A systemmatic literature review on indirect costs of women with breast cancer

Breast cancer has now surpassed lung cancer as the leading cause of global cancer incidence in 2020, with an estimated 2.3 million new cases, representing 11.7% of all cancer cases [1]. The global incidence of breast cancer in women is estimated to reach as many as 3.2 million new cases annually by the year 2050 [2]. Breast cancer is the fifth leading cause of cancer deaths worldwide and is estimated to have caused 684,996 deaths in 2020 [3]. Incidence rates for breast cancer far exceed those of other cancers in both transitioned (55.9 per 100,000) and transitioning (29.7 per 100,000) countries [1]. Breast cancer is considered the primary cause of woman mortality worldwide, accounting for 15% of total mortality among women [4]. According to the American Cancer Society, one in eight women experiences breast cancer during her life [2]. However, the prevalence of breast cancer in developed countries is higher than that in developing countries, also known as low- and middle-income countries (LMICs); nonetheless, the prevalence of breast cancer has recently been growing in LMICs as well [4].

The impact of this disease is clear not only in terms of mortality and morbidity but also in terms of economic consequences for all National Health Services (NHSs) and from a social point of view [5, 6]. The three cancers with the highest economic burden in the world are lung cancer ($188 billion), colon/rectal cancer ($99 billion), and breast cancer ($88 billion) [7]. Therefore, studies on the economic burden of diseases are valuable because of the rising costs of cancer diagnosis and treatment [8].

Ranganathan et al. suggested that due to the high economic burden of breast cancer in LMICs, the need to improve the management of patients with breast cancer in these countries is of great importance [9]. In this regard, various studies have been conducted on the economic burden of breast cancer in LMICs such as Iran [8, 10]. Also, studies have shown that different breast cancer treatments can impose different costs on society and patients [5, 6]. Cost of illness studies can be very helpful in determining the cost effectiveness of diagnosis and treatment of the disease and thus the optimal use of resources.

The cost of illness is investigated using a variety of methods [11]. From a social perspective, the cost of a disease consists of three main components: direct costs, indirect costs, and intangible costs [6]. Indirect costs are caused by the productivity loss resulting from disease or treatment side effects, which also affect patient’s family and those who care about them [6]. Indirect costs consist of two parts, temporary and permanent. The temporary indirect costs are the reduction of productivity due to disability and the permanent indirect costs are the loss of productivity due to mortality [12]. Indirect costs are an important component of costs of illness studies, especially in the management of chronic diseases that may require lifelong treatment [13]. In addition to medical and therapeutic expenses, women must shoulder the costs pertinent to missed work days or productivity costs in paid employment or at home [14‐16]. Absenteeism can vary from a few weeks to several months. The risk of job loss among people diagnosed with cancer is 1.3 times higher than those without cancer [17]. Even when diagnosed at an early stage, breast cancer can adversely affect an individual’s ability to work for up to 5 years after the original diagnosis [18].

Factors associated with impaired productivity include adverse effects and treatments, such as progression and exacerbation of disease, cognitive and neurological disorders, poor physical and mental health, chemotherapy, and the time and cost required to receive treatment [19]. In Zheng et al.’s (2016) study, nonelderly women with breast cancer, compared with other people, significantly experienced job incapacity (13.6%), including reduced productivity at work (7.2 days) and at home (3.3 days) [20]. In another study, reduction in productivity due to adverse effects from breast cancer in the Netherlands and Sweden was 68% and 72% respectively [21]. Some patients may never return to work due to disability or premature death. Between 2012 and 2018, the lost productivity cost of premature deaths due to cancers in Iran has increased from $2453 million to $2887 million (An 18% increase) [22]. The issue of indirect costs is important in high income countries due to increasing prevalence rates of breast cancer in these countries [23]. Indirect costs are critical in LMICs not only because the growing burden of cancers in LMICs—but also issues of resources and affordability [4, 24, 25].

Despite the simplicity of expressing the components of indirect costs, the proper method of measuring and evaluating the productivity costs of breast cancer can be problematic. There are several methods to measure indirect costs [26]. The most accurate estimation of indirect costs requires the use of micro-costing methods; thus, it requires relatively large sample sizes, well-designed protocols, and well-trained interviewers [11, 27]. In an economic evaluation, the methods used for the measurement and evaluation of productivity costs can affect the results of the studies [26]. The use of different methods for calculating the productivity costs may impede the comparison of results between countries. Possible reasons for the differences in indirect costs include methodology, the value of local productivity, disease and patient characteristics, social security systems, and epidemiologic environments [28].

Therefore, the aim of this study was to systematically review the indirect costs and the monetary value of productivity costs due to breast cancer in women.

This systematic review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [29].

We conducted a systematic review of recently published studies on the indirect costs of breast cancer with the goal of identifying those whose methodological similarities would allow us to make comparisons and draw conclusions from the indirect cost burden of the disease [63]. According to evidence, cancer patients and their companions face high indirect costs. Indirect costs of cancer are the monetary losses associated with time spent receiving medical care, time lost from work or other usual activities (morbidity costs), and productivity costs due to premature death (mortality costs) [14].

The evaluation of the studies showed that most studies have calculated the productivity costs due to premature death, which can be because of easier access to the mortality data, while more data are needed to calculate other costs. The cost burden imposed by the productivity costs from premature death contributes profoundly to indirect costs and decreases productivity/efficiency. This number, as reported, ranges from $22,386 to $52 billion with the HCA and ranges from $1488.61 to $4,518,628.5 with the FCA. Moreover, housewives, too, get diagnosed with breast cancer alongside working women, more often resulting in early death, further contributing to the premature death rate. The cost of informal care, which involves non-monetary assistance provided by those around the cancer patient, was also witnessed to be high. With the HCA, this amount ranged from $297,548.46 to $308 billion. This is because of the fact that basically a cancer patient needs to be supported by family or friends either to be accompanied to the treatment centre or to receive high quality treatment at home. This forces the accompanying person to take time off to serve the patient.

