A monoclonal antibody against HER-2 (trastuzumab) for metastatic breast cancer: a model-based cost-effectiveness analysis

J. Norum1,2,*, T. Risberg1,2 and J. A. Olsen3,4

1 Department of Oncology, University Hospital of North Norway; 2 Institute of Clinical Medicine and 3 Institute of Community Medicine, University of Tromsø, Tromsø; 4 Health Economics Research Programme, University of Oslo, Oslo, Norway

* Correspondence to: Dr J. Norum, Department of Oncology, University Hospital of North Norway, P.O.B. 13, N-9038 Tromsø, Norway. Tel: +47-776-69366; Email: jan.norum{at}unn.no


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background:: The aim of this study was to evaluate the cost-effectiveness of trastuzumab in patients with metastatic breast cancer (MBC) in a model-based cost-effectiveness analysis (CEA). Trastuzumab has shown considerable activity in patients with MBC that overexpress HER2. However, significant resources have been allocated to finance this new therapy. Due to ever increasing pressures on health care budgets, economic evaluations are requested in order to compare health effects with costs.

Methods:: All available data on trastuzumab in MBC presented at the San Antonio breast cancer conference in late 2003 and all data on Medline in December 2003 were analysed for life years (LY) gained and quality of life (QoL) with regard to the use of this new monoclonal antibody. Randomised studies comparing standard chemotherapy, with or without trastuzumab, were focused. The costs were calculated according to Norwegian prices as of January 2003.

Results:: The LY gained ranged between 0.3 and 0.7 years. The median cost per patient treated was {euro}44 196 yielding costs per life year saved in the range {euro}63 137–{euro}162 417 depending on survival gain and discount rate employed. A sensitivity analysis documented the price of trastuzumab and the survival benefit the two major factors influencing the cost-effectiveness ratio.

Conclusion:: The economic evaluation indicates that trastuzumab is not cost effective in metastatic breast cancer. Reduced drug costs and/or improved survival may alter the conclusion.

Key words: HER-2/neu, metastatic breast cancer, trastuzumab, health economics


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Breast cancer is the most common form of cancer among women in North America and throughout Europe. More than half a million women develop the disease every year. The high incidence indicates that diagnosis and treatment of breast cancer place a significant financial burden on health care systems. New drugs introduced in the treatment of cancer usually raise treatment costs. One of the latest drugs launched in the management of breast cancer is trastuzumab, a humanised anti-p185HER2/neu monoclonal antibody (mAb). During the last several years, laboratory studies have demonstrated that the HER2/neu gene, which encodes the transmembrane receptor p185HER2/neu, has partial homology with the epidermal growth factor receptor (EGFR) and both share a tyrosine kinase activity [1Go]. HER2/neu amplification is recognised in 20%–30% of breast cancers [2Go–5Go] and is associated with an aggressive form of the disease with significant shortened disease-free survival and overall survival [6Go–8Go]. It is also an important predicting factor of response to chemotherapy and hormonal therapy [9Go]. In the majority of cases, HER2 overexpression is caused by amplification of the HER2 gene. This amplification results in the production of increased HER2 mRNA levels and concomitant increased synthesis and overexpression of the HER2 receptor on the cell surface [10Go].

This transmembrane receptor has been a target for manipulation with monoclonal antibodies. Researchers at Gentech Inc. have produced a series of mu-mAbs capable of inhibiting the proliferation of monolayer cultures of HER2-positive breast tumour cells. The most known antibody in today's clinical practice is trastuzumab (Herceptin: Genentech, Inc, So. San Francisco, California). It is an IgG antibody that is 95% human and 5% murine.

Trastuzumab is safe and has been documented to inhibit tumour growth when used alone. It has synergistic effects when employed in combination with cisplatin and carboplatin, docetaxel and ionizing radiation, and additive effects when used with doxorubicin, cyclophosphamide, methotrexate and paclitaxel [11Go–15Go].

This new compound in the treatment of metastatic breast cancer has put a significant burden on health care budgets worldwide. In Norway, the price of 150 mg trastuzumab is NOK 8 145 ({euro}928) (see www.felleskatalogen.no).

Most countries today experience increasing pressures on health care budgets to finance new treatments for all sorts of diseases. The effect of spending money in one area of the battle against cancer must continuously be compared with alternative uses of the same resources, e.g. money spent on treatment of metastatic breast cancer might alternatively be allocated to prevention, primary therapy or palliative care.

