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Journal of Clinical Oncology, Vol 25, No 6 (February 20), 2007: pp. 625-633 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.4220 Cost Effectiveness of Adjuvant Trastuzumab in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
From the Azienda Ospedaliera della Provincia di Pavia, Divisione di Medicina Interna, Ospedale Civile, Casorate Primo; and Laboratorio di Epidemiologia Clinica, Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico S Matteo, Pavia, Italy Address reprint requests to Nicola Lucio Liberato, MD, Divisione di Medicina Interna, Ospedale Civile "C. Mira", 27022 Casorate Primo, Pavia, Italy; e-mail: lucio_liberato{at}ospedali.pavia.it
PURPOSE: To evaluate the cost-effectiveness of 12-month adjuvant trastuzumab therapy in women with high-risk human epidermal growth factor receptor 2 (HER2) –positive early breast cancer. METHODS: A Markov model tracked quarterly patients’ transitions between five health states: disease free, local relapse, disease free after local relapse, metastatic disease, and death. Patients were allowed to incur symptomatic or asymptomatic transient cardiac dysfunction during trastuzumab administration. Probabilities were derived mainly from the combined report of the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 trials (95% node positive) and a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group. Costs were estimated from the perspective of the Italian and US health care systems. The analysis was run during a 15-year time horizon. A 3% yearly discount rate was applied to both costs and life-years. Second-order Monte-Carlo and probabilistic sensitivity analyses were performed.
RESULTS: Adjuvant trastuzumab increases life expectancy by 1.54 (1.18 discounted) quality-adjusted life-years (QALYs). At a cost of CONCLUSION: In a long-term horizon, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk, early breast cancer.
The human epidermal growth factor receptor 2 (HER2), encoded by the HER2/neu proto-oncogene, is a member of a transmembrane growth factor receptor family with tyrosine kinase activity. HER2 is overexpressed in approximately 25% to 30% of cases of breast cancer and is associated with a poor prognosis, but retrospective data have shown that it is associated with an enhanced benefit for the use of anthracycline-based chemotherapy over nonanthracycline-based chemotherapy.1-3 Trastuzumab is a recombinant humanized monoclonal antibody that binds the extracellular domain of HER2, consequently blocking intracellular signaling. It was approved for clinical use alongside chemotherapy for metastatic breast cancer overexpressing HER2 because it was found to confer longer disease-free and overall survival than chemotherapy alone.4,5 Trastuzumab has been used subsequently in combination with adjuvant chemotherapy in patients with high-risk early breast cancer. Published interim analyses of four randomized controlled trials unanimously showed an improved disease-free survival.6-8 Furthermore, the combined analysis of two randomized trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] trial B-31 and North Central Cancer Treatment Group [NCCTG] trial N9831) showed a statistically significant, 33% reduction in mortality.6 With the increasing evidence of a clinical benefit of trastuzumab in the adjuvant setting, this benefit needs to be balanced against the economic impact of the drug. Therefore, we performed a literature-based decision analysis assessing the cost effectiveness of trastuzumab in conjunction with adjuvant chemotherapy.
Model We implemented a decision tree (TreeAgePro, TreeAge Software Inc, Williamstown, MA) comparing long-term costs and effectiveness of adjuvant chemotherapy plus trastuzumab and chemotherapy alone for patients with HER2-positive early breast cancer. We considered a hypothetical cohort clinically similar to that enrolled onto the NSABP B-31 and NCCTG N9831 trials6: patients with a median age of 50 years and HER2-positive early breast cancer, principally associated with positive lymph nodes (95% of enrolled patients). A Markov model simulated the long-term clinical evolution of such patients. Markov processes track patients’ transitions among mutually exclusive health states that last a fixed length of time. During each cycle patients cumulate life-years, quality-adjusted life-years (QALYs), and costs. Transitions occur according to input probabilities. We implemented a Markov model including five health states of 3-month duration (Fig 1): disease free, local relapse, disease free after local relapse, metastatic disease, and death.
