Factors Associated with Health-Related Quality of Life in Women with Breast Cancer in the Middle East: A Systematic Review

Objectives: The aim of the present systematic review was to identify the factors that potentially influence health-related quality of life (HRQoL) in women with breast cancer (BC) in the Middle East. Methods: A systematic search of the PubMed, Ovid Medline, Cochrane, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Ebscohost databases was conducted to identify all relevant articles published in peer-reviewed journals up to April 2018. The keywords were “Health related quality of life”, “Breast Cancer”, and “Middle East countries”. The Newcastle–Ottawa (NOS) scale was used to evaluate the methodological quality of the included studies. Due to the methodological heterogeneity of the identified studies, no statistical pooling of the individual effect estimates was carried out; instead, the results were summarized descriptively. Results: A total of 5668 articles were screened and 33 studies were retained. The vast majority of these studies were cross-sectional and only two were longitudinal prospective studies. Concerning the methodological quality, only 39% were of high quality. Our comprehensive literature review identified several modifiable and non-modifiable risk factors associated with HRQoL, including sociodemographic, clinical, and treatment-related factors as well as behavioral and psychosocial factors. Conclusion: This study has many implications for clinical practice and may provide a framework for establishing policy interventions to improve HRQoL among women with BC. Healthcare systems in the Middle East are encouraged to develop interventional programs targeting modifiable factors, particularly socio-demographic, behavioral, and psychosocial factors.


Introduction
Globally, breast cancer (BC) is the most commonly occurring cancer in women [1]. The worldwide GLOBOCAN estimates revealed that 2,088,849 new BC cases and 626,679 cancer-related deaths occurred in 2018, with a projected number of over 3,059,829 women to be diagnosed in 2040 [1]. This reflects a significant global increase of 46%, albeit with significant differences in incidence between countries [1].

Eligibility Criteria
Articles were included if they met all of the following criteria: 1.
Population: women diagnosed with BC only; 2.
Setting: studies conducted in one or more Middle East countries; 3.
Outcome Experimental or observational study investigating any associated factors with HRQoL; 5.
English language articles.
Articles were excluded if they met any one or more of the following criteria: 1. Narrative or systematic reviews; 2.
Assessment of the effect of specific interventions on HRQoL, such as sport, exercise, yoga, or focus groups.

Data Extraction and Synthesis
Titles and abstracts identified from searches were screened for relevance, and duplicates were excluded. The full texts of all relevant articles were retrieved and their eligibility for inclusion was assessed.
Two reviewers (R.H. and L.A.A.) performed data extraction independently. Any disagreements were resolved by discussion and by cross-checking the papers. The following information was recorded from each paper: basic study information (last author's name, publication year, and country), study design, sample characteristics (sample size and age), clinical data (BC stage and treatment), HRQoL questionnaire used and time of assessment, as well as the results of the studies, including global HRQoL (Mean and SD), determinants, and signs of the association.

Methodological Quality Assessment
The methodological quality and risk of bias of the included studies was assessed independently by two reviewers (R.H. and L.A.A.) using the Newcastle-Ottawa scale (NOS), a quality assessment tool [20]. Ratings are made using a "star" system to assess the quality of a study for eight items grouped into three domains: (1) selection of participants, (2) comparability of study groups, and (3) verification of the exposure or the outcome of interest. According to the NOS scale, a maximum of nine stars can be allocated for case-control or longitudinal studies and a maximum of six stars can be obtained for cross-sectional studies. Case-control or longitudinal studies that score five or more stars and cross-sectional studies with four or more stars are considered to be of high quality.

Study Selection
The literature search identified a total of 5668 records. After the exclusion of duplicate records and articles with non-relevant title and abstracts, 5227 published studies were retained for screening. Screening of titles and abstracts identified 137 potentially eligible articles. Full-text analyses of these 137 articles identified 56 relevant articles, of which 33 finally met the eligibility criteria for inclusion in the present review ( Figure 1).
Cancers 2020, 12, www.mdpi.com/journal/cancers treatment), HRQoL questionnaire used and time of assessment, as well as the results of the studies, including global HRQoL (Mean and SD), determinants, and signs of the association.

