## Abstract

Background: Herceptin® (trastuzumab) is a humanized monoclonal antibody that is being tested in the adjuvant setting. Cost implications of using trastuzumab, as administered in the Breast Cancer International Research Group 006 trial, are being calculated. This provides information on the treatment's value for money.

Methods: Standard breast cancer treatment models were set up for different subpopulations according to stage (I, II, III) and menopausal condition (<50 and >50 years). Costs were calculated from the hospital's point of view, using the micro-costing method. Life expectancy data were based on literature. Our comparator was the existing practice. In addition to a sensitivity analysis, a threshold analysis on the prices of trastuzumab and docetaxel was performed to target an acceptable incremental cost-effectiveness ratio.

Results: Treatment costs were €45 034 (doxorubicin and cyclophosphamide → docetaxel and trastuzumab) or €47 765 (docetaxel, carboplatin and trastuzumab). This was largely (79% and 75%, respectively) attributed to trastuzumab. According to our threshold analysis, an acceptable incremental cost-effectiveness ratio can be reached if health improvements are large enough and/or price discounts are given.

Conclusions: Trastuzumab is a promising but very expensive antibody. With the current pressure on health-care budgets, cost implications of using trastuzumab in adjuvant setting must be calculated before use of the product becomes wide-spread. This provides essential information for price-setting policies and for policy makers considering reimbursement.

## introduction

Herceptin® (trastuzumab; Genentech, South San Francisco, CA, USA) is a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2), an important mediator of cell growth, differentiation and survival [1]. HER2 overexpression occurs in approximately 25–30% of human breast cancers [2, 3], and is associated with a poor prognosis, i.e. a greater risk of relapse and a decreased survival [36]. Trastuzumab has proven efficacy and safety in several clinical trials for patients with HER2-overexpressing metastatic breast cancer, as a single agent [79] as well as in combination with chemotherapy [1012]. Trastuzumab improves time to disease progression or median duration of response, response rate and survival. With respect to quality of life (QoL), the high tolerability of trastuzumab is very favorable [9, 13].

Owing to these positive evaluations in metastatic setting, trastuzumab is being tested as adjuvant therapy. Currently, there are four major randomized, multicenter trials of trastuzumab in patients with HER2-positive primary breast cancer. Two of them, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and Intergroup N9831 trials, are being conducted in the USA. The Breast Cancer International Research Group (BCIRG) 006 trial is being conducted globally and the Herceptin Adjuvant trial involves countries outside the USA [14]. In this analysis we focus on the BCIRG trial. The purpose is to give early information on treatment's value for money. This can support decision making before the product is widely spread.

## methods

Resource consequences of using a new technology in a non-trial situation may be unknown. In these circumstances, modeling can overcome the classical decision-maker's dilemma in which a decision has to be taken regarding a new drug based on information from randomized trials without disposing of data concerning the usage in real-life conditions [15, 16]. The basis is constructing a model which reflects real-world conditions [17].

### perspective

A model can be set up from different point of views. The purpose of the analysis determines the chosen perspective. We wanted to analyse the influence of using trastuzumab in adjuvant setting on real costs for a hospital. As a result, we constructed our model from the hospital's point of view. We did this more specifically for a university hospital, located in Flanders, the northern part of Belgium.

### treatment and comparator

The question is not whether a technology is cost-effective in itself, but whether it results in better outcomes than a certain comparator or benchmark. This should be the therapy most likely to be replaced [18], or the expected main comparator once the new drug arrives on the market [15]. In this study the comparator is the existing practice for breast cancer treatment in the university hospital. Oncology experts from this hospital are of the opinion that implementing trastuzumab in adjuvant setting as in the BCIRG trial would in the first place replace the current post-operative 5-fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy for patients with HER2-overexpressing tumors. Treatment schedules for patients receiving pre-operative chemotherapy are left out of consideration since the trials deal with post-operative treatment.