Among economic evaluation methodologies, the cost-effectiveness analysis (CEA), is clearly the most frequently applied. This study was undertaken to compare expected health outcomes of trastuzumab in advanced breast cancer with costs. Available national cost data and studies from the international English-language literature, documenting the effectiveness of this drug, were implemented in the analysis.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this survey, data from the literature on the efficacy of trastuzumab, tolerability, survival gains, drug charges and production gains/losses were included.

Medline was searched in January 2004 employing the words ‘trastuzumab with metastatic breast cancer’. In addition, all abstracts at the San Antonio Breast Cancer Meeting (3–6 December 2003) were searched for the word ‘trastuzumab’. In total 317 publications were identified (Medline 284, San Antonio 33). We also searched the abstracts at the American Society of Clinical Oncology Meeting in New Orleans in June 2004. A total of 13 abstracts were detected. It is standard practice in CEA to discount future benefits and costs. A 5% discount rate was employed in this survey.

Benefits
The benefits in this setting are, primarily, life years (LY) gained. None of the studies reviewed had quality adjusted the increased survival time in order to estimate quality-adjusted-life-years (QALYs). We focused on randomised clinical trials employing chemotherapy with or without trastuzumab and written in English, but also included non-randomised studies. Few randomised trials were detected [16Go, 17Go]. An overview of the benefits is given in Table 1. The survival with standard chemotherapy only was about 2 years. The incremental survival from trastuzumab ranged between 3.7 (0.3 years) and 8.4 months (0.7 years). A report from the National Institute for Clinical Excellence (NICE) argues for a mean survival advantage of approximately 10 months [18Go]. However, this number looks too ambiguous and is only included in the discussion. Following standard practice in cost-effectiveness methodology, future survival benefits are discounted.


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Table 1. Results of randomised trials with standard chemotherapy for metastatic breast cancer with or without trastuzumab

 
Costs
Costs associated with trastuzumab therapy were calculated from the perspective of a third-part payer. All costs are calculated according to Norwegian unit costs and converted to Euros at the rate of 1{euro}=8.78 NOK. All costs included occurred within the first year and were not discounted.

Costs may be divided into direct and indirect costs. The direct costs in metastatic breast cancer are mainly related to hospitalisation, outpatient therapy, drugs and travelling. The indirect costs are production losses.

Direct costs
Drug costs. In most clinical trials, trastuzumab is delivered at a standard schedule of herceptin 4 mg/kg i.v. initial dose followed by 2 mg/kg i.v. weekly until disease progression. This is based on preclinical data [19Go]. This schedule was therefore selected in the model. Trastuzumab is delivered in 150 mg standard units ({euro}928/unit). Thus in women having a weight of more than 75 kg, two units (three units for the first cycle) are necessary for a sufficient dose. To indicate the number of units needed, we registered the weight of all women referred to our outpatient unit in January and February 2004 for chemotherapy for breast cancer: 23% had a weight of more than 75 kg (mean 70.2 kg, range 56.5–92 kg). This weight is in accordance with the mean weight among Norwegian adult women of 69.5 kg according to Statistics Norway (www.ssb.no). It is believed that clinicians still employ the 150 mg unit for economic reasons, even when the woman is slightly above 75 kg weight. We therefore employed in our model a qualified guess, by two medical oncologists at our department, of 15% needing more than one unit.

In the study by Slamon et al. [16Go], the median time in study was 40 weeks and the median number of doses of trastuzumab was 36 (range 1–98). Based on these figures, we included a dose intensity of (36/40) 90% in our model. As all costs occur within the first year of treatment, they were not discounted.

Trastuzumab may introduce a prolonged chemotherapy treatment as time to progression is delayed. Patients with tumour progression on first-line chemotherapy are usually offered a second-line regimen. It is therefore difficult to estimate differences in costs and total chemotherapy cycles administered in a chemotherapy alone setting versus chemotherapy plus trastuzumab. In the study by Slamon et al. [16Go], chemotherapy was administered for six cycles and additional cycles were administered at the investigator's discretion. Extra et al. [17Go] employed only six cycles of docetaxel in both arms. Other investigators employed a fixed number of cycles of chemotherapeutic agents in metastatic breast cancer [20Go]. Based on these data, we concluded that there seems to be only minor differences in chemotherapy costs. This factor was, therefore, not implemented in the model.

Based on all information, the mean drug cost per patient treated with trastuzumab may be calculated as [(cost/unit x units 1st week (including 15% needing three rather than two units) + (cost/unit x units 2nd–40th week x dose intensity]=[(({euro}928 x 2) + ({euro}928 x 0.15)) + (({euro}928 x 39 x 1.15) x0.9)]={euro}1856+ {euro}139.2+ {euro}37 458.7={euro}39 454. This figure together with the additional cost items discussed below is listed in Table 2.


