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Journal of Clinical Oncology, Vol 25, No 6 (February 20), 2007: pp. 634-641 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.3081 A Cost-Effectiveness Analysis of Adjuvant Trastuzumab Regimens in Early HER2/neu–Positive Breast Cancer
From the Department of Medicine, Division of Oncology; Department of Health Research and Policy, Division of Epidemiology; Department of Biological Sciences; Department of Medicine, Division of Bone Marrow Transplantation; Graduate School of Business; and the Veterans’ Affairs Palo Alto Health Care System and Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA Address reprint requests to Allison W. Kurian, MD, MSc, Division of Oncology, Stanford University School of Medicine, 875 Blake Wilbur Dr, Stanford, CA 94305-5820; e-mail: akurian{at}stanford.edu
PURPOSE: One-year adjuvant trastuzumab (AT) therapy, with or without anthracyclines, increases disease-free and overall survival in early-stage HER2/neu-positive breast cancer. We sought to evaluate the cost effectiveness of these regimens, which are expensive and potentially toxic. METHODS: We used a Markov health-state transition model to simulate three adjuvant therapy options for a cohort of 49-year-old women with HER2/neu-positive early-stage breast cancer: conventional chemotherapy without trastuzumab; anthracycline-based AT regimens used in the National Surgical Adjuvant Breast and Bowel Project B-31 and North Central Cancer Treatment Group N9831 trials; and the nonanthracycline AT regimen used in the Breast Cancer International Research group 006 trial. The base case used treatment efficacy measures reported in the randomized clinical trials of AT. We measured health outcomes in quality-adjusted life-years (QALYs) and costs in 2005 United States dollars (US$) and subjected results to probabilistic sensitivity analysis. RESULTS: In the base case, the anthracycline-based AT arm has an incremental cost-effectiveness ratio (ICER) of $39,982/QALY, whereas the nonanthracycline AT arm is more expensive and less effective; this result is insensitive to changes in recurrence rates, but if there is no benefit after 4 years, ICERs exceed $100,000/QALY for both AT arms. Results are moderately sensitive to variation in breast cancer survival rates and trastuzumab cost, and less sensitive to variations in cardiac toxicity. CONCLUSION: AT has an ICER comparable to those for other widely used interventions. Longer clinical follow-up is warranted to evaluate the long-term efficacy and toxicity of different AT regimens.
Trastuzumab (Herceptin; Genentech, San Francisco, CA) is a humanized monoclonal antibody that binds to the extracellular epidermal growth factor receptor-2, which is encoded by the HER2/neu gene and is amplified in 25% to 30% of all breast cancers. Adding trastuzumab to chemotherapy for HER2/neu-positive metastatic breast cancer lengthens median survival by approximately 5 months, compared with chemotherapy alone.1 Trastuzumab was approved by the US Food and Drug Administration to treat metastatic disease in 1998, and testing for HER2/neu protein overexpression and gene amplification has become standard in the evaluation of women in the United States with early or advanced breast cancer. Combined HER2/neu testing and trastuzumab in metastatic breast cancer have an estimated incremental cost-effectiveness ratio (ICER) of $145,000 per quality-adjusted life-year (QALY) gained.2 Multiple randomized trials have reported that trastuzumab during or after primarily anthracycline-based chemotherapy prolongs survival when used for 1 year as adjuvant therapy. A combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, both of which evaluated doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab, reported that at 2 years the risk of death was reduced by one third and the risk of breast cancer recurrence was reduced by one half.3,4 The main adverse effect of treatment with trastuzumab was cardiac systolic dysfunction, with 4.1% of patients in the trastuzumab arm experiencing cardiac events, versus 0.8% in the nontrastuzumab (NT) arm.3 According to preliminary results of the Breast Cancer International Research Group (BCIRG) 006 trial, the nonanthracycline (NAT) adjuvant trastuzumab (AT) regimen of docetaxel and carboplatin appeared less efficacious than an anthracycline-based AT (AAT) regimen, although the difference did not reach statistical significance. However, the NAT regimen caused significantly less cardiac toxicity.5 With these results, AT has entered mainstream clinical practice,6 and is reimbursed by health plans, despite remaining concern about the short duration of follow-up in the trials and the cost of the drug. Patients are now treated for 1 year with infusions of trastuzumab weekly or once every 3 weeks.3,4 Recent evidence for a substantial clinical benefit from trastuzumab in the adjuvant setting, coupled with ongoing concern about the escalating cost of targeted cancer therapies,7,8 motivated us to undertake a cost-effectiveness analysis of treating women with early-stage HER2/neu-positive breast cancer with AT. We analyzed the costs and health benefits of AT administered with anthracycline and NAT chemotherapy regimens, as evaluated in the randomized clinical trials to date.3-5
Model Structure Using TreeAge Pro 2005 software (TreeAge Software Inc, Williamstown, MA), we created a Markov state-transition model, with a cycle length of 1 month, to evaluate the long-term health outcomes, quality-of-life effects, and costs associated with three adjuvant treatment strategies for resected early-stage HER2/neu-positive breast cancer. Markov modeling allowed extension of the time horizon of the model beyond the 2-year median follow-up available from randomized clinical trials.3,5 Results are presented as ICERs, in cost per QALY saved; both costs and QALYs are discounted at 3% in the base case. We performed this analysis from the societal perspective, per recommendations of the Panel on Cost-Effectiveness in Health and Medicine.9 Key model features are shown in Figures 1A and 1B.