Methodological Quality Assessment
The methodological quality and risk of bias of the included studies was assessed independently by two reviewers (R.H. and L.A.A.) using the Newcastle-Ottawa scale (NOS), a quality assessment tool [20]. Ratings are made using a "star" system to assess the quality of a study for eight items grouped into three domains: (1) selection of participants, (2) comparability of study groups, and (3) verification of the exposure or the outcome of interest. According to the NOS scale, a maximum of nine stars can be allocated for case-control or longitudinal studies and a maximum of six stars can be obtained for cross-sectional studies. Case-control or longitudinal studies that score five or more stars and cross-sectional studies with four or more stars are considered to be of high quality.

Study Selection
The literature search identified a total of 5668 records. After the exclusion of duplicate records and articles with non-relevant title and abstracts, 5227 published studies were retained for screening. Screening of titles and abstracts identified 137 potentially eligible articles. Full-text analyses of these 137 articles identified 56 relevant articles, of which 33 finally met the eligibility criteria for inclusion in the present review ( Figure 1).

Characteristics of the Included Studies
The characteristics of the articles included in the present systematic review are summarized in Table 2. Almost half of the studies were conducted in Iran (n = 15, 45%), followed by Turkey (n = 9,

Characteristics of the Included Studies
The characteristics of the articles included in the present systematic review are summarized in Table 2. Almost half of the studies were conducted in Iran (n = 15, 45%), followed by Turkey (n = 9, 27%), Saudi Arabia (n = 3, 9%), Jordan (n = 2, 6%), and one each (3%) from Lebanon, Kuwait, Bahrain, and Yemen (Table 2). More than half of the studies in were from Cancer Centers (n = 17, 52%) and the rest (n = 16, 48%) were conducted in hospitals. First authors of the published studies were mainly affiliated with universities. Articles were published in medical (42%) or medical oncology journals (18%). About two-thirds of the studies (64%) used interviews as a method to collect data. Concerning study designs, the majority had a cross-sectional design (n = 28, 85%). Three studies used a case-control design, while only two were longitudinal studies.

Description of the Selected Atudies
A detailed description of the included studies is presented in Table 3. The majority of the women participating in the studies had stage II BC and were treated with chemotherapy.

Characteristics of the Cross-Sectional Studies
Sample sizes of the included cross-sectional studies (n = 28) ranged from 42 to 762 patients, and totaled 8764 women with BC included in all studies. Age ranged from 25 to 60 years. The studies included were published between 2004 and 2018. For outcome assessment, specific BC questionnaires, such as the European Organization for Research and treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30) associated with the breast cancer module (QLQ-BR23) (n = 8), the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) (n = 4), as well as generic tools were used.

Characteristics of the Case-Control Studies
The total number of women with BC in case-control studies was 318, with a mean age ranging from 32 to 49 years. These studies were published between 2015 and 2017, and were reported from Iran. One study used the EORTC QLQ-C30, the second one used the EORTC QLQ-C30 associated with the QLQ-BR23, and the third used the generic SF-36 questionnaire.

Characteristics of the Longitudinal Studies
Concerning the two longitudinal studies, a total number of 241 BC women with mean ages of 46.9 and 47.2 years were included. The two studies were published in 2008 and were reported from Turkey and Iran. With regard to the instruments used to assess HRQoL, one study used the FACT-B and the other used the EORTC QLQ-C30.

Factors Associated with HRQoL in Women with BC in the Middle East
The authors of the included studies identified several factors associated with global HRQOL in women with BC. Table 5 presents a summary of these factors. Table 5. Global health-related quality of life (HRQoL) and its associated factors in women with breast cancer in the Middle East.

