The Quality of Life and Psychosocial Implications of Cancer-Related Lower-Extremity Lymphedema: A Systematic Review of the Literature

Lower-extremity lymphedema (LEL) is a progressive, lifelong complication of cancer that places a substantial burden upon cancer survivors’ quality of life (QOL) and psychosocial well-being. Despite its prevalence, cancer-related LEL is inconsistently diagnosed, treated, and poorly recognized by health care professionals. The purpose of this systematic review was to summarize and appraise the quantitative literature evaluating the impact of cancer-related LEL on patients’ psychosocial well-being and QOL. Three databases (PubMed, PROQuest, and Scopus) were searched for observational research articles published before May 1st, 2020. Twenty-one articles were eligible (cross-sectional (n = 16), prospective cohort designs (n = 3), and retrospective cohort designs (n = 2)). The majority of studies reported a negative relationship between cancer-related LEL and global QOL and/or one or more psychosocial domains including (1) physical and functional; (2) psycho-emotional; (3) social, relational and financial. A greater number of LEL symptoms and higher LEL severity were associated with poorer QOL. Although the evidence to date suggests a negative relationship between cancer-related LEL and patients’ QOL and psychosocial well-being, there is a substantial need for longitudinal analyses to examine the directionality and temporality of this effect in order to inform cancer survivorship care modelling and improve patient outcomes after cancer.


Introduction
Lymphedema is a chronic, progressive and potentially disabling condition associated with cancer treatment and/or tumour obstruction of the lymphatic system [1]. Across all cancer types, upwards of 60% of people who have undergone surgery, radiation, and/or chemotherapy may later develop lymphedema after active treatment has subsided [2]. Furthermore, tumour obstructions of lymphatic vasculature or nodal regions can induce cancer-related secondary lymphedema development.
The literature has demonstrated that heightened psychological distress, depression, and anxiety are associated with the development of lymphedema after cancer [3,4]. These psychological sequelae are often linked to feelings of hopelessness, fear of the future and isolation due to immobility, social avoidance, and/or sexual dysfunction [4][5][6]. As a result of the skin changes and swelling associated with lymphedema, cancer survivors have also reported the negative impact of this condition on their appearance [3]. Considering the psychosocial complexity of life after cancer alone, these patients are now faced with a unique burden in the form of a secondary chronic illness that is associated with potential negative consequences on quality of life (QOL). QOL is a multifaceted concept that encompasses different domains of one's life, including physical well-being, social/familial well-being, emotional well-being, and functional well-being [7]. Health-related QOL (HRQOL) specifically explores the physical, psychological, and social domains of health within the context of a person's subjective experience [8], whereas global QOL is usually not referring specifically to the effects of a disease or condition on functioning. However, these terms are often used interchangeably and definitions of HRQOL and QOL vary within the literature [9]. Therefore, for the purposes of this systematic review, the terms HRQOL and global QOL are used as specified within each article reviewed.