In the BCIRG 006 trial two treatment schemes include trastuzumab. In the first one (AC → TH), patients receive doxorubicin (A, 60 mg/m2) and cyclophosphamide (C, 600 mg/m2) for four cycles followed by docetaxel (T, 100 mg/m2) for four courses and trastuzumab (H) for 1 year. The initial doses of trastuzumab are administered concomitantly with docetaxel (loading dose 4 mg/kg, followed by 2 mg/kg weekly). Afterwards, trastuzumab is administered 3-weekly (6 mg/kg). In the second scheme (TCH), patients receive docetaxel (T, 75 mg/m2) and carboplatin (C, 300mg/m2) for six courses with concurrent trastuzumab given for 1 year [19, 20]. During treatment with chemotherapy, trastuzumab is administered weekly (loading dose 4 mg/kg, followed by 2 mg/kg weekly), and afterwards 3-weekly (6 mg/kg).

The most important serious adverse event associated with trastuzumab therapy is cardiac dysfunction, which is greatest when receiving concurrent anthracyclines [10, 11, 21, 22]. This risk is reduced in the first treatment arm by administering the anthracycline and trastuzumab sequentially and without overlap. The second regimen does not contain an anthracycline, to avoid the adverse interaction with trastuzumab [19, 23]. Nevertheless, It is clear that trastuzumab should not be used in adjuvant setting without cardiac monitoring, which results in higher follow-up costs.

### standard costs and micro-costing

The breast cancer treatment model reflecting reality was set up from diagnosis until the metastatic phase. Included phases are: diagnosis, surgery, breast reconstruction, radiotherapy, pre- and post-operative chemotherapy, hormonal treatment, and metastatic treatment. Although we are making a pharmacoeconomic analysis of trastuzumab in adjuvant setting, the metastatic phase has to be included. Consequently, we can incorporate the effect of a possible diminished percentage of breast cancers becoming metastatic in a threshold analysis. It also allows us to calculate the impact on total standard costs for breast cancer treatment.

An initial cost model set up during 2002–2003 [24] was drastically expanded during 2004–2005. With the help of our oncology experts, data from a study by Evans et al. [25] and internal documentation received from Statistics Canada, we refined and updated our initial model. A distinction was made between stage I, II and III breast cancer and the age categories >50 or <50 years. The latter is a proxy for menopausal estrogen-receptor status. This distinction is necessary since these different populations do not receive the same treatment and have other medical outcomes. In other words, both costs and health outcomes depend on the analyzed subpopulation.

In the BCIRG 006 trial, node-positive and fluorescence in situ hybridization (FISH)-positive breast cancers are admitted. Stage I is entirely node-negative. Stage II is predominantly node-positive. Patients with large tumors (T2 and T3) that are node-negative are also included, although these are a minority. Stage III is entirely node-positive. If trastuzumab treatment as administered in the BCIRG 006 trial were to be implemented in the current treatment practice, it would in the first place be implemented in stage II and III breast cancers; consequently, it is more interesting to perform the evaluation in these subpopulations. We present the results for women >50 years old with stage III diagnosed breast cancer. Figure 1 shows the decision tree for the standard breast cancer treatment model for this subpopulation in our university hospital.

Figure 1.

Treatment model for women >50 years, diagnosed with stage III breast cancer: treatment model with treatment phases and transition probabilities.

Figure 1.

Treatment model for women >50 years, diagnosed with stage III breast cancer: treatment model with treatment phases and transition probabilities.

For each phase the standard diagnostic and treatment options were defined and costs were calculated. Actual costs of providing care are likely to differ substantially from charges submitted by the providers to patients or third-party payers [26]. Even a consistent relationship between hospital charges and actual costs hardly exists [27]. Therefore, we opted to work with standard costs that were gathered in close collaboration with the staff of the university treatment center. The main direct cost-drivers were the use of personnel, medication, materials, equipment and the hospital-stay costs. The personnel, medication, material and equipment costs were calculated using the micro-costing method, in which the costs are calculated directly by tracing resources. The hospital-stay costs were estimated indirectly by a top-down calculation, which was adjusted to avoid double counting since some costs were already included directly. Other cost-drivers, such as the costs made by the pharmacy for preparing medication, anaesthetic costs, costs for sterilizing instruments, laboratory costs for investigating the cancer before treatment was started and checking the blood image before medication was administered and the different follow-up investigations, were also taken into account using the micro-costing method [24].

