Breast cancer is the most common cancer among women around the world (22). It was estimated that 129,300 women died due to breast cancer in Europe in 2008 (Reference Ferlay, Parkin and Steliarova-Foucher6). Previous studies reported breast cancer as first prevalent cancer among Iranian women (Reference Sadjadi, Nouraie and Mohagheghi19). A recent study reported an age standardized incidence rate of 23.65 per 100,000 females for 2006 in the country (Reference Mousavi, Gouya and Ramazani16). The results of burden of disease survey showed that mortality rate of breast cancer was 2.7 per 100,000 women population and estimated 16,040 years life lost in the twenty-three provinces of country in 2003 (Reference Naghavi17). Moreover, the examination of breast cancer trend over 20 years showed that despite relative improvement in patients’ status, most patients are in advanced stage of disease in country (Reference Harirchi, Kolahdoozan and Karbakhsh8). In addition to these, it was reported that breast cancer affects women at least one decade younger than their counterparts in developed countries (Reference Harirchi, Karbakhsh and Kashefi7) and this may lead to longer duration of living with disease and in turn, higher expenditures for patients, their families, and society. Hence, prevention and treatment of breast cancer with cost-effective strategies should be considered as a health priority in Iran.
Trials have shown that adjuvant therapy reduces the risk of recurrence and death from breast cancer (5). There are different therapeutic regimens which are used as adjuvant therapy in breast cancer. Docetaxel with doxorubicin and cyclophosphamide (TAC) and 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) are two of these regimens. Comparison of TAC with FAC in a randomized controlled trial showed that although adjuvant therapy with TAC was associated with higher adverse effects, it significantly improved the rate of disease-free and overall survival in node-positive breast cancer (Reference Martin, Pienkowski and Mackey14).
The results of recent studies in Iran showed that although TAC had a more negative impact on QoL during chemotherapy, it created a higher improvement than FAC during 4 months since the end of treatment (Reference Bastani and Ahmad Kiadaliri3;Reference Hatam, Ahmadloo and Ahmad Kiadaliri9). TAC, however, is expected to be more costly than FAC, possibly due to the management of its side effects.
To determine the cost-utility of TAC versus FAC in Iranian healthcare system, we performed an economic evaluation study using data gathered in a clinical setting in the south of Iran.
METHODS
Patients and Treatment
In a double-blind cohort study, one hundred node-positive breast cancer patients were divided into two chemotherapy groups by physicians' decision: TAC (n = 32) and FAC (n = 68). Study was done between September 2008 and February 2010 in a hospital radiotherapy center in the south of Iran. Decision on allocating patients between two groups was based on severity of disease and patients who were in more advanced stage of disease usually received the TAC regimen and randomization was not applied. However, the patients and researchers were blind to this allocation.
Patients in TAC arm received 75 mg/m2 docetaxel, 50 mg/m2 doxorubicin, 500 mg/m2 cyclophosphamide intravenously (IV) in each session for six times every 3 weeks that prolonged approximately 4 months. During same period, participants in FAC arm received 500 mg/m2 5-flurouracil, 50 mg/m2 doxourbicin, and 500 mg/m2 cyclophosphamide. Patients were followed during 4 months after completing the chemotherapy cycle by their physicians monthly except those who needed more care in the hospital.
Patients gave their consent to participate in study and filled in QoL questionnaire. The study was approved by ethics committee of Shiraz University of Medical Sciences. No severe and serious co-morbidities were reported during the chemotherapy cycle that made patients quit their treatment or change their protocols; in addition there were no cases of death in study period possibly due to they were early stage breast cancer patients.
Inclusion & Exclusion Criteria
Patients with severe renal failures; hepatic impairments; karnofsky performance status less than 70; age older than 75 years; and all the cases of metastasis and node negative were excluded.
All patients younger than 75 years with node-positive (>1) were included.
Outcome Measurement
Quality-Adjusted Life Years (QALY) was used as outcome measure. Details on measuring the health related quality of life (HRQoL) were described elsewhere (Reference Bastani and Ahmad Kiadaliri3;Reference Hatam, Ahmadloo and Ahmad Kiadaliri9). In summary, before treatment, in last session of treatment, and 4 months after the end of chemotherapy the HRQoL was assessed using the standard questionnaire of European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) (Reference Aaronson, Ahmedzai and Bergman1). As the scores in EORTC QLQ-C30 are not utility-based, these scores were mapped to 15-D (Reference Sintonen20) and EuroQoL 5D (EQ-5D) (Reference Brooks4) using equations in Kontodimopoulos et al. (Reference Kontodimopoulos, Aletras, Paliouras and Niakas10) which were previously applied in another economic evaluation study (Reference Soinin, Garcia San Andres and Joensuu21). Then, differences in utility scores between different points of time (0, 4, and 8 months) were calculated and multiplied in related time period to get QALY gained for each arm.