Cancer-Related Lower-Extremity Lymphedema
The cancer-related lymphedema literature primarily focuses upon breast cancer-related arm lymphedema, given that approximately 40% of breast cancer patients develop lymphedema after cancer treatment [10]. It is important to recognize, however, that lymphedema not only affects the upper extremities, but also lower extremities, trunk, and/or mixed regions of the body. Amongst other tumour groups, 53% of melanoma, 73% of gynecological, and 29% of prostate/penile cancer patients may develop lymphedema after cancer treatment [10][11][12]. Despite its localization, cancer-related lymphedema is classified under one individual disease, and yet it often poses unique challenges to patients depending upon its location.
Similarly to upper-extremity lymphedema, patients experiencing cancer-related LEL are often required to comply with tedious and physically-demanding therapies to manage symptoms and prevent disease progression [16]. However, LEL often requires increased attentiveness, accommodation, and radical adjustments to activities of daily living (ADLs) in order to comply with treatment [17]. Constant disruptions to daily living and stressors associated with cancer-related LEL are not without financial repercussions. Cancer-related LEL costs have been reported as high as $2000 per month, with the majority of these costs not covered by public or private health plans [17,18]. The financial burden of cancer-related LEL may be further exacerbated due to patients' inability to work following lymphedema onset [5].
Taken together, patients with cancer-related LEL may experience poor QOL and psychosocial sequelae due to numerous and complex challenges that include, but are not limited to decreased self-confidence, changes to social/familial relationships, psychological distress, loss of identity, emotional and financial stressors, and isolation as a result of their under-recognized and complex complication of cancer treatment [15,19]. Nevertheless, the majority of the relevant literature continues to primarily focus on upper-extremity breast cancer-related lymphedema. While research on upper-extremity cancer-related lymphedema should continue to expand, exploring and recognizing the unique deleterious effects of cancer-related LEL on patient QOL and psychosocial well-being is another critical prospect for future research. It is crucial to critically evaluate the current state of knowledge regarding the unique psychosocial burdens experienced by patients with cancer-related LEL in order to inform timely intervention and the development of novel care models of cancer survivorship to improve patient outcomes after cancer. Therefore, this review aimed to evaluate the impact of cancer-related LEL on patient QOL and psychosocial well-being. Specific objectives include: (1) Summarize and critically evaluate the literature on the impact of cancer-related LEL on patient QOL and psychosocial well-being. (2) Identify potentially modifiable factors associated with poor QOL and psychosocial well-being in patients with cancer-related LEL.

Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [20]. Three electronic databases were searched: PubMed, PROQuest, and Scopus. The search terms and strategy used within PubMed are outlined within Appendix A (Table A1). Terms were categorized into four domains: lymphedema (e.g., "lymphedema", "lymphoedema", and "secondary lymphedema"), lower-extremity (e.g., "lower-extremity", and "lower limb"), cancer-related ("neoplasm", "cancer-related", and "oncology"), and psychosocial well-being/QOL (e.g., "quality of life", "well-being", and "anxiety"). The search strategy was modified and applied to PROQuest and Scopus with the aid of a professional librarian.
The inclusion criteria included articles: (1) published prior to 1 May 2020; (2) that examined relationships between cancer-related LEL and global QOL; (3) and/or at least one of the following psychosocial domains: psychological distress (e.g., depression, anxiety, or any other mood state), physical, social, family, emotional, or functional well-being, sexual function, body image, or financial implications (primary or secondary measures). The exclusion criteria were articles published in non-English languages and/or those published before 1 January 2000.

Data Extraction
An initial search was conducted by a professional librarian and the search strategy was refined in collaboration with two reviewers (C.B. and K.-A.P.). Following PRISMA guidelines (Table A2), two reviewers (C.B. and K.-A.P.) completed the refined literature search, eligibility screening, data extraction, and performed quality assessments of the articles included. Discrepancies between reviewers were discussed until consensus was met. After removing duplicates, each reviewer screened titles and abstracts using the aforementioned inclusion/exclusion criteria (level 1). Remaining abstracts were then screened as full-text articles (level 2) and data extraction was undertaken using a previously designed form [21]. Data extraction summarized details including study objectives, patient demographics and disease-related characteristics, lymphedema status determination, design and data collection methodology, and psychosocial and/or QOL-related findings. If raw instrument scores were reported, differences in overall and subscale scores were calculated and verified by two authors (C.B. and K.-A.P.). Literature synthesis was performed by reading all the articles several times to become familiar with the results, methods used and methodological limitations. After summarizing the findings, studies with similar and conflicting results were identified and supporting data were extracted from articles. Conclusions from this review were then made.

Quality Assessment
Quality assessments of included articles were undertaken using the National Institutes of Health (NIH) Quality Assessment Tools [22]. These tools include appraisal criteria specific to study design. For instance, observational cohort and cross-sectional studies were rated as "poor", "fair", or "good" based upon the following criteria: exposure-related considerations (timeline relative to outcome measurement, frequency of measure, and categorization of exposure levels), methodological validity of exposure and outcome measurements, participation and post-baseline follow-up rates, adjustment for confounding variables, outcome assessor blinding, and explicitness of aims, sample, and study setting.

