarized in Table 4.The nature of the interventions included meant that              participants could not be blinded to experimental or control arms meaning performance bias was unavoidable.Similarly, participant attrition was prominent in many studies; it is unclear whether this was directly related to the interventions under study or other confounders.Although selection bias was not evident, some studies included more male participants.Reporting bias appeared low.

Review findings
The identified RCT studies were grouped into the following categories based on the content of the intervention: physical therapy (n = 13), psychological therapy (n = 9), complementary therapies (n = 5), nutritional therapy (n = 1) and spiritual therapy (n = 1).Types of physical therapy intervention ranged from endurance training to mixed modality exercise programs, with some programs implemented independently at home whilst others were supervised by healthcare professionals, and one used a combination of supervised and unsupervised training.The length of the physical therapy interventions studied ranged from one day to 36 wk.Studies were categorized as psychological interventions if they included known psychological therapies such as Cognitive Behavioral Therapy (CBT), or core components of psychological therapies such as psychoeducation about anxiety and depression, developing problem-solving skills to help individuals cope with symptoms and the challenges they experience.Counseling or peer support programs that were designed to reduce anxiety, depression, distress and improve HRQoL were also included in this category.These therapies varied in format, including face-to-face and/or virtual sessions, and duration the varied from weeks to months.The RCT studies identified as complementary therapy interventions included art therapy (n = 1), hypnosis (n = 1), music (n = 1), mindfulness (n = 1) as well as Tibetan yoga, which incorporated mindfulness (n = 1).Only one RCT investigated nutritional therapy.This study compared the effect of individualized nutritional support to usual diet on the HRQoL of patients undergoing allogeneic hematopoietic stem cell transplantation. 45Similarly, this review identified one RCT study of an intervention consisting of a planned spiritual care program designed to improve depression, anxiety and stress scores in blood cancer patients. 38
Fifteen studies found significant improvements in HRQoL post-intervention.Of these studies, six were exercise interventions. 17,20,26,30,48,52These exercise interventions varied in formats with two studies, with two studies 17,30 examining physical therapy programs implemented independently at home, whereas the other four assessed the efficacy of supervised training. 20,26,48,52Seven studies that found significant HRQoL improvements were psychological therapy interventions. 6,22,23,24,33,44,49The psychological therapies also differed in structure and content.One RCT investigated a face-to-face palliative care intervention focusing on the management of physical and psychological symptoms, 24 whereas another two RCTs focused on the efficacy of problem-solving training to improve psychosocial outcomes. 6,49Three RCTs investigated CBT interventions, delivered by a therapist either via telephone 23 or in a virtual setting, 33 or as a self-directed internet-based program. 22A fourth RCT investigated the efficacy of a novel program combining trauma-focused CBT and psychotherapy, delivered face-to-face. 44The two complementary therapies were similar, with one RCT studying the efficacy of a mindfulness intervention to improve psychosocial outcomes 55 and the other of a Tibetan yoga intervention, which also incorporated mindfulness. 19ignificantly improve anxiety and/or depression. 6,7,23,24Similar to the psychological therapies that were shown to improve HRQoL 6,7,22,23,24,44,49 also utilized telephone counseling as well as health education and psychological guidance as part of their intervention designed to improve psychosocial outcomes in acute myeloid leukemia patients.Four complementary therapies were found to improve anxiety and depression: a study examining the effect of hypnosis on anxiety and pain relief prior to bone marrow biopsy, 46 an RCT examining the effect of listening to live or prerecorded music on anxiety levels in patients undergoing chemotherapy, 14 an RCT assessing the effect of the art therapy on anxiety, depression, and distress in patients undergoing stem cell transplantation 36 and a mindfulness intervention. 55Additionally, one spiritual care intervention, which included two major components of supportive presence and support for religious rituals, was also found to be effective in reducing anxiety and depression. 38