Cost Measurement
The costs were identified and measured from third-party payer perspective. Thus, only the direct medical costs of treatment and follow-up were considered. These include adjuvant therapy, other relevant drugs, physicians' visits, consultation with the other specialists, hematological and radiological exams, and admissions in the hospital because of treatment's side effect. A checklist was designed to gather these data from hospitals records and health insurance organizations. The time horizon of study was 8 months, and data was gathered for this period.
All costs are expressed in Iranian Rial (1 Rial = USD 0.0001) and were converted to 2008 price level.
Incremental Cost Effectiveness Ratio
Having measured and valued the costs and outcomes, the incremental cost-effectiveness ratio (ICER) was calculated as follows:
In nominator, the differences in average costs per patient in two arms were calculated. This figure, then, was divided on differences in QALY between two groups to get the cost per QALY gained of TAC compared with FAC.
Sensitivity Analysis
To assess the robustness of the study results, a two-way sensitivity analysis was performed. In consultant with experts in health insurance organization it was decided to change the cost as 10 percent in both groups. At the same time, the improvements in utility scores after treatment (over follow-up) were increased as 25 percent for both groups based on clinicians opinions and literature.
RESULTS
Table 1 shows the demographic and socioeconomic characteristics of patients in baseline. The mean age was 49.29 ± 11.59 and 46.71 ± 8.23 years in FAC and TAC groups, respectively. All patients were members of one of health insurance organization in country and have access to coverage provided by these organizations.
Clinical and Socioeconomic Characteristics of Patients in Baseline
Table 2 shows the costs of health services consumed in both treatment groups. It can be seen from Table 2 that in both groups, chemotherapy drugs constitutes the main component of costs. Moreover, on average, the management of adverse events for a patient in TAC group was approximately five times more costly than counterpart in FAC arm. The total cost of treatment was 39490010.6 Rials (USD 3949) and 2559622.3 Rials (USD 256) per patient during 8 months in TAC and FAC groups, respectively. This differences in cost was statistically significant based on Wilcoxon sum rank test (p < .001).
Total Costs (USD) of Treatments Over Study Period
Table 3 shows the mean values of EORTC QLQ-C30 scales which were used to map to 15D and EQ-5D based on regression model from Kontodimopoulos and colleagues (Reference Kontodimopoulos, Aletras, Paliouras and Niakas10), before the onset of treatment in two groups. As can be seen from this table, there were no significant differences in HRQoL scores between two groups before the onset of treatment. Corresponding 15D utility weights for these level of HRQoL are equal to 0.746 for both groups (p = .93). This figures were 0.720 and 0.718 using EQ-5D in FAC and TAC groups, respectively (p = .61).
The Mean of HRQoL Scale Values Before the Onset of Treatment
a A higher score represents a better functioning.
b A higher score represents a worse symptom.
The mean values of HRQoL scales and corresponding utilities in last session of treatment and 4 months after the end of treatment have been reported in Table 4. Utility weights calculated by 15D and EQ-5D showed that patients in TAC arm experienced a higher deterioration than FAC during treatment. However, over 4 months follow-up, the patients in TAC arm had higher improvements in their utility and reached to same level as FAC group.
The Mean of HRQoL Scale Values and Corresponding Utilities in Last Session of Treatment and 4 Months Later
Note. *β coefficients from Table 3 in Kontodimopoulos et al. (Reference Kontodimopoulos, Aletras, Paliouras and Niakas10). These are used to predict 15D and EQ-5D utility scores from EORTC QLQ-C30.
a The mean value of scale in sample
b Outcome = scale value x multiplier
Utility weights at 4 and 8 months were multiplied in related duration (4 months for treatment period and 4 months for follow-up) and then were summed to calculate the QALYs. Using 15D equation, the QALY was equal to 0.471 and 0.486 for TAC and FAC groups, respectively (p < .001). These figures for EQ-5D equation were equal to 0.427 and 0.457 (p < .001).
Incremental Cost Effectiveness Ratio
The results showed that TAC regimen was more expensive and less effective than FAC over 8 months of study period. This means that there is a dominant option (FAC regimen), and there is no need to calculate the ICER.