Results
A total of 3171 unique articles were retrieved using the aforementioned search strategy. After screening article titles and abstracts (level 1) for inclusion based upon eligibility criteria, 77 articles remained and were subject to full-text screening. Of these articles, 56 were excluded based upon the following: case reports (n = 7), review (n = 1), intervention (n = 3), solely qualitative analysis (n = 4), not specific to lower extremities and/or solely included combined extremity analyses (n = 19), addressed general cancer survivorship (n = 4), non-cancer-related lymphedema (n = 10), or lacked psychosocial/QOL analyses (n = 8). A total of 21 articles remained after all screening processes were completed. A PRISMA diagram outlining the literature search and screening outcomes is presented in Figure 1.
psychosocial/QOL analyses (n = 8). A total of 21 articles remained after all screening processes were completed. A PRISMA diagram outlining the literature search and screening outcomes is presented in Figure 1.

Quality Assessments
Quality assessments are provided in Tables 2 and 3, and a summary of key findings is reported below.

Observational Cohort Studies
Five studies used an observational cohort design [30][31][32][33]35]. The study by Cromwell et al. [30] was the only observational cohort study to receive a 'good' quality rating. The study was adequately powered (n = 277) and used a clinically valid method to identify LEL cases (≥10% volume increase at three months post-baseline), while further identifying and assessing QOL and psychosocial well-being in patients "at risk" for and/or with lower severity LEL using validated outcome measures.
The remaining studies were appraised as "fair" (n = 3) [32,33,35] and "poor" (n = 1) quality [31]. The work by Franks et al. [31] received a "poor" rating due to several methodological limitations and unmet criteria on the NIH Quality Assessment Tool. LEL identification relied upon self-reported 'prolonged swelling that fails to resolve on bedrest and/or an indication of cancer within medical records, both of which are not individually sufficient for formal cancer-related lymphedema diagnosis/identification. Furthermore, HRQOL scores for LEL patients with ulcerations were not directly compared to normative values; rather, scores were compared between these patients and individuals with leg ulcerations. The authors deduced that because ulcerations can cause major deficits in HRQOL, lymphedema patients are more likely to experience greater problems.

Summary of Outcomes
Twenty-one studies evaluated the implications of cancer-related LEL on global QOL and/or one more of the following QOL domains: (i) physical and functional well-being (i.e., fatigue, pain, ADLs); (ii) psycho-emotional well-being; (iii) social, relational and financial well-being.

Global QOL Implications
The majority of studies evaluated the relationship between LEL status and global QOL scores and all found a negative correlation. For instance, in one cross-sectional study by Dunberger et al. [5] (n = 616), gynecological cancer survivors with cancer-related LEL were more likely to report lower overall QOL scores than participants without LEL (RR = 1.4). In another prospective, longitudinal study of cervical cancer patients, Ferrandina et al. [26] found that the global health status (EORTC QLQ-C30 and CX24) was associated with early worsening of LEL following cancer treatment, which was common across women treated for early stage and locally advanced cervical cancers [26]. Taken together, data from these studies suggest that LEL correlates negatively with QOL.

Physical and Functional Implications
Many of the studies assessed physical and/or functional well-being in relation to cancer-related LEL status and reported a negative relationship between these factors. In an observational cohort study of 147 women who received treatment for cervical, endometrial, or ovarian cancer, Omichi et al. [33] reported FACT-G scores within the physical domain were significantly lower in patients with LEL compared to those without LEL. Similarly, in a cohort study by Stolldorf et al. [35] (n = 178), participants with cancer-related LEL reported higher physical symptom scores (16.1% of participants). These findings were supported by cross-sectional analyses [23][24][25]29,34,[36][37][38][39]. It should be noted, however, that two studies failed to show significant results [39,42]. A cross-sectional case-control study by Kim et al. [42] did not report significant differences in EORTC QLQ-C30 (functional and physical symptom domains) scores between 25 women with gynecologic cancer-related LEL and 28 gynecological cancer survivors without LEL, potentially due to a small sample size that resulted in low statistical power. Brown et al. [39] also indicated no significant differences in patient-reported changes to physical activity between women with cancer-related LEL and those without LEL. Nevertheless, this same study reported a significantly increased odds of reporting poor physical function within the LEL group compared to the non-LEL group (OR 5.25) [39]. Overall, findings from these studies suggest that cancer-related LEL status negatively influences the physical and functional domains of patient QOL, but further suggest a need for increased research in order to better under the specific effects of lymphedema on these domains.