Costs caused by complications, such as a second reconstructive intervention because the first reconstruction did not provide a satisfactory result, were not interpreted as standard costs and therefore not taken into account. Overhead costs and costs linked to research activities were also disregarded since they are in the first place related to a specific department and not to a specific diagnostic or treatment option. In other words, the real costs are higher than our calculated standard costs and only reflect a part of total department expenditures [24].

### total costs

The standard costs for each phase in the treatment model were calculated by multiplying the cost of each diagnostic or treatment option by the probability of using it. If possible, the probabilities of using a certain diagnostic or treatment option were based on databases of the university hospital. If such databases did not exist, we relied on information of the university experts based on their knowledge and perception of the current treatment and diagnostic options used in their department. The costs for the complete model were calculated by using the transition probabilities, i.e. how many patients on average went from one phase in the model to another phase. These are shown in Figure 1. Follow-up costs and laboratory costs were finally added to become total costs [24]. Most authors use discount rates between 3% and 5% to incorporate future health outcomes and costs [28]. We used a 5% discount rate, as recommended by the Belgian health economic guidelines [29].

### sensitivity and threshold analysis

The influence of changing the variables across a plausible range on the results has to be examined [30]. We performed a one-way analysis to establish the individual effect of each component. Regarding the discount rate, the Belgian guidelines recommend rates in the 0–5% range for sensitivity analysis [29], as is often recommended [31]. Other countries such as Germany, Switzerland and Norway even recommend a 10% discount rate for sensitivity analysis [32]. We preferred to perform a sensitivity analysis on both sides, i.e. from 0% to 10%. Concerning HER2, some studies make reference to a 20–25% overexpression [22, 33] instead of 25–30%. Therefore, we varied HER2 overexpression between 20% and 30%. We performed an analogous sensitivity analysis on the transition probabilities, i.e. increasing/decreasing parameters with five percentage points. Resource costs (personnel, material, medication, etc.) and costs for a certain phase (diagnosis, surgery, radiotherapy, etc.) were also submitted to a 5% sensitivity analysis.

The BCIRG trial is still ongoing. No effectiveness data are available regarding the use of trastuzumab in the adjuvant setting. Nevertheless, it is interesting to perform threshold analysis, especially when a parameter is indeterminate [30]. In threshold analysis we search the critical value of parameters at which the conclusion of a study will change [34]. In the ongoing trials, clinicians try to improve effectiveness. Since these improvements are the principal aim but yet undetermined, we take this into account as a variable. The possible improvements taken into account in this threshold analysis are two-fold. First of all, less breast cancers may become metastatic, and secondly, there may be a prolongation of time to disease progression. For these different values of health improvements, incremental cost-effectiveness ratios (ICER) are calculated.

How much people are willing to pay for health improvements is not a certainty. Some studies suggest that in the USA, societal willingness to pay for health improvements is at least US$100 000 per quality-adjusted life year (QALY) gained, and is probably even higher. They even recommend that the societal threshold should be US$200 000 per QALY [35]. Comparing with cost-effectiveness levels of existing practices may be better. In the UK, the implicit threshold value per QALY was £30 000 per additional QALY [36]. In our threshold analysis, we set our acceptable ICER at €50 000. We questioned how much the prices of trastuzumab and docetaxel, i.e. the two most expensive products used in the trial, had to change to equal this acceptable ICER level. This approach provides a first good insight on whether or not, and under which conditions, the new treatment options can offer value for money.