Patient Population Our model applies to 49-year-old women with early-stage breast cancer positive for amplification or overexpression of the HER2/neu oncogene, corresponding to the median age of participants in the published randomized AT trials; these results are most applicable to women with central-laboratory–confirmed HER2/neu positivity, as was required for participation in the randomized clinical trials. The analysis applies to women who have undergone surgical resection of all apparent disease, with and without involved axillary lymph nodes, comparable to the trial populations.3-5
Prognosis of HER2/neu-Positive Breast Cancer
Prognosis of Metastatic Breast Cancer Reflecting current US clinical practice, we assumed that all patients receive trastuzumab on diagnosis of recurrent systemic HER2/neu-positive breast cancer.6 Using data from the pivotal randomized trial of trastuzumab for metastatic disease, we assumed a median survival of 25 months with 9 months of trastuzumab therapy.1
Treatment Strategies
Treatment-Related Toxicity
Quality of Life
Costs The costs of each arm appear in Table 3. Costs of AT included costs of the drug,26 drug infusion, monthly oncologist visits, and cardiac monitoring with echocardiogram or multigated acquisition scan every 3 months during therapy as per clinical trial protocols.3,5,27 We estimated total costs of adjuvant chemotherapy without trastuzumab, including supportive medications and other supportive care, from a recent publication which used Regence Blue Shield claims data linked with the Cancer Surveillance System of the US Surveillance, Epidemiology, and End Results database to evaluate costs of adjuvant chemotherapy for breast cancer according to age, stage, type of surgery, and comorbid conditions.28 For the docetaxel and carboplatin regimen, we added the difference between the cost of these agents and those in the NT arm to the total adjuvant chemotherapy cost.26,28 We estimated costs of breast cancer recurrence from publications which incorporated costs of chemotherapy, supportive, and end-of-life care29,30; we added the cost of 9 months of trastuzumab therapy.1,26,27 Costs of asymptomatic left ventricular ejection fraction decrease include monitoring with echocardiogram or multigated acquisition scan every 3 months, cardiologist visits, and therapy with a beta-blocker and angiotensin-converting enzyme inhibitor. Costs of symptomatic heart failure are those of asymptomatic left ventricular ejection fraction decrease, plus the cost of an initial 3-day hospital stay.16,26,28 All costs were updated to 2005 US dollars.
Sensitivity Analyses Because long-term effects of therapy are unknown, we evaluated the impact of changes in recurrence rates under each treatment strategy using probabilistic sensitivity analysis. Base case recurrence rates were varied within the 95% CIs reported in the AT randomized clinical trials3,5; rates under each strategy were varied under an independentdistribution, and 1,000 samples were simulated. We varied all other variables for which uncertainty existed in one-way sensitivity analyses; ranges of variation were based on published data whenever available, and otherwise varied within 20%.
Base Case In the base case analysis, treatment with the NT regimen yields 9.35 QALYs at a cost of $133,429, the AAT regimen yields 10.77 QALYs at a cost of $190,092, and the NAT regimen yields 10.61 QALYs at a cost of $206,561. Compared with the NT regimen, the AAT regimen yields an ICER of $39,892/QALY. The AAT regimen dominates (costs less and is more effective than) the NAT regimen. In an analysis of life-years (LYs) saved, without quality weights, the NT arm yields 12.29 LYs, the AAT arm yields 14.01 LYs, and the NT arm yields 13.56 LYs. Base case results are listed in Table 4.
Sensitivity Analyses Results of the probabilistic sensitivity analysis of recurrence rates under different treatment strategies are listed in Table 5. In the NT arm, QALYs range from 7.80 to 11.05 and costs range from $125,499 to $140,332; in the AAT arm, QALYs range from 9.47 to 12.13 and costs range from $183,058 to $196,546; in the NAT arm, QALYs range from 9.22 to 12.21 and costs range from $198,683 to $213,097. The AAT regimen dominates the NAT regimen in probabilistic sensitivity analysis of cost-effectiveness ratios (Fig 2). In a sensitivity analysis that assumed that recurrence rates were minimally improved with either AT arm after year 4 (hazard ratio 0.99, as found for women age 50 to 69 years reported by the Early Breast Cancer Trialists' Collaborative Group),13 the ICER increased to $142,516/QALY for AAT and $157,078/QALY for NAT (Table 6).