Sensitivity Analysis
The two-way sensitivity analysis showed that results were insensitive to changes in cost and utility values. This showed the robustness of the results against uncertainty in variables.
DISCUSSION
The aim of this study was to perform a cost-utility analysis of TAC versus FAC in women with node positive breast cancer. To our knowledge, this is first full economic evaluation study in breast cancer patients in Iran.
Results showed that patients in TAC regimen experienced a more intensive deterioration in HRQoL and utility scores during treatment than FAC ones. This higher deterioration in TAC was caused that despite higher improvements in HRQoL and utility scores for TAC over follow-up, the QALY was lower for TAC than FAC over study period. This observed deterioration of HRQoL during treatment and improving over time is in accordance with other studies in breast cancer (Reference Larsson, Sandelin and Forsberg11;Reference Martin, Lluch and Segui13;Reference Martin, Pienkowski and Mackey14).
The cost of treatment per patient in TAC was approximately fifteen times higher than FAC arm. The main cost drivers were chemotherapy drugs in both arms. Moreover, the management of adverse effects in TAC group was more costly than FAC. Similar findings were reported by previous economic evaluation studies (Reference Au, Golmohammadi and Younis2;Reference Lee, Jee and Chung12;Reference Mittmann, Verma, Koo, Alloul and Trudeau15;Reference Wolowacz, Cameron, Tate and Bagust23) over 5–10 years and life time follow-up.
In terms of incremental cost-effectiveness analysis, the results showed that FAC was a dominant option against TAC in the 8 months of study period. This is in contrast to the previous economic evaluation analyses of TAC against FAC (Reference Au, Golmohammadi and Younis2;Reference Lee, Jee and Chung12;Reference Mittmann, Verma, Koo, Alloul and Trudeau15;Reference Wolowacz, Cameron, Tate and Bagust23). For example, Au et al. (Reference Au, Golmohammadi and Younis2) over 10 years of follow-up found that TAC would lead to a gain of 313 QALY (370 life-years) at an additional 5.8 million Canadian dollars. The main explanation for this difference between current and previous studies is related to differences in time horizon of studies. While the time horizon of our study is 8 months, the previous studies modeled 5–10 years and life time costs and effects of these treatments. It seems that long-term benefits of TAC compensate its more side effects during chemotherapy and, hence, it was cost-effective compared with FAC in previous studies. The lack of data on costs and effects in longer-term limited the possibility of capturing full effect of these treatments over life time by conducting a long-term economic evaluation model for Iran. This restricts the generalizability of our findings.
Although, the nonrandomized and uncontrolled design of the study may cause bias in our results, it makes it closer to routine practice in clinical setting.
The small number of participants may limit the generalization of the results to other setting, as these patients may not be representative for all Iranian patients specially those who are treated in nonpublic centers. Moreover, the utilities were estimated using mapping and these scores may not represent the utility weights for Iranian patients. In other words, while mapping is increasingly used to measure health state utility values when those are not directly available, these values are subject to uncertainty (Reference Soinin, Garcia San Andres and Joensuu21). For example, Rowen et al. (Reference Rowen, Brazier and Roberts18) found that mapping of SF-36 into EQ-5D is not accurate and reliable for more severe EQ-5D health states. These issues should be considered in interpreting our study. Our results may not be directly transferable to other jurisdictions also due to third party payer perspective and the time horizon.
In summary, there were similarities between current study with previous studies in terms of costs and outcomes of TAC versus FAC during short-term. However, in terms of cost-utility analysis the shorter time horizon of current study was resulted in a different conclusion compared with previous ones. The results of the study showed that FAC was a dominant option compared with TAC in short-term. Indeed, the higher improvements in HRQoL after treatment in TAC could not compensate the deterioration caused during treatment in short-term. We suggest that there is a need for a long-term economic analysis whenever data is available to informed decision making. We hope that current study can bring the interests of policy makers and researchers to conduct economic evaluation studies in healthcare system of Iran.
CONTACT INFORMATION
Peivand Bastani, MSc, PhD student, Department of Health Services Management, Tehran University of Medical Sciences, Tehran, Iran
Aliasghar Ahmad Kiadaliri, MSc, PhD student, Division of Health Economics, Department of Clinical Sciences–Malmö, Lund University, Sweden; Department of Health Management and Economics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
CONFLICTS OF INTEREST
Both authors report they have no potential conflicts of interest.