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Table 2. Model employed: the cost is indicated per patient treated

 
Assessment of HER2 status, hospitalisation and outpatient clinic costs. There are two major alternatives for the assessment of HER2 status: immunohistochemical (IHC) assay (i.e. HerCep test: DAKO, Carpinteria, CA) or fluorescence in situ hybridization (FISH). Whereas IHC is inexpensive, available and easily performed in clinical pathology laboratories, FISH is more predictive and frequently employed to confirm positive IHC results [21Go]. A score of 2+ reflects weak to moderate complete membrane staining in more than 10% of tumour cells and is considered weakly positive for HER2 overexpression. A score of 3+ reflects moderate to strong complete membrane staining in more than 10% of tumour cells and is considered a strong positive result [21Go]. In this model we included the cost of analysis for HER2 status employing IHC (£21/test={euro}31.7/test) [18Go]. Calculating 25% of patients with HER2 overexpression, four tests have to be performed per positive test result (£21 x 4=£84={euro}127).

By adding trastuzumab to standard chemotherapy in MBC, new side-effects and an altered need for hospitalisation occur. Congestive heart failure is the most important factor in this setting: 11.3% had an early stop due to a drop in left ventricular ejection fraction (LVEF) in the study by Greyer et al. [22Go]. They observed a 3.5% increase in cardiac event among patients receiving AC plus herceptin. Pooled results by Marty et al. [23Go] from six studies revealed a LVEF event in 6.7% and 0.7% in the trastuzumab and control arm, respectively. The event was, in most cases (84%), asymptomatic. This is supported by the findings of 75% by Guillem Porta et al. [24Go]. Based on this meta-analysis, it was suggested that 1.3% (6.7% x 16/84) in the trastuzumab group and 0.1% (0.7% x 16/84) in the control group will experience a symptomatic drop in LVEF and need to be investigated by a cardiologist. The Diagnosis Related Groups (DRG) 127 (36 228 NOK={euro}4126) was employed to reflect this cost. The mean raised cost per patient included can then be calculated as ({euro}4126 x (1.3–0.1)/100={euro}50). Due to recommendations and the risk of congestive heart failure, we included in our model two regular visits at the cardiologists' outpatient clinic during tratuzumab therapy. The costs were calculated according to the Norwegian tariff [25Go]. (Tariff code A05a + 201b = 918 + 245 NOK = {euro}132.5, Tariff code 708ca + 202 = MUGA = 185 + 359 NOK={euro}62.) The cost of two regular visits can then be calculated at {euro}389.

For every drug prepared at the pharmacy for intravenous therapy, an administration cost is charged (NOK 245.5={euro}28). Calculating a median number of 36 cycles, the cost included in Table 2 was ({euro}28 x 36) {euro}1008.

Another factor is a raised risk of brain metastasis among patients receiving trastuzumab [26Go]. The risk seems to be doubled and it may introduce a need for preventive therapy as prophylactic whole brain irradiation. However, this factor has so far undergone few investigations and the available data are limited. In this study, this factor was therefore not included.

The introduction of trastuzumab does alter the time spent at the outpatient clinic due to a prolonged infusion time and a need for further observation following the first cycle. According to recommendations, the first dose is administered at 90 min and if well tolerated, subsequent infusion periods are shortened to 30 min. To reflect this cost, we employed the tariff of the National Health Administration (NHA) [25Go] for prolonged treatment (H06e—total treatment lasting 1 h); 775 NOK = {euro}88. The dose intensity of 36/40 cycles then indicates the total cost per patient treated of {euro}3 168 ({euro}88 x 36).

Travelling costs. Since 1 January, the hospital owner pays all costs related to the transport of patients. In Norway, a weekly schedule of chemotherapy (taxane) is combined with trastuzumab. Thus, we concluded for practical reasons that the cost of travelling is the same whether the patient received standard chemotherapy with or without trastuzumab. This factor, therefore, could be excluded from the analysis.