Other uncertain parameters of the model were varied in one-way sensitivity analyses (Fig 3). Parameters included the median survival after breast cancer recurrence; the cost of metastatic breast cancer therapy; the cost of trastuzumab; the probabilities of developing, recovering from, and dying as a result of cardiac toxicity after the AAT arm; and the cost of treating cardiac toxicity, the utilities of congestive heart failure, and AT. The discount rate was varied from 0% to 5%. The results are most sensitive to the discount rate, the cost of AT, the median survival after breast cancer recurrence, and the cost of treating metastatic breast cancer. The results are least sensitive to changes in the probability of dying as a result of or recovering from cardiac toxicity, costs of cardiac toxicity, and all utilities.
In this comparison of conventional treatment, anthracycline, and nonanthracycline AT regimens for early-stage HER2/neu-positive breast cancer, an anthracycline-based regimen yields an ICER of $39,892 per QALY in the base case. This ICER is comparable to or less than that of widely accepted therapies, including treatments for early stage breast cancer. For example, adjuvant chemotherapy for women over 65 with lymph node–positive breast cancer has an ICER of up to $43,000/QALY, axillary lymph node dissection in postmenopausal women with estrogen receptor–positive breast cancer has an ICER of $36,000/QALY, and electron-beam boost after whole-breast irradiation has an ICER in excess of $300,000/QALY.31-33 In our base case analysis and in a probabilistic sensitivity analysis of recurrence rates under different treatment strategies, the anthracycline dominates the NAT arm. The high cost of docetaxel and carboplatin and the infrequency and low cost of the cardiac toxicity state after the anthracycline-based regimen drive this result. The major limitation of this analysis is the absence of long-term clinical experience with AT, leading to uncertainty about efficacy and toxicity of the alternative approaches to care over the years. Studies of long-term trastuzumab use in metastatic breast cancer suggest that it is capable of producing a sustained survival benefit.34,35 However, if the dramatic improvements in overall and disease-free survival seen in the randomized AT trials do not persist over time, then the ICER of an anthracycline-based regimen may be considerably higher than in our base case. When we assumed no benefit after year 4, a result consistent with a meta-analysis of polychemotherapy in women age 50 to 69 years by the Early Breast Cancer Trialists' Collaborative Group,13 ICERs exceeded $100,000/QALY for both AT arms. An age-specific subset analysis of the joint NSABP B-31 and NCCTG 9831 trials suggests a trend toward greater benefit of trastuzumab with increasing age3; regardless of age, HER2/neu amplification frequently associates with pathologic findings, such as absence of hormone receptors and high grade, which may account for the greater benefit of polychemotherapy observed in younger women.36-38 We might therefore anticipate that the benefit of AT over time will more closely resemble that of adjuvant chemotherapy in premenopausal rather than in older women; however, extended clinical experience with AT regimens is required to answer this question. In the published trials, cardiac toxicity did not cause short-term cardiac deaths, and most patients recovered from their symptoms promptly.3-5,16 In sensitivity analyses, 20% variation in cost and incidence of cardiac toxicity, and a three-fold increase in the cardiac death rate,17 had little effect on the ICER. However, cardiac toxicity could be observed more often when AT is in widespread clinical use, or could prove more persistent, costly, or fatal. The relative risks and benefits of anthracycline versus NAT regimens are also in question. If cardiac or other toxicities prove more common, lethal, or expensive in the AAT arm, or if efficacy increases or cost decreases in the NAT arm, then the ICER of a NAT-based regimen would improve. Initial subset evaluation of the NSABP B-31 trial has reported that certain groups of women, including older women and those with a decline in left ventricular ejection fraction after anthracycline treatment, may have increased risk for cardiac toxicity after AAT.16 Preliminary reports from the BCIRG 006 trial suggest that tumor amplification of the topoisomerase II alpha amplicon may identify the subgroup of HER2/neu-positive patients who benefit significantly from an AAT regimen.5 Longer follow-up and additional study of outcome predictors may help to target specific AT regimens to specific populations, with the potential to maximize efficacy, minimize toxicity, and improve the cost effectiveness of trastuzumab therapy. Our analysis is based on the assumption that the HER2/neu status of the patient is already known, given that current guidelines recommend HER2/neu testing for all breast cancer patients.6 If we had included HER2/neu testing costs, as did a previously published cost-effectiveness analysis of trastuzumab in metastatic breast cancer,2 the ICER for trastuzumab-based therapies would be less favorable. Not surprisingly, our results are highly sensitive to the cost of trastuzumab. Other influential parameters include the median survival after breast cancer recurrence, and cost of metastatic breast cancer therapy. Given the historically poor prognosis and early recurrence risk with HER2/neu-positive breast cancer, a halving of the hazard ratio for recurrence corresponds to a dramatic absolute benefit.3,5 Conversely, some of the least influential model inputs are those related to cardiac toxicity, which likely results from the relatively short duration of this health state as reported in the clinical trials. If cardiac toxicity from AT lasts longer or is more severe, then variations in its incidence, cost, or utility may have a more significant impact on the cost effectiveness of AT. Many questions remain about how best to use trastuzumab in the adjuvant setting, including its optimal duration. A recent randomized trial found similar efficacy for a 9-week regimen as reported in the 1-year adjuvant trials, and a 2-year regimen is being studied.3,5,39 Initial results from another trial suggest that a dose-dense biweekly anthracycline-based regimen, including filgrastim support, is safe; longer-term efficacy data are pending.40 However, the conclusion that AT is a cost-effective approach to treating HER2/neu-positive early breast cancer is likely to stand, unless additional observation reveals substantial declines in efficacy or worsening toxicity. In an era of concern about the increasing costs of novel oncologic therapies, an ICER in the $40,000 range represents a good value.