Pain and Fatigue
Although pain and fatigue may not be considered direct signs of lymphedema, many of the studies described the incidence or frequency of pain and fatigue, and suggested that they were commonly reported with negative effects on QOL [23,24,29,32,38,41,46]. For instance, pain was one of the most commonly reported physical symptoms in a study of 38 cancer survivors with LEL [38]. Gane et al. [32] reported tingling and weakness of moderate or severe intensity amongst cancer-related LEL patients. The presence of these symptoms was associated with lower QOL (any symptom estimate −13.29; moderate to extreme symptom estimate −11.35) [32].

Activities of Daily Living
Within the context of physical and functional QOL, some studies found that cancer-related LEL was associated with physical limitations and unmet needs, thus interfering with ADLs [34,38,41,47]. For example, in one study by Beesley et al. [34], patients with endometrial cancer-related LEL had a higher odds ratio (OR) for physical or daily living unmet needs (OR 2.21) when compared to endometrial cancer survivors without LEL. Furthermore, 3% of these participants had mild difficulty completing ADLs, whereas 26% had moderate and 5% had severe difficulty, illustrating the varying impact of LEL on daily activities, which is likely associated with varying severity of LEL itself. These findings were echoed within a cross-sectional study by Kusters et al. [37] (n = 160), which found that gynecological cancer survivors with self-reported LEL (30%) described significantly more unmet needs relating to physical/daily living, health needs, and patient care after 5-30 months of receiving a cancer diagnosis (SNCS SF-34) [37]. Taken together, data from these studies indicate that the repercussions of LEL on ADLs need to be addressed in an attempt to improve patient physical and functional well-being and subsequently, overall QOL.

Social, Relational and Financial Implications
Ten studies evaluated the impact of cancer-related LEL on the social, relational, and financial dimensions of one's life and suggested a negative association [5,23,24,[28][29][30][34][35][36]42]. For instance, within two studies by Beesley and colleagues [23,34], patients with endometrial cancer-related LEL experienced unmet needs relating to the cost of LEL and management of LEL within the workplace. In addition, both Yost [29] and Rowlands [36] reported patients with LEL had significantly lower social domain scores on the EORTC QLQ-and MOS SF-12 relative to non-LEL comparison groups. With regard to relational QOL outcomes, Dunberger et al. [5] found no difference in perception of sexuality and prevalence of feeling attractive as women between 218 gynecological cancer survivors with LEL and 388 counterparts without LEL. It may be the case that gynecological cancer survivors are highly vulnerable to sexual dysfunction with or without lymphedema. However, experiences of poor body image and sexual dysfunction among patients with LEL were reported in three other studies [28,29,35]. For instance, one study reported that among 37 patients with cancer-related LEL, 11.5% of participants felt misunderstood by their significant other, less sexually attractive (13.8%), lacked interest in sex (21.4%), and unable to take part in sexual activity (18.1%).

Modifiable Factors Associated with Poor QOL in Patients with Cancer-Related LEL
While several studies evaluated the impact of cancer-related LEL on patient QOL and psychosocial well-being, very few provided insight into potentially modifiable factors related to QOL and suggested that a greater number of LEL-related symptoms and higher LEL severity were associated with poorer QOL. For instance, Kim et al. [42] found that high GCLQ-K LEL symptom scores were negatively and strongly associated with overall global health (EORTC QLQ-C30) scores (r = |0.64|) of LEL patients (Cohen's d = 1.26) and more strongly correlated with physical, role, emotional and social function, symptom scales, dyspnea, constipation and financial difficulties EORTC QLQ-C30 domains (range across domains; r = |0.31-0.72|). Gane et al. [32] also reported on the negative influence of lower limb symptom prevalence and severity in relation to patient QOL.