Patients entered the model in the disease-free state, after completing the first part of adjuvant chemotherapy (doxorubicin plus cyclophosphamide were administered in the NSABP B-31 and NCCTG N9831 trials). During the first quarter, patients were allowed to receive paclitaxel alone or the same chemotherapy regimen plus trastuzumab (2 mg/kg/wk), whereas during the subsequent three quarters, only patients assigned to the trastuzumab strategy continued to receive weekly treatment. Disease-free patients receiving adjuvant trastuzumab were allowed to incur symptomatic or asymptomatic cardiac dysfunction, which suggested interruption of the trastuzumab and temporary changes of both costs and quality of life. Disease-free patients could incur a relapse. Most patients incurring a local relapse were allowed to receive effective treatment and return to a disease-free health status (referred to as disease-free after local relapse) within 12 months, whereas 10% of the patients shifted to a systemic disease status. All of the patients incurring a systemic relapse entered the metastatic disease state and could only move to the death state.
Clinical Data
Long-term outcomes of disease-free patients could not be derived from published randomized trials selectively enrolling HER2-positive patients, but were obtained from a large meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group: relapse rates of patients with node-positive early-breast cancer receiving adjuvant anthracycline-based chemotherapy were adopted.10 The natural history of patients undergoing local relapse has been reported only in longitudinal nonrandomized studies; we adopted the long-term outcomes of a large cohort of women who had had a local relapse.12 To simplify the model, we assumed that all reported local relapses occurred during the first 5 years of follow-up. Patients with early relapses (ie, those occurring within 2 years from the end of adjuvant therapy) were assigned a different history than those with late relapses. Patients with metastatic disease were assumed to receive first-line therapy including chemotherapy and trastuzumab if they had not received adjuvant trastuzumab, or chemotherapy alone if they had received adjuvant trastuzumab. Patients were modeled to incur death according to the survival rates reported by a published randomized study.4 We assumed that patients in any health state might die of causes not related to breast cancer; national mortality rates for females were adjusted according to the patients’ age.
Costs
The cost of local relapse in Italy was calculated considering the mix of therapies adopted for such patients and the cost of each therapy.11 The cost of radiotherapy was calculated according to the local treatment protocol (25 fractions) and unit charges. For the US setting, we adopted the final estimate from a specific economic evaluation.19 The cost of metastatic disease in the Italian health care setting was derived from a published Markov model.20 The undiscounted quarterly cost of metastatic disease from the start of chemotherapy until death was calculated from the published model: it included the costs of hormone therapy, up to two lines of chemotherapy (cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; or cyclophosphamide, epirubicin, and fluorouracil) and palliative care (including bisphosphonates and home care). The cost of metastatic disease in the US setting was derived from a recent economic analysis.13
Quality of Life Utilities of health states were obtained from the literature and are listed in Table 3. Patients with symptomatic cardiac dysfunction were assigned the same utility as those with moderate (New York Heart Association III) heart failure, whereas no reduction in quality of life was assumed for patients with asymptomatic cardiac dysfunction. On the basis of published data,9 the symptomatic phase was modeled to last for 6 months.