The current study found that the HCA was more commonly used to calculate indirect costs. This method calculates the monetary value deterred from the productivity costs due to disability or premature death based on a person's wage prior to disability or death. This is considered an easy approach employed by many studies owing to the ease of access to the required data. The drawback of this approach is that it only considers the work that gets paid and does not include costs associated with home care and responsibilities outside the work place as with the case of housewives.

The study noted that five studies used the incidence approach and three studies used the prevalence approach. The incidence approach only examined new disease cases, but the prevalence approach examined both new patients and patients from the previous years. Unfortunately, the heterogeneity of the studies made it impossible to combine the results together to provide a single output in this field. Thus, this necessitates more research in this area. When evaluating indirect costs, the study perspective should be either focused on patients or communities. In addition, the community perspective tends to be the one widely used in the studies.

The magnitude of variability can be explained by the finding that different indirect cost elements are evaluated. Moreover, different methodologies for evaluating the same cost elements were used, and country differences can also provide reasoning to some extent [64]. Various methods were used to collect the data. These include questionnaire-based face-to-face interviews [40], telephone interviews [15], national study data [48‐50], and even international data [35, 36].

Comparing indirect costs between the studies revealed in the systematic review is very difficult because of the possibility of the application of two different methods: the HCA and the FCA [65]. The results generated with these methods cannot be compared since the HCA estimates potential productivity costs, whereas the FCA presents the real value of it; the results achieved with these two methods are not comparable [66]. It should be noted that the HCA estimates costs more than the FCA. When assessing the indirect cost calculation methods, the willingness-to-pay (WTP) methodology did not appear in the studies included in this review.

Due to the methodological heterogeneity of the studies included in the review, focus was given to the qualitative analysis [64]. Thus, a great variety of methods and indirect cost components were shown in the studies, and it was impossible to carry out a meta-analysis. This review showed that further research is needed due to the lack of information on the topic, and a precise methodology of indirect cost estimation must be developed [65].

It appears that since breast cancer did not cause morbidity to the extent of, the DALY index (the disability-adjusted life year) was not used except in two studies [35, 58]. The high cost burden of mortality is reflected in the loss of active labour in society. Regardless of whether a woman is employed or not, women are traditionally responsible for domestic production; thus, premature mortality reduces domestic production. On the other hand, although gender wage gap exists where women are usually, on average, paid lower than men, there is still no evidence of lower productivity of women from various studies [39]. The world mathematician community may better be able to understand the impact of indirect costs of breast cancer after the death of Maryam Mirzakhani from breast cancer.

The great variety of indirect costs resulted from different cost components and macroeconomic indicators that were used for estimation purposes [65]. Economic results are difficult to compare on account of monetary issues, such as fluctuating exchange rates and different purchasing powers of currencies. Domestic characteristics also dramatically affect resource consumption and unit costs, including differences in clinical practice and the health-care system framework [67]. Using many macroeconomic characteristics for the purpose of indirect cost estimation is one of the major reasons for the significant variety of costs [68].

With regards to indirect costs, studies usually considered the average wage or per capita as a representative of lost earnings on working days. However, wage rate in developing countries such as Iran may be lower than optimal/average due to low labour productivity, but this is not expressed in the indirect costs.

Methods used to estimate disease costs vary widely across studies in the literature, which is probably due to the lack of consensus on the methodology. Few studies have been carried out around the world with a control group [33, 50]. Conducting case–control studies on national and international levels to calculate indirect costs associated with breast cancer is not a practical idea.

However, it should be added that comparing the costs between a group of patients with a disease and others that match in terms of confounding variables lends a better understanding of the cost burden of the disease. A study in Iran showed that the covid-19 pandemic caused an average of 16.44 absenteeism days and cost of $671.4 per patient [69]. It should also be kept in mind that almost all the studies carried out considered the natural history of disease in diagnosis and treatment. After the outbreak of the Covid-19, studies have been conducted on the changes in the course of the disease and the delay in the diagnosis and treatment of breast cancer, which has also affected the indirect costs of the disease [70‐72].

A review of the studies showed that the researchers did not focus on foreseeing the indirect costs of this disease, and only one study foresaw the indirect costs of breast cancer [48]. Therefore, the definition of standards and consensus in the methodology selected to conduct these studies should be major concerns for the scientific community [67]. The review was limited to articles written in English, and we excluded non-English articles. Different studies accounted for different indirect cost elements and even used different methodologies for quantification.

The current review provides important evidence of indirect costs associated with breast cancer which enables the economic burden of breast cancer to be predicted. Evaluating and measuring indirect costs give a better grasp of the reasons for the decline in productivity, for instance, informal assistance from those around the patient to the patient, the productivity costs from missed work days, the cost resulting from premature death and the damping cost elicited through the analysis of indirect costs. Women today make up a large portion of the labour force, while still in some communities they are responsible for household chores; hence, more focus on the disease often associated with women could provide more insight on the disease burden and its impact on the economy. While the findings of this study could be used to distinguish indirect and direct costs of breast cancer, it will also be helpful in economic evaluations of different treatment methods for this disease. Furthermore, it is necessary to mention the study approach (whether calculations were based on prevalence or incidence) to designate the appropriate sample size. Our study found that the indirect costs of breast cancer add highly to the cost burden of the disease. Also, the heterogeneity of various study results does not allow a consensus to be reached; therefore, it is imperative to standardise calculations, and since most of the studies have been conducted in high income countries, policy makers of the healthcare in middle and low income countries must prioritise research of such contexts.