Health-related quality of life in breast cancer patients: review of reviews from 2008 to 2018

Background Breast cancer still is a topic. This overview of the literature aimed to update the current knowledge on quality of life in breast cancer patients. Methods A review of literature in MEDLINE, Cochrane Database of Systematic Reviews and Google Scholar were carried out to identify review papers on health-related quality of life in breast cancer during the 2008 to 2018. All publications were screened using the PRISMA guideline. The methodological quality of reviews was assessed using the AMSTAR. The findings were summarized and tabulated accordingly. Results Within over a decade, a total of 974 review papers were identified which according to the study selection criteria finally we have evaluated 82 reviews. Of these about 85% had a reasonable methodological quality. The findings were mainly summarized on several headings including instruments used to measure quality of life, treatment, supportive care, psychological distress, and symptoms. Questionnaires had a good performance to quantify quality of life in breast cancer patients. Most reviews were focused on the impact of treatment including endocrine therapy as well as integrating complementary and alternative medicine into the current practice. According to the reviews, yoga was the most recommended exercise to improve quality of life in breast cancer patients. Conclusion Overall, the findings from this overview indicated that quality of life in breast cancer patients enhanced during the last decade. Several simple but effective interventions such as physical activity and psychosocial interventions proved to be effective in improving quality of life in this population. However, management of symptoms such as pain, and lymphedema, issues related to worry, sexual function especially for young patients, and the future outlooks all are among topics that deserve further consideration. Also, this overview indicated that methodological issues in measuring quality of life in breast cancer patients improved greatly, but still there is a long way to go to understand what really matter to patients.


Background
Breast cancer remains the most common cancer among women worldwide [1]. According to 2018 GLOBOCAN, approximately 2.1 million cases worldwide were diagnosed with breast cancer and about 630,000 died from the disease [2]. Due to the increasing in breast cancer incidence, advances in the treatment of the disease have been achieved. Local modalities and systemic anticancer therapies, therefore, lead to improve patients' survival outcomes including disease-free survival and overall survival [3]. However, since the disease diagnosis and treatment have improved greatly over time, at present in addition to survival, quality of life has become an important outcome measure in breast cancer clinical investigations and survivorship studies [4,5]. Hopefully, at present a compile of evidence exist on the topic and sometimes even it is very difficult to adhere to evidence in practice Open Access *Correspondence: montazeri@acecr.ac.ir since conflicting findings are reported. Thus, to evaluate and summarize the existing evidence on quality of life in breast cancer patients a review of reviews was conducted.
Previously we have summarized all reviews on breast cancer patients' quality of life that covered the literature from publication of the first review up to year 2008 [6]. The lists of those reviews are supplemented (see Additional file 1). Now we are updating the review by focusing on review papers which appeared in biomedical journals since then. Systematic review of reviews will allow the creation of a summary of reviews in a single document in order to enhance evidence-based knowledge and support well-informed clinical decision-making [7]. The present review of reviews aimed to address the primary question of whether the quality of life has been improved over the last decade and what factors have played the key role in patients' quality of life. In fact, the goal of this review of reviews was to identify the impact of breast cancer and its treatment on quality of life and to determine ways to improve quality of life in breast cancer patients.

Definition
Quality of life or specifically health-related quality of life was defined as breast cancer patients' perception of their own physical, mental and social health that influenced by diagnosis, treatment, post-treatment, and survivorship as assessed by using well validated instruments.

Search engines and time period
Studies identified through the available literature in MEDLINE (PubMed), and Goggle scholar to identify review papers on health-related quality of life in breast cancer. Also, an extra search was performed to check reviews indexed in the Cochrane Database of Systematic Reviews (CDSR). Current study covers all full review publications that appeared in English language biomedical journals between January 2008 and 31 December 2018.

Search strategy
This study used comprehensive evidence map of overview of systematic reviews introduced by Lunny et al. [8]. All databases were searched using the combination of keywords 'quality of life' and 'breast cancer' or 'breast carcinoma' in the titles of publications and limited to review articles. This provided the initial database for the review. Initial search was carried out in late January 2017, twice on March, and August 2017 and once for a final update on February 2019. A manual search also was performed for possible additional references. Key words and search strategy were as follows: (

Selection criteria
Eligibility criteria for inclusion were: all review papers that published in English language, and reviewed quality of life as a main outcome in breast cancer patients. All other papers were excluded. All publications were screened using the PRISMA guideline. The AMSTAR checklist is used to assess the quality of reviews [9].