Indirect costs
The indirect costs in this setting are production losses. The median age of women receiving trastuzumab (Table 1) ranged between 42.3 and 77.8 years (median age 52.1 years). Women undergoing chemotherapy for metastatic breast cancer are usually reported ill by their doctors and employees receive a pension from the National Insurance Administration. They rarely return to the work force. Keeping the limited side-effects of trastuzumab in mind, we believe there are no significant differences in indirect costs whether the patient receives trastuzumab or not.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The results from the randomised trials listed in Table 1 suggest that the increased lifetime gains range from 3.7 to 8.4 months—in addition to the 22.1 months they would be expected to live with standard chemotherapy. We estimated the total costs per patient receiving trastuzumab in metastatic breast cancer to be {euro}44 196. The major cost is the drug itself (89%). The second most important cost item was prolonged treatment at the outpatient clinic. This cost constituted 8% of the total amount. The total costs estimated here are the additional—or incremental—costs, compared with standard chemotherapy treatment only. Hence, when expressed in terms of an incremental cost-effectiveness ratio, the extra costs per life year saved range between {euro}63 137 and {euro}147 320, depending on the survival gain included (from 3.7 to 8.4 months). When discounting the health gains at a 5% rate, the range becomes {euro}69 212–162 417. Details are shown in Table 2.

Sensitivity analysis
A multivariate sensitivity analysis was conducted to test the robustness of results and conclusions. The sensitivity analysis included the following parameters. (1) A variation of the number of HER2-positive patients between 20% and 30% (according to the literature [2Go–5Go]). (2) A reduction of the cost of IHC analysis for HER status by 50%, as there are reasons to believe this cost will be reduced as the test volume is increased. (3) A drop in the cost of outpatient treatment by 50%. (4) Administration costs at the pharmacy are lowered by 25% as it is believed that hospitals in the future will not have to pay tax for this service. (5) A reduced cost of trastuzumab by 25% and 50%. (6) Further improvement in survival by 25% [18Go]. Details concerning the sensitivity analysis can be seen in Table 3.


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Table 3. A sensitivity analysis varying the factors influencing the cost-effectiveness analysis

 
The two major factors significantly influencing the conclusion/results are a reduction of drug costs or further improvement in survival. Savings in drug costs may be achieved by a dose reduction (if the clinical effect is unchanged) or a lowered price of the drug itself. A prolonged treatment interval (3 weeks) would only influence the cost if the cytotoxic drugs are delivered at an equal interval and not on a weekly basis. This is because the dose intensity will be unchanged. However, travelling expenses saved will have very little influence on the cost-effectiveness.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study suggests that costs per life year gained employing trastuzumab in metastatic breast cancer are very high. The cost-effectiveness analysis estimated the extra costs per undiscounted additional life year gained between {euro}63 137 and {euro}147 320. The mean raised cost per patient treated of {euro}44 196 introduces a new level of treatment costs in this common cancer.

Many health care systems worldwide will have significant difficulties in accepting this high cost regimen as standard therapy. Widely used cost-effectiveness thresholds are US$20 000, US$50 000 and US$100 000 [27Go]. In 2002, Winkelmayer et al. [28Go] published in end-stage renal disease treatment with haemodialysis US$ 55 000/LY ({euro} 46 000/LY) a lower boundary of society's willingness to pay for additional life years. Employing this cut-off level, trastuzumab is not cost-effective.

However, before concluding that trastuzumab is not cost-effective, let us look at the validity of this analysis. In the sensitivity analysis, the major factors influencing cost are the price of trastuzumab and the survival gain. None of the other factors would significantly improve the cost-effectiveness ratio. Including extra travelling expenses in a non-weekly chemotherapy setting would even worsen the outcome.

How can the cost-effectiveness of trastuzumab therapy be improved? There are several factors that may have an influence. First, the cost of the drug itself could be reduced. From Table 3, a suggested limit of {euro}46 000/LY saved may be achieved by lowering the cost of trastuzumab by 31%. Whereas the producer (Roche) needs to cover the costs related to this new drug—both the production costs as well as their investments in research and development—there are reasons to believe a lower price might be feasible. Trastuzumab is produced using a genetically engineered Chinese hamster ovary cell line. Standardised recombinant techniques are used to insert the DNA coding sequence of trastuzumab into the cells. The ovary cells, which secrete trastuzumab into the culture medium, are grown commercially on a large scale in a nutrient medium containing the antibiotic, gentamicin. This production technique has, when established, a ‘limited’ production cost. Costs may also be limited if more than one standard unit (150 mg) is made available (i.e. 10 mg and 100 mg units).