Treatment-Related Factors
HRQoL was negatively influenced by chemotherapy, including Docetaxel with doxorubicin and cyclophosphamide/Gemcitabine + cisplatin/FAC/FEC and Docetaxel/Paclitaxel AC/EC in four studies [23,24,31,37] and by breast-sparing surgery in one study [24], whereas other studies reported that HRQoL was positively influenced by hormone therapy [49], early treatment [45], and breast reconstruction surgery [50]. One study found a positive association with radiotherapy [28], while another reported the reverse [49]. HRQoL was positively affected by the use of complementary alternative medicine [26].

Behavioral Factors
Behavioral factors such as physical activity [21], fitness orientation and evaluation [30], body weight [24,29], and nutritional status [38] were reportedly associated with HRQoL, with women of normal weight and exercising regularly, and well-nourished women having better HRQoL. In addition, positive body image [30], body satisfaction [30], as well as positive religiosity [52,53] and spiritual well-being [29,34] were associated with better HRQoL.

Discussion
The main aim of the present review was to synthesize the literature exploring the factors that influence HRQoL in women with breast cancer (BC) in the Middle East. After an extensive literature review, we identified only 33 articles that met our inclusion criteria. The vast majority of these studies were cross-sectional and only three studies were longitudinal prospective studies. In almost 60%, studies were published in medical journals, readily available for both medical practitioners and decision-makers. The methodological quality was high in only 39% of the studies, indicating that there was a high risk of biased results. Our comprehensive literature review identified several sociodemographic, clinical, and treatment-related factors, as well as behavioral and psychosocial factors associated with HRQoL. These findings provide a scientific basis to develop a comprehensive multidimensional program that incorporates these factors, to improve the QoL of breast cancer survivors in the Middle East.
Concerning sociodemographic factors, there was an inconsistency between studies regarding age. The results of three studies suggested that HRQoL was adversely affected in older patients, while three other studies found that younger patients with BC experienced poorer HRQoL than their older counterparts. This discrepancy may be explained by the heterogeneity of the samples, the subjects included, and a lack of power due to the low sample size. Thus, we cannot draw any clear conclusion about the effect of age on HRQoL and further studies are needed to evaluate the association between these two variables. The results of the studies reviewed here consistently suggested that highly educated woman had better quality of life compared to their less well-educated counterparts. A possible explanation for this finding is the ability of educated women to understand the nature of the disease and to comply with the therapeutic recommendations better than the less educated. Moreover, illiterate women with low income are less likely to be screened for breast cancer, delay before seeking care in the presence of symptoms, and are diagnosed at later stages of the disease. Therefore, health care teams should give more attention and support to less well-educated women (i.e., less than secondary level and illiterate individuals) with BC who need extensive information about their treatment and follow-up.
Regarding socioeconomic status, the studies in this review consistently found that patients who were unemployed and had financial difficulties or a lower monthly income reported lower HRQoL than patients who had higher incomes or no financial difficulties [54,55]. In fact, higher economic status can be linked to many aspects of improved patient care, such as rapid access to treatment and rehabilitation, as well as less concern for the financial burden of the treatment [54]. Being married was also found to be associated with better HRQoL in BC patients. In line with this finding, studies from the US and China have found that married BC patients had better QoL compared to single or divorced women [54,56]. This could be explained by the emotional support provided by their spouses. Finally, having children was also found to be associated with better HRQoL, although the number of studies was insufficient to draw clear conclusions.
Regarding clinical and treatment-related factors, HRQoL was significantly impaired by the type of treatment, by advanced stages of disease, and by the symptoms experienced. Chemotherapy was consistently associated with poorer HRQoL in Middle Eastern women with BC. Indeed, patients on chemotherapy are more likely to be diagnosed with advanced stage disease and to experience pain, fatigue, and possibly other severe side effects, which in turn reduce quality of life. Other treatments, such as hormone therapy and breast reconstruction surgery, are less likely to be associated with advance stage disease, and thus less likely to negatively affect quality of life. Regarding radiotherapy, findings were conflicting across studies, and no clear conclusion emerged. Interestingly, one of the studies reviewed [26] reported that complementary and alternative medicine, including spiritual therapy, honey, olive oil, and herbal therapy, was associated with better global HRQoL, physical role, and social functioning, as well as alleviating cancer-related constipation. Since this type of medicine is commonly used in the Middle East, these findings warrant confirmation with a view to incorporating them into medical care and management programs for breast cancer patients.