Data synthesis
Data obtained from each single review were synthesized by providing descriptive tables reporting authors' names, publication year, type of review, number of databases and studies included, analysis, and whether performed quality appraisal and risk of bias assessments. The findings were presented chronologically.

Statistics
A total of 955 unique review articles were identified. In addition, 19 citations were found via manual search (n = 974). After removing duplicates, commentaries and brief communications, 104 reviews seemed relevant for further evaluation. Finally, of these 81 quantitative and one qualitative review were found eligible and included in the study. The study flowchart is shown in Fig. 1. According to the AMSTAR checklist, approximately 85% of the publications had value of 4 or more for methodological quality (Fig. 2).

Overall outlook of reviews
In general, although not having the same quality, currently reviews, systematic reviews and meta-analyses regarding QOL in breast cancer patients are increasing (Fig. 3). However, to summarize evidence, reviews were categorized into the following main topics: reviews on measurements and methodological issue, reviews that dealt with different treatments, and those reviews that touched other topics such as supportive care, physiological distress, age-related reviews, quality of life in different nations/races and qualitative reviews. These are presented in the following sections.

Quality of life measurement
(1) Instruments used There were 17 papers that reviewed literature on instruments to quantify quality of life in breast cancer patients [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. In general, there were three types of instruments: generic, specific, and measures assessing psychological issues or breast cancer related symptoms. Among generic measures the Short Form Health survey (SF-36) and the brief version of World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) had a good performance [20]. Also, the European Organization for Research and Treatment of Cancer quality of life core cancer (EORTC QOL-C30) questionnaire and the Functional Assessment of Cancer Therapy/Functional Assessment of Chronic Illness Therapy (FACIT) were the most commonly used questionnaires [12,13]. Reviews also found that specific measures including the Functional Assessment of Cancer Therapy-Breast quality-of-life (FACT-B) and the European Organization for Research and Treatment of Cancer quality of life core breast cancer (EORTC QLQ-BR23) were the frequently used specific QOL instruments in breast cancer patients [13,[18][19][20]. The FACT-ES and the Hot Flash Related Daily Interference Scale (HFRDIS) had good applicability for patients who receive hormonal treatment and who have hot flashes [17]. A systematic review of QOL instruments in long-term BCS indicated that the Quality of Life in Adult Cancer Survivors Scale has acceptable reliability, • QOL was not a main outcome (n=16) • Full text was not available (n=4) 82 final reviews included validity, and responsiveness [14]. The findings are summarized in Table 1.
(2) The challenges exist Three papers critically reviewed the literature and pointed out that some shortcomings exist among studies reporting quality of life in breast cancer patients. As such a review on quality of life in breast cancer patients who received breast conservation surgery echoed that instruments do not address all important surgery-specific and psychometric issues of oncologic breast surgery patients [10]. Similarly, a systematic review conducted to guide treatment recommendations in breast reconstruction based on patient-reported outcomes and HRQOL revealed that sound scientific methodology in HRQOL were undermined by poorly designed and underpowered studies. The review recommends that studies on the topic 'should incorporate sensitive and condition-specific patient-report outcome measures, provide adequate sample sizes, and respect established guidelines for rigorous HRQOL methodology' [11].
Recently a review including 49 RCTs in locally advanced and metastatic setting concluded that the absence of QOL research hypotheses and overemphasis on statistical than clinical significance is still problematic in measuring quality of life in breast cancer patients. The authors pointed out that 'although most of the experts' recommendations have been broadly followed by the research community during the past decade, the specification of the HRQOL research hypothesis is still underreported' [21].

Treatment
A summary of reviews that focused on different treatment modalities and quality of life are presented in Table 2  .
(1) Systemic therapy Seventeen reviews were focused on HRQOL in patients undergoing systemic therapy including chemotherapy, hormonal therapy, and targeted therapy. Of these, the effect of endocrine therapy alone or combined with adjuvant treatments was the center of focus. Hot flashes were the most common side effect of adjuvant endocrine therapies. Side effects of tamoxifen and aromatase inhibitors including vaginal dryness, vaginal discharge, dyspareunia, and arthralgia were often reported in reviews [28]. A review assessing the impact of adjuvant endocrine therapy in early breast cancer on QOL found that in most        [41]. Despite the current guidelines considering that hormonal therapy is contraindicated in breast cancer survivors, recently a review suggested that in some women, menopausal symptom relief might be more important than the potential risks of hormonal therapy. The review concluded that on the use of hormonal therapy and tibolone in newly diagnosed patients, survivors or suspected to breast cancer will remain contraindicated [44].
(2) Local therapy including surgery and radiotherapy Six reviews addressed the impact of local therapies on quality of life [30, 35-37, 42, 48]. For example, one review found that there was worse body image, disturbances in sexual life as well as great impairment in advanced breast cancer patients after mastectomy [42]. Patients receiving immediate and delayed breast reconstruction experienced increased satisfaction and QOL after reconstruction, and in long-term follow-up, both groups have reported similar satisfaction and QOL scores [48]. Marta et al. found that HRQOL has been infrequently investigated in RCTs in patients who received radiotherapy. QOL can be an important predictor of better treatment outcomes, as significant benefit in HRQOL was often reported once a positive primary outcome was reported [45].