### effectiveness

Cost-effectiveness analysis brings together the results of effectiveness research and cost information. Besides our cost data, we need effectiveness information for our subpopulations. Life expectancy data are based on a study by Berkowitz et al. [37]. This study provides information on the number of cases diagnosed with breast cancer, life expectancy at diagnosis, mean time and percentage of people progressing to metastatic disease and mean survival time of metastatic disease. These data were given for each stage at diagnosis and for five age groups, which could be rearranged to patients <50 or >50 years old. The researchers based their data on large databases, i.e. survival data from SEER (Surveillance, Epidemiology and End Results program maintained by the National Cancer Institute), mortality rates from the US Census Bureau and estimates of progression to metastatic disease from the Canadian provincial cancer registry data. Since no such extensive databases are available for Belgium, we preferred to use the data from this study.

In our subpopulation, i.e. patients >50 years old diagnosed with stage III breast cancer, 68% progressed to metastatic breast cancer. Life expectancy for these people could be calculated by adding up the mean time of progression to metastatic disease and the mean survival time of metastatic disease. The data on life expectancy for the group of women not progressing to metastatic disease could be derived from life expectancy at diagnosis, percentage of people progressing to metastatic disease and the calculated life expectancy of people progressing to metastatic disease [24]. In our analysis, we removed the final 3 months prior to death. These last 3 months before death are considered to be the terminal phase for breast cancer patients [37]. Owing to a lack of treatment standardization in these last 3 months, these costs were not included. To be consistent we similarly removed these final three months out of the effectiveness side. This is a personal choice that did not alter our final results. As a result, the average life expectancy at diagnosis for people >50 years old with stage III breast cancer was 6.7 years for people eventually progressing to metastatic disease and 7.8 years for the other group. For consistency, and following the Belgian health economic guidelines [29], health outcomes were also discounted at 5%.

## results

### micro-costing calculations

Table 1 presents the results of our micro-costing calculations. First of all, the costs for the initial diagnosis, hematoxylin and eosin staining and immunohistochemistry, which are used to identify a long list of antigens, were calculated. Furthermore, the cost of FISH was also calculated. In the group of patients receiving neo-adjuvant chemotherapy, about 60% of patients underwent a sentinel procedure and 40% had a fine needle aspiration. Afterwards, both lumpectomy and mastectomy were performed in combination with the removal of the axillary nodes. In the group not receiving neo-adjuvant chemotherapy, 80% immediately had a mastectomy and removal of axillary nodes and 20% a mastectomy in combination with a sentinel procedure. For 50–55% of the latter, the axillary nodes were removed afterwards.

Table 1.

Calculated costs for several treatment options

 Initial diagnosis €77 Hematoxylin and eosin staining and immunohistochemistry €146 FISH test €167 Sentinel procedure €633 Fine needle aspiration €40 Breast surgery Lumpectomy and rem. ax. €2677 Mastectomy and rem. ax. €2679 Mastectomy and sentinel €2678 Rem. ax. after sentinel €2554 Breast reconstruction DIEP flap €4367 GAP flap €4573 Nipple reconstruction €218 Cost savings through immediate reconstruction After mastectomy and sentinel €2490 After mastectomy and rem. ax. €2523 Radiotherapy 50 Gy/25 fractions €1076 60 Gy/30 fractions €1379 Chemo, hormonal or biological therapy Tamoxifen €1424 Anastrozole in adjuvant setting €7338 Anastrozole in metastatic setting €591 FECa €3592 Docetaxel €6434 CMFa €1536 AC → THa €45 034 TCHb €47 765 Capecitabine €2579 Trastuzumab €10 032 Vinorelbine €2751 Letrozole €573 Exemestane €460 Follow-up Basic check-up €13 Blood test €33 Mammography and ultrasound €59 Ultrasound scan liver €13 Bone scan €73 X-ray thorax €25 LVEF-test €55
 Initial diagnosis €77 Hematoxylin and eosin staining and immunohistochemistry €146 FISH test €167 Sentinel procedure €633 Fine needle aspiration €40 Breast surgery Lumpectomy and rem. ax. €2677 Mastectomy and rem. ax. €2679 Mastectomy and sentinel €2678 Rem. ax. after sentinel €2554 Breast reconstruction DIEP flap €4367 GAP flap €4573 Nipple reconstruction €218 Cost savings through immediate reconstruction After mastectomy and sentinel €2490 After mastectomy and rem. ax. €2523 Radiotherapy 50 Gy/25 fractions €1076 60 Gy/30 fractions €1379 Chemo, hormonal or biological therapy Tamoxifen €1424 Anastrozole in adjuvant setting €7338 Anastrozole in metastatic setting €591 FECa €3592 Docetaxel €6434 CMFa €1536 AC → THa €45 034 TCHb €47 765 Capecitabine €2579 Trastuzumab €10 032 Vinorelbine €2751 Letrozole €573 Exemestane €460 Follow-up Basic check-up €13 Blood test €33 Mammography and ultrasound €59 Ultrasound scan liver €13 Bone scan €73 X-ray thorax €25 LVEF-test €55
a