Discussion
The purpose of this systematic review was to evaluate the impact of cancer-related LEL on patient QOL and to identify potential factors associated with worse QOL among cancer patients with LEL, particularly modifiable factors. The evidence available to date suggests that cancer-related LEL adversely impacts the physical, functional, psycho-emotional, social, relational and financial domains of patients' QOL. A greater number of LEL symptoms and higher LEL severity may catalyze those negative effects, indicating that proper management of modifiable factors (LEL symptoms and severity) may have a positive impact on patient health and well-being. The findings from studies included in this review are supported by the qualitative literature, showing unique factors underlying the LEL experience may diminish patient QOL [17,44,45,47]. For example, Ryan et al. [17] described patients' negative experiences with the frustration of symptoms and treatment, diminished self-confidence and poor self-perception, and changes to body image. These findings were further supported by LEL patients' experiences of isolation, depressive thoughts, and fears of the future, all of which are implicated in patient QOL and psychosocial well-being [17,44].
Five of the twenty-one studies incorporated a temporal analysis (retrospective or prospective cohort design) [30][31][32][33]35], and only one of them received a quality rating of "good". This study concluded that patients with LEL had significantly lower QOL than those with upper-extremity lymphedema [30], with LEL patients also experiencing declining QOL over the course of 18 weeks after cancer treatment. This effect was not shared by other subtypes of lymphedema [30]. Three of the remaining observational cohort studies were appraised as "fair" [32,33,35] and showed that patients with LEL had significantly worse QOL compared to other cancer survivors without LEL. One of these studies also reported a negative association between LEL symptom prevalence and severity, and multiple QOL domains [32]. Sixteen studies included within this review employed a cross-sectional design [5,[23][24][25][26][27][28][29]34,36,37,[39][40][41][42]. The majority were rated as "fair", and supported previous findings from observational cohort studies [30][31][32][33]35]. Overall, while the literature supports a relationship between cancer-related LEL and poor QOL, the quality of evidence is currently insufficient since most studies were cross-sectional, which precludes conclusions regarding directionality or temporality.

Implications for Research and Clinical Practice
This work is one of the first systematic reviews to provide insight into the QOL, unmet needs and psychosocial well-being of cancer survivors with LEL. This review reveals that research in this area is limited, with the majority of studies lacking temporal and directional analyses due to the use of cross-sectional designs. Of note, longitudinal analyses amongst breast cancer-related upper-extremity lymphedema patients demonstrate worsening of QOL and psychosocial functioning as time passes after cancer treatment [48,49]. Considering the unique challenges faced by patients with LEL, who require sufficient function of lower limbs for basic mobility, longitudinal analyses are warranted to examine the QOL implications associated with LEL chronicity and progression.
Although formalized clinical programs are available to aid cancer survivors in addressing common complications of cancer treatment, such as fatigue and distress, few oncology programs provide direct support for cancer-related LEL management, leaving many patients to navigate the complex physical and psychosocial burdens associated with this disease [50,51]. This review demonstrates that LEL patients experience heightened levels of the many long-term common complications of cancer treatment compared to survivors without LEL. These complications are, in part, linked to lymphedema-specific factors, including LEL symptom prevalence and severity. Therefore, this review provides critical information for survivorship program development, emphasizing the profound need for LEL-specific management, clinical guidelines and tools in order to support patients after active cancer treatment and improve their QOL.
This review indicates that evidence is consistent as to whether cancer-related LEL negatively impacts QOL and psychosocial well-being. Studies have assessed QOL and psychosocial well-being at a variety of time points during cancer survivorship, indicating that patients with LEL may require additional assistance to manage their distress effectively across the cancer continuum. In addition, research describing modifiable factors associated with QOL in this population is limited, suggesting a greater number of LEL symptoms and higher LEL severity are associated with poor QOL [32,42]. These studies have focused on medical correlates of QOL, with little attention to the potential influence of psycho-behavioral characteristics. For example, self-efficacy and self-care management are two factors that are modifiable and have been found to moderate the effects of chronic illness on QOL [52,53], yet this relationship has not been examined in patients with cancer-related LEL. These and other potentially modifiable factors need to be assessed and identified to allow for their inclusion in future strategies aimed towards improving QOL and psychosocial well-being within this understudied population.