(3) Side effects of treatments
Five reviews focused on side effects of treatment modalities including topics related to fatigue, insomnia, cognitive dysfunction, reproductive and menopausal symptoms and lymphedema [33,34,38,53,54]. A review of randomized clinical trials found that these symptoms were the most common symptoms affecting survivors' quality of life [33]. Lymphedema in early-stage breast cancer patients who undergo axillary lymph-node dissection is an important concern. The results derived from a total of 8 studies have shown that impact of manual lymphatic drainage had a significant impact on HRQOL, but a recent published review failed to find that the impact of decongestive lymphedema treatment, the most effective treatment to be offered, on patients with early lymphedema due to the weak evidence [53,54].
(1) Physical activity (supportive exercise intervention) There were 6 systematic reviews on physical activity and quality of life in breast cancer patients. Overall, evidence suggests that physical activity could enhance quality of life and reduce symptoms [55,58,60,61,64,69]. For instance, a meta-analysis consisting of 5544 patients found that exercise interventions such as aerobic, Tai Chi, yoga, stretch training, and resistance training in survivors had statistically significant effects on overall QOL and breast and arm symptoms [61].

(2) Complementary and alternative medicine (CAM)
A variety of reviews assessed the effect of complementary and alternative medicine including diet and dietary supplements, energy therapies, manipulative and body-based practices, and mind-body techniques on the QOL aspects. Reviews on the effect of CAM on symptoms showed a significant improvement in symptoms [63]. One study of reviewing publications targeted mind-body exercise including yoga, Tai Chi chuan, and qigong found that breast cancer patients' psychological quality of life benefited from yoga, while physical elements of quality of life were not supported [68]. Yoga is the most studied mind-body therapy. Reviews focusing on the effect of yoga on quality of life among survivors showed that although the literature provided evidence of health related quality of life benefits or significant effects of yoga on reducing fatigue and sleep disturbances, for example, [58,66,70], any specific aspect of yoga was not recognized as being most advantageous [57]. The results of a meta-analysis including 951 patients on mindfulnessbased therapy on QOL aspects indicated an improvement of this therapy on reducing anxiety, depression, fear of recurrence, and fatigue associated with breast cancer [65]. However, a systematic review of the effect of art therapies on anxiety and depression indicated that such interventions could have a significant effect on patients' reduced anxiety [57].

Psychological distress
Reviews concerning psychological issues and quality of life are presented in Table 4 [73][74][75][76][77][78][79]. Psychoeducational support found to be effective in improving breast cancer symptoms and emotional well-being among breast cancer patients [76]. In addition, a review found that reported psychological distress including anxiety and depression were common among breast cancer patients [75] and the treatment of depression could have an important role on improving QOL and increasing longevity [74].

Age-related reviews
Descriptive characteristics of reviews concerning quality of life in young and elderly breast cancer patients are      Table 5 [80][81][82][83]. A review on long-term survivors indicated that it seems older patients are better prepared mentally to deal with treatments, despite of having co-morbidities [80]. While a study on young survivors reported greater fear of death, unmet supportive care needs, financial constrain, and minor physical well-being. Spiritual well-being aspects seemed favorable among this subpopulation. However, these patients generally experience suboptimal HRQOL after breast cancer diagnosis [83].

Assessment of quality of life among nations/races
A number of reviews [84][85][86][87][88][89][90][91] addressed the quality of life among breast cancer patients of different races for instance African American patients [84,88], or among different nations such as Spanish breast cancer patients [85], Latina and non-Latina breast cancer survivors [86], Indian breast cancer patients [87], Arab women [89], Asian breast cancer patients [90] and Iranian breast cancer patients [91] (Table 6). Good scores of global health were recorded for in both African American and white survivors [84,88], but it was reported that Latina breast cancer survivors on average experience worse QOL than non-Latina whites [86]. Asian breast cancer patients with comorbidities and those who treated with chemotherapy, having less social support, and with more unmet needs, had poorer HRQOL [90]. Limited information on quality of life in Arab women with breast cancer patients exist [89].