F, 5-fluorouracil; E, epirubicin; C, cyclophosphamide; M, methotrexate; A, doxorubicin; T, docetaxel; H, trastuzumab.

b

T, docetaxel; C, carboplatin; H, trastuzumab.

FISH, fluorescence in situ hybridization; rem. ax., removal of axillary nodes; DIEP, deep inferior epigastric perforator; GAP, gluteal artery perforator; LVEF, left ventricular ejection fraction.

After mastectomy, ∼7% of patients >50 years old had a breast reconstruction. In our university hospital a deep inferior epigastric perforator (86%) or gluteal artery perforator (14%) flap was performed. Of this group, ∼90% had a nipple reconstruction, which consisted of reconstructing and coloring the nipple and areola. Double counting in the case of immediate breast reconstruction is avoided by calculating and incorporating the cost-savings of immediate versus delayed reconstruction [38].

If radiotherapy was considered, 50 Gy/25 fractions/2 Gy once daily was given after mastectomy. Otherwise, 60 Gy/30 fractions/2 Gy once daily was given. If hormonal therapy was given, 80–85% received tamoxifen (20 mg/daily for 5 years) and the other 15–20% received anastrozole (1 mg/daily for 5 years). In case of neo-adjuvant chemotherapy, half of a normal FEC (5-fluorouracil 500 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 500mg/m2, six cycles, 4-weekly on the first and eighth day) treatment was administered before surgery. If it was successful, the other half of FEC treatment was given. Otherwise, docetaxel (100 mg/m2, four cycles, 3-weekly on the first day) was administered. In the very small group not receiving surgery, 90% received FEC treatment and 10% CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2, six cycles, 4-weekly on the first and eighth day). In the group not receiving neo-adjuvant treatment, this was respectively 75% and 25%. The costs of our alternative AC → TH and TCH treatments were of course also calculated.

Finally, the follow-up costs were taken into account. A basic check-up and blood test are performed every 3 months during the first 2 years. For the next 2 years, it is twice a year and after that, once a year. A mammography and ultrasound scan of the breast, bone scan, ultrasound scan of the liver and X-ray of the thorax are performed every year. Concerning the heart function, a baseline left ventricular ejection fraction (LVEF) evaluation is performed before treatment is started. With AC → TH treatment, LVEF evaluations are made 2 weeks after the fourth and sixth cycle, 3–4 weeks and 3 months after the last chemotherapy, after 1 year and finally after 3 years. With TCH this is about the same. Since this regimen does not have six but only four cycles of chemotherapy, the third and fourth LVEF evaluations happen 3–4 and 7–8 weeks after the last chemotherapy.

### total costs and sensitivity analysis

With the transition probabilities shown in Figure 1, the probabilities of using the several treatment options and the micro-costing data, total costs could be calculated. Concerning the FISH test it must be remembered that only the patients not receiving neo-adjuvant chemotherapy were seen as candidates for AC → TH or TCH treatment and thus received this test.