Limitations
There are several limitations associated with this systematic review. To begin, the heterogeneity of studies in terms of study design and measures prevented pooling the data in a meta-analysis, and therefore, an analysis of risk of publication bias could not be conducted. Furthermore, studies that conducted combined primary lymphedema, secondary non-cancer-related lymphedema and cancer-related LEL analyses were not included. It is possible that these studies presented important information pertaining to QOL and psychosocial well-being of patients living with cancer-related LEL.
However, the heterogeneity among participants with and without a history of cancer was deemed inappropriate for inclusion within this review. Furthermore, some studies on cancer-related LEL may have been missed due to the databases searched in this review. Additional literature searches in databases such as CINAHL and PsychInfo may have provided a greater breadth of studies on practical LEL literature and psychological studies.
Limitations also existed within the literature included within this review. Included studies lacked age-and sex-related diversity of study participants. Sixteen of the twenty-one articles included focused on women with LEL related to gynecological cancer treatment [5,[23][24][25][26][27][28][29]32,33,35,36,38,39,42,46]. Furthermore, articles that reported on other cancer types, such as melanoma and colorectal cancer, primarily included female participants. This finding not only emphasizes the need for more diversity related to disease characteristics and demographics, but further suggests a potential imbalance in patients seeking medical care and/or reporting lower-extremity swelling and symptoms within the literature. To further augment demographic limitations, the mean age of participants included within this literature review was 60.7 year, representing a relatively older cohort of survivors. Although this is representative of the population of people typically diagnosed with cancer, without younger survivors included, the full spectrum of survivorship experiences is not identified. For example, several studies emphasized the financial burden associated with cancer-related LEL in regards to treatment-related economic strain and patients' difficulty with symptom management at work. Considering the differences in employment and financial stability that may exist between older and younger adult cancer survivors [54], it is critical that QOL is also assessed within younger LEL populations. To this end, Gjorup et al. [41] reported that younger women with LEL (all cause) had significantly worse social functioning than older women. It is also the case that younger cancer survivors, in general, tend to encounter more psychosocial issues than their older counterparts [55,56]. Therefore, this review, in combination with previous qualitative studies emphasizing the importance of age in LEL symptom management and coping [45], sheds light upon the complex interplay between age, cancer-related LEL and QOL. This relationship should be addressed in future studies in order to strengthen the psychosocial literature within this context.

Conclusions
Cancer-related lymphedema is a progressive, lifelong complication of active cancer and its associated treatment. Despite its prevalence, cancer-related LEL continues to be poorly recognized amongst the health care community, leaving many patients to navigate complex psychosocial and QOL implications. Although the current literature suggests a negative relationship between cancer-related LEL and QOL/psychosocial well-being, there is a substantial need for rigorous longitudinal studies to examine the directionality and temporality of this effect.    Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 2

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. n/a Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 3 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 3 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 3 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 3

Data items 11
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 3

Risk of bias in individual studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. 3

Summary measures 13
State the principal summary measures (e.g., risk ratio, difference in means). 3

Synthesis of results 14
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis. 3 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). 3

Additional analyses 16
Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. 3

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 3,4 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

4-19
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

20-23
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

23-25
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

23-25
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). 25

Limitations 25
Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). 25

Conclusions 26
Provide a general interpretation of the results in the context of other evidence, and implications for future research. 26 + 27

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. 27 Table A3. All measures used to assess psychosocial well-being and/or QOL within the reviewed literature.

Instrument Category Instrument Name
European