Analysis Each rate, cost, and utility was entered into the model along with a distribution: a normal distribution was adopted for age (mean, 50 years; standard deviation, 10 years);  distributions were adopted for all input costs; ß distributions were adopted for probabilities and proportions (the wideness of the distribution was calibrated on the sample size of the study from which the rate was derived); a log-normal distribution was adopted for the relative risk of relapse in patients receiving trastuzumab (the 95% CI of the input distribution was calibrated on the CI reported by the NSABP B-31 trial). According to the guidelines produced by the US Public Health Service Panel on Cost-Effectiveness in Health and Medicine,26 both future costs and life-years were also discounted at a 3% yearly rate to account for time preference (ie, the preference individuals have for earlier rather than later benefits).27 A second-order Monte-Carlo analysis (10,000 simulations) was conducted and acceptability curves were plotted. Base-case analysis was run for a 15-year-long time horizon (ie, life-years and costs cumulated in a 15-year time frame were calculated, because of the long survival of patients with early breast cancer).10 Life-years saved (ie, the difference between the expected survival rates of patients assigned or not to adjuvant trastuzumab) were also weighted by patients’ quality of life (QALY). The incremental cost per QALY was calculated and compared with international benchmarks28: health care interventions for which incremental cost per QALY gained exceed the benchmark conventionally are considered not cost effective and, consequently, have a lower priority for policy makers. Probabilistic sensitivity analysis was run for all the input parameters: the results for the major parameters are reported. Finally, a multiway sensitivity analysis using the main characteristics and results of the HERA trial was performed: it was simulated that patients received trastuzumab (6 mg/kg every 3 weeks) after the end of adjuvant chemotherapy. HER2-positive breast cancer patients were modeled to incur a 1.27 higher risk of relapse in the first 5 years, given that their 2-year disease-free survival was 77% (v 82% in the NSABP B-31 and NCCTG N9831 trials’ combined report). The hazard ratio of relapse in patients receiving adjuvant trastuzumab was calculated according to the hazard ratio reported by the HERA trial (ie, 0.54). The risk of cardiac toxicity was decreased from 17% to 8.8%, and the proportion of symptomatic patients was reduced from 23% to 20%.7
Baseline Analysis The model calculated that adjuvant trastuzumab improved 15-year disease-free survival from 39% to 52%, and improved 15-year overall survival from 44% to 58%. Model-derived survival curves did not differ from the results of clinical trials (Figs 2 and 3). Adjuvant trastuzumab prevented one relapse in six treated patients. The resulting advantage provided by adjuvant trastuzumab was 1.34 life-years (ie, 1.54 QALYs; Table 4).
In the model, each relapse incurred by patients not receiving adjuvant trastuzumab cost about  56,000 ($70,000 in the US perspective), whereas those incurred by patients who received adjuvant trastuzumab cost about 30,000 ($34,000). The overall savings achieved by the adjuvant treatment with trastuzumab were about 16,500 ($19,500), but the cost of the adjuvant trastuzumab treatment offset the savings: costs for each patient starting trastuzumab were about 32,000 ($40,000) for the drug, its administration, and the possible occurrence of cardiac dysfunction. Therefore, the incremental cost of adjuvant trastuzumab was 15,476 ($20,211) and the incremental discounted cost effectiveness was 14,861/QALY ($18,970/QALY). The acceptability curve of adjuvant trastuzumab (Fig 4) showed that it cost less than 20,000/QALY ($27,000/QALY) with a probability of 91%.
Sensitivity Analysis The main results of the probabilistic sensitivity analysis are reported in Table 5. One major (but expected) result was the high dependency of cost effectiveness on the time horizon of the analysis: the incremental cost-effectiveness ratio of adjuvant trastuzumab increased more than 50,000/QALY ($60,000/QALY) and 20,000/QALY ($25,000/QALY) if the analysis was run for shorter time horizons (ie, less than 7.8 and 8.8 years, respectively).
Sensitivity analysis allowed us to change the patients’ age and, therefore, their annual risk of death unrelated to breast cancer. Adjuvant trastuzumab was less cost effective in older women, given that it cost more than 100,000/QALY ($150,000/QALY) in women older than 79 years and more than 50,000/QALY ($60,000/QALY) in women older than 75 years (Table 5). Sensitivity analysis also allowed us to test the impact of the patients’ risk of relapse. Adjuvant trastuzumab cost more than 50,000/QALY ($60,000/QALY) in very low risk patients (ie, those with a forecasted risk of relapse lower than 15% at 10 years), whereas it cost less than 20,000/QALY ($30,000/QALY) if the risk was higher than 40%. The additive impact of the above parameters (ie, age and risk of relapse) was tested in two-way sensitivity analysis (Fig 5). The analysis showed that adjuvant trastuzumab was highly cost effective in medium- to high-risk patients up to 70 years of age. Old age impaired the cost effectiveness of trastuzumab more severely than did the risk of relapse. Indeed, in the low-risk patient subgroup, adjuvant trastuzumab proved cost effective only when assigned to the younger individuals.