Total standard costs for stage III breast cancer patients >50 years old amounted to €16 787 for current treatment. Incorporating the AC → TH or TCH treatment arm, these standard costs increased to, respectively, €21 523 and €21 827. Total treatment costs increased clearly when the post-operative FEC treatment was replaced by trastuzumab treatment, as in the BCIRG trial for HER2-overexpressing breast cancers. From the hospital's point of view, FEC chemotherapy costs €3592. Taking prices of medication at the moment of analysis, this was respectively €45 034 and €47 765 for the AC → TH and TCH treatments. In the two cases, the high costs could be attributed to docetaxel for 14% and 15%, respectively, and to a large extent to trastuzumab, i.e. 79% and 75%. The impact on total treatment costs of these very expensive treatment options depends on the percentage of patients for whom the current treatment option could be replaced. In our analysis this depends on the transition probabilities of patient going to adjuvant therapy and receiving chemotherapy, the percentage of people in this group actually receiving FEC treatment and the proportion of HER2-overexpressing tumors. In our subpopulation of women >50 years old with stage III diagnosed breast cancers, about 11% were eligible for the new treatment options.

Sensitivity analysis must be performed to examine the influence of input uncertainty. As mentioned before, we performed one-way sensitivity analysis on transition probabilities, costs per treatment phase (surgery, breast reconstruction, radiotherapy, etc.) and resource costs (personnel, material, medication, etc.). Since the results were similar with TCH, we only present the results when the AC → TH treatment arm was incorporated. The benchmark is the total standard cost calculated with a 5% discount rate, i.e. €21 523. The variables that had the largest impact on total standard costs are shown in Figure 2.

Figure 2.

Sensitivity analysis. Influence of changing discount rate, HER2 overexpression, transition probabilities, cost of resource inputs or cost of treatment phases on standard treatment costs (initial level: €21 523).

Figure 2.

Sensitivity analysis. Influence of changing discount rate, HER2 overexpression, transition probabilities, cost of resource inputs or cost of treatment phases on standard treatment costs (initial level: €21 523).

The choice of discount rate has a great and asymmetric impact on total standard costs. Taking a discount rate of 0% and 10%, resulted in total costs of respectively €23 132 and €20 245. Having a good knowledge of HER2 overexpression is of major importance. A higher HER2-overexpression rate means more people are eligible for the expensive treatments and a higher impact on total standard costs for our subpopulation. Concerning the cost of input, it is particularly noticeable that changes in purchasing prices of medication have a great influence on total costs, whereas this is not the case for other inputs such as personnel. In line with this, when looking at the several phases in the model, transition probabilities and costs of adjuvant and metastatic treatment have a larger influence on result when comparing with other phases such as radiotherapy or surgery.

### ICER and threshold analysis

An economic evaluation should stand in relation to the health-care system as a whole. Treatment with monoclonal antibodies may have higher immediate costs but can have large longer term benefits. These long-term consequences should be included. Otherwise, efforts to constrain expenditures in one area could be contradictory if they lead to higher total costs. Concerning trastuzumab, the initial costs will certainly increase. However, if less people progress to metastatic breast cancer, economizing on expensive future treatments is possible. Furthermore, the number of life years, and the accompanying follow-up costs, will increase. We modeled possible improvements by trastuzumab treatment and calculated the following ICER. The results are presented in Figure 3. The x-axis shows the percentage point improvement of cancers not becoming metastatic. The y-axis presents the possible improvement in time to disease progression to metastatic disease. We presented the improvement in relation to those patients receiving trastuzumab treatment (i.e. 11.15% in our analysis). The z-axis shows the ICER of trastuzumab treatment. The initial point with no improvement is not given since the denominator of the ICER would be zero.

Figure 3.

Incremental cost-effectiveness ratio (ICER). x-axis: percentage point improvement of cancers not becoming metastatic. y-axis: improvement in time to disease progression to metastatic breast cancer (in months). z-axis: incremental cost-effectiveness ratio.

Figure 3.

Incremental cost-effectiveness ratio (ICER). x-axis: percentage point improvement of cancers not becoming metastatic. y-axis: improvement in time to disease progression to metastatic breast cancer (in months). z-axis: incremental cost-effectiveness ratio.