Qualitative reviews
Although some reviews included both quantitative and qualitative studies [84,86,89], there was only one review that exclusively reviewed qualitative studies [32]. The review included seven qualitative studies focusing on quality of life of breast cancer patients during and up to 10 years after treatment. Studies were from both developed and developing countries. The review generated three synthesized findings: to achieve effective care, clinicians are required to be aware of the impact of the disease and its treatment on physical and psychosocial domains of quality of life, for effective patient-centered care, they need to know about these effects on social relationships; finally, clinicians should be aware that women use religion and spirituality in order to cope with breast cancer treatment and to improve their own quality of life [32].

Achievements so far and a brief synthesis
During 2008 to 2018 the number of reviews increased to 82 compared to 29 reviews during 1974 to 2007. This in fact is a reflection of the increase in the number of studies on quality of life among breast cancer patients worldwide. Of these, reviews emerging from less developed countries were evident. Even though the quality of these reviews was relatively poor, data from such studies surely provided more understanding on quality of life in breast cancer patients with different cultural backgrounds. According to the AMSTAR on average above 85% of publications had moderate to high quality, as we shown in Tables 1, 2, 3, 4, 5 and 6, but a considerable number of published reviews lacked standards for reporting, 56 out of 82 (68%) did not followed the PRISMA, 51% did not performed quality assessment, and 75% did not reported how risk of bias was evaluated. However, it is difficult to synthesis the data, we provided a tabulated summary of factors that might improve or decrease (worsen) quality of life in breast cancer patients. The summary is derived from review papers that included in this overview (Table 7).

Patient reported outcomes
Instruments introduced to quantify quality of life in breast cancer patients have developed frequently over the last decade. From the health professionals' and patients' views among specific measures, the EORTC QLQ-BR23 and the FACIT-B were the most acceptable instruments. However, despite of reporting the good performance for these measures [17][18][19][20], others found that current instruments do not address important specific issues such as surgery-specific conditions [10]. In addition, a recent review suggested that developing well-designed and more specific tools are needed to evaluate the side effects of novel therapies [21]. We believe that there is no need to develop new instruments, and rather if needed could add extra items to the existing questionnaires to fill the gaps as the EORTC quality of life study group did. They currently updated the EORTC QLQ-BR23 and introduced the QLQ-BR45 to cover all existing gaps. Two main reasons for this revision was indicated: the obvious changes in standard therapy and consequently emergence of new therapies that led to new different side effects, and the impacts of new drugs on patient's quality of life [92,93]. Above all we think the new direction for setting international standards for the analysis of quality of life and patient-reported outcomes in cancer trials is a step forward to prevent disorganized reporting, and to encourage using appropriate instruments to measure quality of life in cancer patients in general and in breast cancer patients in particular [94][95][96].

Methodological issues
A number of reviews indicated that although methodological issues improved greatly, still reviews suffer from poor transparency in reporting on quality appraisal and  risk of bias assessment. A review indicated that the sound scientific methodology in HRQOL was undermined by poorly designed and underpowered studies [11]. The current overview indicated that although all reviews have considered the principle components of AMSTAR checklist, the vast majority of reviews not included publication bias. However, the quality of reviews published during the last decade seems did not changed so much and thus that there is a need to further increase their quality. One way to achieve this might be registration of reviews in PROSPERO (International prospective register of systematic reviews).

Treatment modalities
Quality of life can be an important predictor of better treatment outcomes [45]. A review, as an example, indicated that most studies reported increase in long-term satisfaction among patients who underwent surgery [48]. However, as a recent review suggests quality of life in breast cancer patients who receive surgery even might depend on decision-making process and communication style of care physicians. As such the review found that patients who received physician-dominated communication had lower physical function compared with those who took a more active role in their treatment choices processing [97]. This therefore sustains the need to increase the patients' information in order to prevent decisional regret, a common phenomenon after breast reconstruction [98]. In fact, this reflects a previous recommendation to clinicians that: there is a long life after breast cancer and clinicians should consider this while discussing treatment options with patients [33].

Physical activity
Studies and reviews on physical activities have received much attention over the last decade. Reviews showed that interventions based on physical activities have not only improved breast cancer patients' quality of life, but also could reduce symptoms including breast, arm and early menopausal symptoms [55,75]. Moreover, positive effects and significant benefits of supervised combined aerobic resistance exercise on fatigue and QOL were reported in patients during their adjuvant radiotherapy [63]. Overall, one might argue that simple and inexpensive interventions or scheduling social events or even providing the green environments and neighborhoods might help to improve quality of life in breast cancer patients.