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: Allison F. Gaw, Genentech Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Allison W. Kurian, Alan M. Garber Collection and assembly of data: Allison W. Kurian, Rebecca Newton Thompson, Allison F. Gaw, Sally Arai, Rafael Ortiz, Alan M. Garber Data analysis and interpretation: Allison W. Kurian, Alan M. Garber Manuscript writing: Allison W. Kurian, Rebecca Newton Thompson, Sally Arai, Alan M. Garber Final approval of manuscript: Allison W. Kurian, Rebecca Newton Thompson, Allison F. Gaw, Sally Arai, Rafael Ortiz, Alan M. Garber
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Schrag D: The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med 351:317-319, 2004 8. Dent R, Clemons M: Adjuvant trastuzumab for breast cancer. BMJ 331:1035-1036, 2005 9. Gold MR, Siegel JE, Russell LB, et al: Cost-effectiveness in health and medicine. New York, NY, Oxford University Press, 1996 10. Riou G, Mathieu MC, Barrois M, et al: C-erbB-2 (HER-2/neu) gene amplification is a better indicator of poor prognosis than protein over-expression in operable breast-cancer patients. Int J Cancer 95:266-270, 2001[CrossRef][Medline] 11. Ferrero-Pous M, Hacene K, Bouchet C, et al: Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. Clin Cancer Res 6:4745-4754, 2000 12. Tsutsui S, Ohno S, Murakami S, et al: Prognostic value of c-erbB-2 expression in breast cancer. J Surg Oncol 79:216-223, 2002[CrossRef][Medline] 13. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 14. National Center for Vital Statistics: Census data 2002. http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr53_06.pdf 15. Miller DK, Homan SM: Determining transition probabilities: Confusion and suggestions. Med Decis Making 14:52-58, 1994 16. Tan-Chiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811-7819, 2005 17. Williams S, Jackson M, Cooke G, et al: How do different indicators of cardiac pump function impact upon the long-term prognosis of patients with chronic heart failure? 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Hayman JA, Hillner BE, Harris JR, et al: Cost-effectiveness of adding an electron-beam boost to tangential radiation therapy in patients with negative margins after conservative surgery for early stage breast cancer. J Clin Oncol 18:287-295, 2000 34. Marty M, Cognetti F, Maraninchi D, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 23:4265-4274, 2005 35. Stemmler HJ, Kahlert S, Siekiera W, et al: Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC). Onkologie 28:582-586, 2005[CrossRef][Medline] 36. Ariga R, Zarif A, Korasick J, et al: Correlation of HER-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J 11:278-280, 2005[CrossRef][Medline] 37. Kronqvist P, Kuopio T, Helenius H, et al: Predicting aggressive outcome in T1N0M0 breast cancer. Br J Cancer 91:277-281, 2004[Medline] 38. Prati R, Apple S, He J, et al: Histopathologic characteristics predicting HER-2/neu amplification in breast cancer. Breast J 11:433-439, 2005[CrossRef][Medline] 39. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-820, 2006 40. Dang C, Smith K, Lake D, et al: Preliminary cardiac safety results of dose-dense (DD) doxoru-bicin and cyclophosphamide (AC) followed by paclitaxel (T) with trastuzumab (H) in HER2/neu overexpressed/amplified breast cancer (BCA). Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005 Submitted February 22, 2006; accepted September 14, 2006.
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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