The analysis reveals that with small health outcome improvements, the ICER is extremely high. An acceptable ICER can only be reached if health improvements are large enough. However, even if policy makers judge the ICER to be too high, an acceptable level can be reached by changing the price of drugs. The price at the moment of analysis was €647 per vial of 150 mg of trastuzumab and €676 and €174 for 80 and 20 mg vials of docetaxel, respectively. Since the products are also used in metastatic setting, we had to take into account that changing these prices not only changed adjuvant treatment costs, but also influenced metastatic treatment costs. As mentioned before, we linked the hypothetical improvements in health outcomes to the price changes to meet an ICER of €50 000 per life year (Figure 4). The x- and y-axis are the same as in Figure 3. The z-axis shows the price discounts to meet the predetermined ICER level.

Figure 4.

Threshold analysis. x-axis: percentage point improvement of cancers not becoming metastatic. y-axis: improvement in ‘time to disease progression’ to metastatic breast cancer (in months). z-axis: price changes to equal an incremental cost-effectiveness ratio (ICER) of €50 000.

Figure 4.

Threshold analysis. x-axis: percentage point improvement of cancers not becoming metastatic. y-axis: improvement in ‘time to disease progression’ to metastatic breast cancer (in months). z-axis: price changes to equal an incremental cost-effectiveness ratio (ICER) of €50 000.

Smaller health improvements go together with higher price discounts and vice versa. Logically, if this threshold was set less stringently, i.e. at a higher level, lower price discounts would be needed to meet the threshold value. The threshold analysis reveals that targeting an acceptable ICER level with AC → TH or TCH treatment is possible if great effectiveness improvements can be proven and/or price discounts are given. This is in line with results of previous pharmacoeconomic studies performed on trastuzumab in the metastatic setting [24, 43]. On one hand, analysis in adjuvant setting is less promising for trastuzumab when comparing with metastatic treatment, since the targeted population will increase and budget implications will be more pronounced. Next to price changes, reallocations of resources, i.e. delisting treatments that are no longer cost-effective, or expansion of budgets could be considered. On the other hand, the ICER of trastuzumab in adjuvant setting can reach a more acceptable level than in metastatic setting, because next to the health improvements, it can save on expensive future metastatic breast cancer treatments.

## discussion

The large pressure on health-care budgets forces governments to consider carefully how to spend their money. Monoclonal antibodies are considered as being expensive. A recent study listed the most recent drugs receiving FDA approval for cancer therapy and their average wholesale price per dose and per cycle [44]. Whereas for Herceptin (trastuzumab) the average wholesale price per cycle was US$3672, the price was US$15 048, 15 723, 30 662, 32 400 and 199 332 per cycle for, respectively, Rituxan (rituximab), Mylotarg (gemtuzumab ozogamicin), Zevalin (ibritumomab tiuxetan), Bexxar (tositumomab) and Campath (alemtuzumab). The study results showed that the average wholesale price of monoclonal antibodies was clearly above the average price of other cancer therapies. Significant better health outcomes should justify the higher treatment costs. The trade-off between the costs and value of a treatment is a key criteria for reimbursement. Economic evaluations can give an idea on whether or not the drugs offer value for money.

Our analysis was performed from the hospital's point of view applying the micro-costing method. For further research, it may be appropriate to extend the data-gathering to other hospitals. This would enable us to set up probabilities on input variables. However, we should not forget that this would be a time-consuming exercise in which good cooperation with the staff of the different hospitals will be a prerequisite. Furthermore, we would like to remark that these costs reflect only part of societal costs. Other costs could also be involved, especially when discussing whether or not to administer the drugs weekly or 3-weekly. Administering a triple dose every 3 weeks would not compromise on the efficacy and safety of the drug [45]. Although this schedule would not make a difference for drug costs, it would economize two-thirds on several aspects such as nursing, pharmacy and other facilities, and improve QoL by reducing traveling, parking, waiting and infusion time [46]. Consequently, the 3-weekly schedule should be preferred. Implications on indirect costs such as production losses could also be concerned. Norum et al. [43], who performed a cost-effectiveness analysis of trastuzumab in metastatic setting, believed there were no significant differences in indirect costs, owing to the limited side-effects of trastuzumab. To measure this, a QoL questionnaire with labor-specific items should be completed during trials.