Discussion
To our knowledge, this is the first systematic review of RCTs assessing the effectiveness of physical health and psychosocial interventions on anxiety, depression and quality of life in patients with blood cancer.Nineteen RCTs investigating a range of interventions utilized primary outcomes measures of anxiety, depression or HRQoL.A further 10 RCTs, of which all were physical interventions, investigated these as secondary outcomes.
Six studies that examined supervised or home-based exercise interventions 17,20,26,30,48,52 yielded statistically significant results regarding quality of life, depression and/or anxiety.A common factor between these studies was that participants had contact with hospital or research staff during the study duration. 17,20,26,48,52While Hathiramani et al. 30 explored the effects of a home-based exercise intervention, participants had personal interaction with research staff at baseline for advice, instruction, demonstration, and practice.This pattern of personal contact suggests that this element of the intervention is an important factor in their success.A previous review of exercise adherence in cancer patients also found support from coaches was an important predictor of patients' adherence to exercise interventions. 40Although those interventions aimed to improve physical health through increased engagement, similar findings in the current review potentially suggests that support from professionals is also important for the improvement of blood cancer patients' mental health.
The findings relating to the effectiveness of complementary therapies in reducing depression and anxiety in blood cancer patients indicate that more research in this area is required.The included studies encompassed complementary therapies including art therapy, yoga, mindfulness, music and hypnosis.Most of these studies reported a significant reduction in anxiety and/or depression when comparing the intervention to usual care.Though different measurement scales were used across studies to measure levels of depression and anxiety, making cross study comparisons difficult, the findings do indicate that a variety of complementary therapies can be offered to blood cancer patients to provide them with psychological support throughout their cancer journey.Similarly, the significant improvements in depression scores in blood cancer patients who received a spiritual care program 38 highlights the important role of spiritual therapy in supporting blood cancer patients, something which is identified by other research in this area. 11,16,42However, more studies are needed to investigate the effects of spiritual care interventions on a variety of cultures and populations to make generalizable conclusions regarding their effectiveness.
Of the four studies that investigated the use of CBT in improving blood cancer patients HRQoL and/or anxiety/depression 22,23,33,44 two utilized a virtual setting. 22,33David et al. 22 did not find significant changes in anxiety or depression, only an increase in patients "fighting spirit", whereas Jim et al. 33 found significant improvements in HRQoL more broadly.Another study that utilized a survivorship program in a virtual environment also did not find any significant improvement on measures of depression, and only found a reduction in distress in participants who also engaged in additional problem-solving sessions via telephone. 49Online interventions have many advantages, including convenience and ease of access, and their potential has been realized more fully during the recent COVID-19 pandemic.However, participants who took part in the modular format CBT sessions 22 reported limited benefits to the programme and that they would have appreciated the opportunity to share their experiences with other participants.This may suggest that although online and virtual sessions have benefits in terms of accessibility, flexibility, cost-effectiveness and inclusivity, the added value of interacting with others may have more widespread benefits than can be achieved through the sharing of information alone.This corroborates a recent systematic of the use of digital technologies in mental health. 12espite differences between the interventions included in this systematic review, common themes were identified across all studies.Many psychosocial interventions reported statistically significant improvements in the mean scores of depression, anxiety and health-related quality of life of blood cancer patients when the delivery of these included some form of face-to-face interaction between those delivering the intervention and the participants.This finding was consistent across four of the five psychosocial intervention types, suggesting that the development of an interactive relationship between session facilitators and patients may be an important factor in improving symptom management and HRQoL in blood cancer patients.However, considerations need to be given regarding the cost and feasibility of implementing interactive psychosocial interventions outside of research settings, and further research on the outcomes of interactive relationships in interventions is required.

Clinical implications
This systematic review demonstrates that the majority of studies and types of intervention were found to be effective in reducing anxiety, depression and/or health related QoL.This therefore suggests that hematological cancer patients could have a choice in the type of intervention that they engage in to reduce the psychological burden of their condition.The evidence-based intervention(s) that a patient chooses may depend on their preference and/or their stage of treatment, but with many options available this could make psychosocial support more accessible to this population.Findings from a recent study 27 suggested that people living with blood cancer were at increased risk of depression during COVID-19, due to an increasing sense of isolation.What is more, Harada, Masumoto and Kondo 29 examined the relationship between exercising alone, exercising with others, and mental health among middle-aged and older adults and discovered that exercising with others had a positive influence on participants' mental well-being compared to exercising alone.Many psychosocial interventions are currently hosted online, as a way of minimizing unnecessary face-to-face contact during COVID-19.This may result in fewer face-to-face interventions being delivered in the longer term, due to the benefits outlined above, which potentially has implications for blood cancer patients.This review suggests there may be advantages of blood cancer patients maintaining some human interaction with others, as the benefits of the psychosocial interventions may not be purely due to the content delivered within them.Though our findings potentially indicate that the relational aspects of face-to-face interventions are beneficial, many blood cancer patients may not be able to finance or access face-to-face supervised training sessions due to a lack of resource.Therefore, further work is needed to fully understand if and what the benefits of face-to-face interventions are, and how these elements can be incorporated into future online interventions.

Strengths and limitations
To date little systematic evidence has focused on the impact of psychosocial interventions in improving quality of life, anxiety and depression in blood cancer patients.The clearly defined eligibility criteria, search terms and selection strategy in this review yielded a large number of RCTs across many continents, though only two carefully selected databases were searched, which was a study limitation Most studies were of adequate to quality, adding confidence in the reliability of the findings.However, the heterogeneity amongst the different psychosocial interventions, as well as the time between participants' cancer diagnoses and their study participation, means that any findings should be interpreted with caution.There were noticeable differences in the intensity, duration and frequency of some of the psychosocial interventions, as well as the way they were delivered, making it difficult to draw true comparisons across studies.Across the included studies, participants received a wide range of treatments and their time since diagnosis was variable, making comparisons across studies limited.A range of scales were also used to measure anxiety, depression, and quality of life across the studies, increasing the heterogeneity of the findings.Greater consensus and consistency on scales used to measure these outcomes in future studies would improve understanding of intervention efficacy.

Conclusions
This systematic review has examined the effectiveness of RCT interventions aimed at improving HRQoL, depression and anxiety for people living with blood cancer.Most studies identified were physical therapy interventions, with some psychological, complementary, nutritional and spiritual therapy interventions.Four of the five intervention types demonstrated improvements in HRQoL, depression and/or anxiety.Future research is required to build on the review findings; however, policy makers and clinicians should consider these findings when deciding which types of psychosocial interventions to recommend to blood cancer patients.Whilst a variety of psychosocial interventions can be recommended to patients depending on their needs, preferences and beliefs an interactive component appears crucial for generating long standing improvements in the HRQoL, anxiety and depression of blood cancer patients.

Table 1 .
Keywords and index terms used in systematic search of literature.

Table 2 .
Picco criteria for included studies.

Table 3 .
characteristics of randomized control trials included in the systematic review.

Table 4 .
risk of bias for studies included in this systematic review.