The results were not sensitive to the proportion of women receiving trastuzumab either in the adjuvant or in the metastatic phase or to changes in the quality of life assigned to the health states. The results also were not sensitive to the mortality rate of patients developing symptomatic cardiac toxicity (Table 5).
Multiway sensitivity analysis allowed us to simulate a HERA-like scenario: in such a setting, adjuvant trastuzumab cost
There was great enthusiasm in the oncology community after the consistent reports of a clinical benefit from adjuvant trastuzumab in four clinical trials.6-8 However, the enthusiasm was accompanied by trepidation concerning the widespread use of the drug and a subsequent dramatic increase of health care costs.29,30 Both clinicians and administrators felt the urgent need for economic evaluations of trastuzumab in this clinical setting.
The present study estimates, based on literature data, the cost effectiveness of adjuvant trastuzumab in the Italian health care setting. The decision model calculated that, in a trial-like scenario, adjuvant trastuzumab cost The clinical advantage (ie, life-years gained) of adjuvant trastuzumab, as well as of other adjuvant and preventive interventions, was gained gradually in time and was relevant only in the long term.35 Therefore, the drug proved cost effective only after 7 to 10 years. Similarly, the clinical advantage of adjuvant trastuzumab depended on the life expectancy of the modeled patients: it proved quite cost effective for patients up to the age of 70 years, but not for the older patients. The ability of trastuzumab to prevent relapses was also a major determinant of clinical and economic outcomes, independently of the frequency of trastuzumab use in the metastatic phase of the disease. Therefore, adjuvant treatment with trastuzumab might not be cost effective in older HER2-positive patients who have a low risk of relapse. We assessed the pharmacoeconomic profile of adjuvant trastuzumab also in the US perspective and found that it cost $21,946 per life-year saved. Adjuvant trastuzumab was also reported to have a positive pharmacoeconomic profile in a preliminary analysis for the US health care setting.36 We are confident that the results of the present analysis can be generalized to other European countries, where reported costs of metastatic disease and of trastuzumab are not dissimilar from those in the Italian reports.37,38 Finally, relevant changes in the cost effectiveness of adjuvant trastuzumab in different regions of Italy seem unlikely, despite local variations in follow-up practices.39,40
We still consider that the present economic evaluation might be improved in the future. In particular, we have not fully explored risk subgroups. Unfortunately, no well-designed, large, longitudinal study has ever reported the natural history of patients with HER2-positive early breast cancer and, consequently, we could not fully consider the patients’ case mix (ie, we could not assign different relapse risks on the basis of histology, number of involved nodes, or patient’s age). However, because the relative effectiveness of adjuvant trastuzumab did not appear to be different in different subgroups,6 we are confident that no bias either for or against trastuzumab was introduced. Also, the model did not fully detail the natural history of the disease and did not model different sites of metastasis separately. However, a much more solid body of evidence was available for metastatic patients as a whole than for different clinical subgroups. Third, we did not perform a formal budget impact analysis. Considering the incidence of breast cancer in Italy (approximately 28,000 patients per year), adjuvant trastuzumab might be prescribed to more than 2,000 women each year. Based on our model results, the administration of adjuvant trastuzumab to this cohort of patients would ultimately increase health care costs by approximately In conclusion, in the subgroup of patients with HER2-positive, high-risk breast cancers, trastuzumab amplifies the clinical advantage of adjuvant chemotherapy at a cost generally considered appropriate for the added value that trastuzumab produced.
The authors indicated no potential conflicts of interest.
Conception and design: Nicola Lucio Liberato, Monia Marchetti Collection and assembly of data: Nicola Lucio Liberato, Monia Marchetti Data analysis and interpretation: Nicola Lucio Liberato, Monia Marchetti, Giovanni Barosi Manuscript writing: Nicola Lucio Liberato, Monia Marchetti, Giovanni Barosi Final approval of manuscript: Nicola Lucio Liberato, Monia Marchetti, Giovanni Barosi
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC 