Another way of improving effectiveness is to look at the intervals of administration. Today, trastuzumab is administered on a weekly basis. With a half-life of up to 1 month this seems unnecessary. In Norway, except for a small share provided by the patients, all travelling expenses are covered by the hospitals acting on behalf of the National Insurance Administration. Thus hospital owners may allocate resources saved on travelling expenses into treatment, education or research. Focusing on trastuzumab, the hospital owners have a clear interest in administrating the drug every 3rd week. Leyland-Jones et al. [29Go] recently published such a study. However, in our model-based analysis this will not influence the cost significantly, as long as the dose intensity is unchanged. There are reasons to continue on the 1-week interval, especially when paclitaxel is used. Perez et al. [30Go] revealed weekly paclitaxel, carboplatin and trastuzumab to be superior to a 3-week schedule. The median progression-free survival (PFS) was 8.8 and 13.4 months, respectively.

At present, there are investigators advocating that trastuzumab therapy should continue beyond disease progression. This is based on the synergistic and additive effects observed between trastuzumab and chemotherapeutic agents due to different interactions between their mechanisms of action [20Go]. Bringing this suggestion into clinical practice will surely raise the overall costs significantly. On the other hand, almost no studies have focused on the benefit of a shortened trastuzumab therapy. The present standard has been treatment until disease progression. However, keeping the long half-life of the trastuzumab in mind, a shortened treatment period, either by administering the drug for a fixed number of weeks or employing an ‘on and off’ schedule, will clearly save money. Even side-effects may be reduced. From an economic point of view this type of study is strongly requested.

Could there be an association between HER2 overexpression and racial type, making the total expenses needed for proper therapy lower in underdeveloped countries with limited resources? To our knowledge very few studies have focused on HER2 status among races. Santillan et al. [31Go] revealed no difference between the prevalence of HER2/neu expression among Mexican–Americans (23%) and non-Hispanic white women (25%). In male breast cancer, a lower incidence has been observed (15%) by Rudlowski et al. [32Go]. In the future automated scanning digital microscopy may improve the cost-effectiveness of this analysis [33Go].

Is there a possible risk of over-treatment if HER2 expression analysis in the primary setting is employed in the metastatic situation? There seems to be very small economic benefits in analysing HER2 overexpression in the metastatic setting, as there is a strong concordance (74%–98%) between the HER2 status of primary tumours compared with metastatic disease [33Go, 34Go].

According to today's knowledge about one-quarter of the patients suffering from metastatic breast cancer are candidates for trastuzumab therapy. Some cases may be excluded due to cardiac status, as the drug may raise the risk of congestive heart failure. Love et al. [35Go] reported from Miami Florida, 6% of 193 breast cancer survivors at a ‘town meeting’ having already received trastuzumab. A Canadian study presented at ASCO 2004 reported that trastuzumab was used in 6.6%–10.7% of the estimated women that died from metastatic breast cancer in three Canadian provinces [36Go].

Employing a 5% discount rate, the health authority could save approximately {euro}2200/patient by simply delaying the therapy by 1 year. For example, only chemotherapy, hormonal therapy or radiotherapy could be employed in the first-line setting. This has also been suggested by Dranitsaris et al. [37Go] who concluded that employing first-line letrozole (without trastuzumab) will cause a cost delay to the health care system. The cost of 16 months letrozole therapy was calculated as $Cdn 2928/patient. In the case of trastuzumab with paclitaxel they showed a cost of therapy of $Cdn 27 450/patient treated.

In this study, we employed the available data from the literature. So far, these data are limited and two randomised ‘small’ studies [16Go, 17Go] are the basis of today's recommendation of trastuzumab in metastatic breast cancer. These data show a range in survival benefit between 3.7 and 8.4 months, the latter disclosed by Extra et al. [17Go]. In their study there was a crossover following progressive disease, causing 44% of the patients enrolled to receive trastuzumab, although they were included in the docetaxel alone arm. The study was also limited by a short median follow-up of 12.4 and 14.6 months in the docetaxel alone and the docetaxel plus trastuzumab arm, respectively. These two factors may hide an even larger true difference in survival between the two arms. Whereas Slamon et al. [16Go] included IHC 2+ and 3+ HER2 positive patients in their survey, the great majority of other studies [17Go] employed IHC 3+ and/or FISH-positive women only. This may explain the low efficacy of trastuzumab in the study by Slamon et al. [16Go]. In our sensitivity analysis, the survival benefit is one of the major factors influencing cost-effectiveness. A true difference in survival of 9 months instead of 4.5 months will give a cost per life year of {euro}58 927. Future studies investigating the benefit of trastuzumab is, therefore, of clear interest for future cost-effectiveness analysis.

In conclusion, trastuzumab is not cost effective in metastatic breast cancer today, employing a cut-off at {euro}46 000/LY. A reduced drug cost or improved survival data may in the future alter this conclusion.

Received for publication July 6, 2004. Revision received December 10, 2004. Accepted for publication January 21, 2005.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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