Concerning behavioral factors, well-nourished women [38] with normal weight [24,29] and those who exercise regularly [21] tended to have better quality of life. In line with these findings, Gong et al. reported a positive effect of physical exercise and healthy diet on HRQoL [54,56]. Thus, promoting patient participation in rehabilitation programs, including nutritional education and physical exercise, might be one way to improve HRQoL in patients with BC. Moreover, consistent with previous findings reported by Wildes et al. [57] our literature review revealed that positive religiosity [52,53] and spiritual well-being were associated with better HRQoL. However, body image disturbance and dissatisfaction were found to be associated with poor HRQoL. In fact, body image disturbance following treatment of cancer may be associated with a variety of changes, such as depression and anxiety, that can have a significant negative impact on HRQoL. Therefore, it is important to evaluate body weight perception in BC patients after chemotherapy or mastectomy, as this may affect biopsychosocial functioning [42].
Several psychosocial factors were found to be associated with HRQoL. As expected, depression and anxiety had a significant negative impact on HRQoL. This is in agreement with the findings of Poleshuck et al. and Shelby et al., who found that patients with BC may experience anxiety and depression regarding surgical experience, coping with acute pain, treatment regimens, financial burden of care, and disruptions to their personal and professional lives [58,59]. All of these factors may in turn adversely affect their quality of life. Thus, early identification and interventions to alleviate depression, anxiety, and stress may help improve HRQoL. It was also found throughout the literature review that having higher scores of self-efficacy [39], self-regulation [42], and sense of coherence had a positive impact on HRQoL. As psychosocial factors are considered to be modifiable, there may be substantial gains to be yielded from paying greater attention to these factors, with a view to improving HRQoL among patients with BC. This systematic review of 33 studies totaling 5735 participants is the first systematic review to investigate the factors associated with HRQOL in women with BC in the Middle East. Our review has, however, several limitations which need to be considered with caution when interpreting the results. First, despite the rigorous and extensive search strategy with no restrictions on year of publication, there may have been some potentially relevant studies that were eligible, but excluded, because we limited our review to studies published in English. As in any systematic review, publication bias may have affected our findings. Second, the lack of data for some countries may decrease the generalizability of findings to all Middle East regions. Third, due to the heterogeneity among the studies included in the review, only a narrative review was possible. Fourth, the majority of studies had a cross-sectional design, and small sample sizes, implying a low level of evidence, and as such cannot be used to determine causal mechanisms. Finally, although based on the best available data, our review was limited by the quality of studies reported from the Middle Eastern countries.
Despite these limitations, the current review addressed critical factors that were significantly associated with HRQoL in patients with BC. Emphasis should be given to empowering women through education, as this is a key tool for avoiding unemployment and tackling the psychological impact of BC. Financial aids may also significantly improve the HRQoL of BC patients. Thus, healthcare systems in the Middle East are encouraged to expand interdisciplinary palliative and supportive care services that have the necessary expertise to help financially strained patients to navigate the BC care pathway. Moreover, there is also a compelling need to provide social support over the long-term to patients with BC. We recommend that clinicians pay attention to modifiable risk factors that have an influence on HRQoL, such as psychological factors. They should also encourage their patients to strengthen their social relationships with family members and friends, to adhere to a healthy diet, and to practice any kind of sport.

Conclusions
In summary, the present study identified several modifiable and non-modifiable factors that affect HRQoL in women with BC in the Middle East. This study has many implications for practice and provides a framework for establishing policy interventions to more efficiently improve the QoL of women with BC. Healthcare systems in the Middle East are encouraged to develop targeted interventional programs on modifiable factors, particularly socio-demographic, behavioral, and psychosocial ones. Further research on these factors is warranted, preferably through prospective longitudinal studies.