Alternative therapies
Studies suggest that complementary and alternative therapies have achieved the potential of integrating into clinical practice [56]. However, according to the existing evidence with regard to CAM, yet, further high quality randomized clinical trials or longitudinal studies are required to evaluate net benefits of such treatments on quality of life of breast cancer patients [56,63]. Yoga as a complementary therapy was frequently recommended in reviews. It seems that since practicing yoga as mindbody exercise could enhance psychological and social well-being, thus it could improve quality of life among breast cancer survivors [68]. Based on the quality of the evidence, for instance, an evidence (with moderate quality) supported the recommendation of yoga as a supportive intervention for improving HRQOL and reducing fatigue and sleep disturbances when compared with no therapy, as well as for reducing depression, anxiety and fatigue, when compared with psychosocial/educational interventions [62]. In spite of suggesting yoga in most studies, a review found that the most advantageous aspect of yoga is still not clear [57].

Symptoms
Symptoms including anxiety, pain, fatigue and menopausal symptoms can significantly impact patients' daily live activities and subsequently their quality of life. It appears that the more affecting symptoms in breast cancer patients are still neglected topics in reviews. Studies are required to be carried out on symptoms' burden and functional decline in breast cancer patients and survivors. The most frequently reported bothersome symptoms in breast cancer survivors were fatigue, insomnia, depression, cognitive dysfunction, reproductive and menopausal symptoms, and lymphedema [33]. Physical, psychological and emotional well-being of breast cancer patients are affected by lymphedema [53]. Reviews referenced to the treatment of lymphedema indicated that depending on the type of therapy such as manually lymphatic drainage or combined decongestive therapy, a significant positive impact on patient's quality of life is observed [16,53], although recently it has been suggested that still there is a need for high-quality evidence to talk about the effectiveness of combined decongestive therapy [54].

Psychological interventions
'The day you lose your hope is the day you start to die' is a key sentence that implies the key role for psychological interventions in improving breast cancer symptoms and enhancing patients' quality of life [99]. Psycho-educational support, for example, in improving breast cancer symptoms and in improving emotional well-being is an effective intervention [76]. Moderate to strong evidence reported a relationship between fatigue and depression, anxiety, pain, sleep disturbances, insufficient physical activity, and difficulties with coping with cancer, all of which can be addressed in psychological interventions [79]. Cognitive behavior therapy as an effective therapy in reducing symptoms and in improving QOL and psychological health of survivors has been reported [78]. Interestingly, it can be seen that joint effect of behavioral techniques and physical exercise can improve psychosocial functioning and HRQOL in breast cancer patients and survivors further [74]. In addition, as recently suggested, specific mindfulness activities also might help patients of all ages to cope with their diagnosis [99].

The elderly and quality of life
Overall, we found that elderly patients reported moderate to good quality of life. Older patients are perhaps better equipped mentally to deal with treatments compared to younger patients [80]. According to the findings of a review, the impact of local or systemic treatments on QOL in the elderly early-breast cancer patients was maintained or improved [31] or adjuvant chemotherapy and radiotherapy did not have detrimental effects on QOL in most elderly patients with solid tumors [52].

Limitations and the future directions
One should note that this review of reviews has some limitations. The main critic is the fact that it is difficult to evaluate in what way the results add to existing knowledge since 82 reviews with different objectives were evaluated. While a more focused and in-depth reviews are recommended, it is useful to bear in mind that this review of reviews in fact is a bibliometric analysis of review papers and provides a representation of what achieved during the last decade studying quality of life in breast cancer patients. We believe this even could highlight repetitions, discrepancies, and indicate areas that require more investments. For instance, we noticed that although reviews included both breast cancer patients and survivors, no specific reviews on quality of life in breast cancer survivors could be identified. Perhaps this is an area that could be addressed independently since there are differences in quality of life between newly diagnosed breast cancer patients, patients who are receiving different treatments, and the long-term survivors who successfully completed their treatments and now they have back to normal life. Survivorship in breast cancer patients is a very important and relevant topic and deserves more attention. Finally, it is important to notice that this review of reviews did not separate the interventional studies from other types of studies (usually descriptive or correlational). Perhaps a better organization might be to reporting reviews based on separate objectives. However, we have tried to provide a summary table (Table 7) which could help to identify factors that might improve or deteriorate quality of life in breast cancer patients.

Conclusion
Quality of life in breast cancer patients improved greatly during recent years as several simple but effective interventions such as physical activity and psychosocial interventions proved to be effective. However, symptoms caused by different treatment modalities are still under estimation and need more serious attention. Pain, lymphedema, worry, sexual function especially for young