Concerning efficacy, preliminary results reported at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO) are very promising. Results from three large randomized prospective phase III trials were presented, i.e. NSABP B-31, NCCTG N-9831 and BIG HERA. Women with HER2-positive early breast cancer show significant and clinically important improvements in disease-free and overall survival when receiving trastuzumab [47]. In the HERA trial, trastuzumab given after primary therapy reduced the rate of recurrence, particularly distant recurrence, by ∼50% [48]. The addition of trastuzumab to paclitaxel after a regimen of doxorubicin and cyclophosphamide also reduced the rates of recurrence by half among women with HER2-positive breast cancer [49]. For the BCIRG 006 trial, efficacy data are not yet available. Preliminary safety data presented at the same ASCO meeting are in favor of the treatment arm administering docetaxel with platinum salts and trastuzumab (TCH). In contrast to the AC → TH treatment arm, the TCH combination did not elevate cardiac toxicity when compared with an AC → T regimen [50]. If this is true, extra treatment costs due to cardiac dysfunction should be added when evaluating the AC → TH treatment arm, whereas this would not be the case for TCH. Further results of the BCIRG 006 trial will be presented at the San Antonio Breast Cancer Symposium [51].

We have to wait for future trial results to confirm the promising preliminary results. Nevertheless, in comparison with metastatic setting, the potential of trastuzumab and health gains are greater in adjuvant setting. Therapeutic response usually improves when drugs are used earlier in the disease [52]. Concerning the higher costs, we should not forget that treatment in adjuvant setting is curative in the first place. If more people can be cured, expensive future costs for treatment of metastatic disease are avoided. Depending on the willingness to pay for health improvements, price efforts may be needed to reach an acceptable extra cost for these health gains. Even after the company has set its price at a level that results in an acceptable price for the company and an acceptable ICER, it is possible that present budgets cannot bear the extra expenses. In comparison with trastuzumab for treatment of metastatic disease, budget implications of using the drug in adjuvant setting will be much larger.

The budget impact analysis should take into account the amount of people who would be treated with trastuzumab. If, for example, policy makers would decide to reimburse trastuzumab for HER2-overexpressing stage II and III breast cancers, the initial budget impact can be calculated as follows. In Belgium, in 1998, there were 6628 cases of newly detected breast cancers in females [53]. About 45% of patients are diagnosed with stage II and III breast cancer [37]. As being tested in several trials, patients with HER2-overexpressing breast cancer, i.e. 25%, could receive trastuzumab for 1 year. Taking the price of €647 per vial, extra initial budget implications by reimbursing the drug for stage II and III breast cancer in Belgium amount to €25 569 084/year [6628 cases/year × 45% × 25% × (52 weeks + one extra initial loading dose) × €647]. If this treatment leads to less cancers progressing to metastatic disease, long-term budget impact analysis should take into account the future cost-savings.

In conclusion, improved survival data and/or reduced drug costs may result in acceptable incremental cost-effectiveness levels. Nevertheless, the combination of a relative high drug price, long treatment duration and the large population it is targeting can pose a financial burden on the health-care system. Reallocations of resources, in the first place delisting treatments which are no longer cost-effective, and price-volume agreements may offer part of the solution to this budgetary problem. As concluded by Mason and Drummond [54], careful resource planning is required so that cost-effective innovations are not denied to patients.

The process of developing a standard breast cancer treatment model required input from numerous persons. The authors wish to acknowledge the support of the staff of Ghent University Hospital. This analysis was performed independently. It is not related to studies recently presented at ASCO and has not been sponsored by industry.

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## Author notes

1Faculty of Economics and Business Administration, Department of Economics, Ghent University, Ghent; 2Faculty of Medicine and Health Sciences, Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium