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Journal of Clinical Oncology, Vol 25, No 6 (February 20), 2007: pp. 611-613 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.3542
Do the Large Benefits Justify the Large Costs of Adjuvant Breast Cancer Trastuzumab?Department of Internal Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA In the 1990s, breast cancer mortality rates in middle-age women declined by 25% to 30% in the United States. This decline was primarily due to adjuvant hormonal therapy or chemotherapies.1 The efficacy of adjuvant therapy was determined in randomized trials to form a rich evidence base and the rapid adoption of this knowledge by cancer providers into routine care. Separate from the effectiveness assessments, the vast majority of these interventions also met typical criteria for acceptable cost effectiveness—as defined by the WHO as interventions with a cost-effectiveness ratio less than the per capita gross domestic product.2,3 Since 2000, innovative approaches to adjuvant therapy for breast cancer patients have emerged using a new class of hormonal therapies (aromatase inhibitors), new schedules of delivering chemotherapy (dose-dense therapy), and targeted treatments at specific newly identified features of the breast cancer cells (trastuzumab). Unfortunately, the financial price of these new interventions has been an increase in costs of five- to 10-fold compared with the preceding standard approach. Such marked increased adjuvant therapy costs are a microcosm of broader trends pushing up health care costs in the United States—patients continue to want the newest (and most expensive) drugs and medical devices, patients are relatively protected from the prices of new agents (excluding potential copayments), the US Food and Drug Administration does not regulate or negotiate prices as part of its approval process for new agents, and Medicare does not consider costs in any of its reimbursement decisions. Given this perfect storm environment in the United States, cost-effectiveness analyses that attempt to estimate the incremental costs per additional year of survival may be highly important in deciding whether we can justify these new treatments compared with other uses of the same or additional health care dollars. In this issue of the Journal of Clinical Oncology, two reports (Kurian et al4 and Liberato et al5) assess the projected long-term costs and benefits of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. Does the unprecedented reduction by about one half in the risk of breast cancer recurrences represent a good value given that the drug costs alone for 1 year of trastuzumab exceed the average lifetime costs of the typical breast cancer patient of 10 to 15 years ago? First, we discuss the methods used. Both reports were conducted without financial support from manufacturers of trastuzumab. Each used a Markov model to track the long-term natural history of hypothetical cohorts of women with node-positive, HER2-positive breast cancer similar to the entry criteria of National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 trials. Each attempted to take a societal perspective but in their conduct actually took a health care insurer perspective because only direct health care costs were considered. Given that the median follow-up was only 2 years, it is not surprising that the reports differed in the assumptions used for the benefits and risks in subsequent years. Tables 1 and 2 summarize and compare important differences. The two most important factors were the duration of trastuzumab's benefit and the annual risk of systemic recurrence. The assumption of Liberato et al that the benefit of trastuzumab would persist only for 5 years is well supported by the Early Breast Cancer Trialists' Meta-Analysis.1 In contrast, the assumption of Kurian et al that a one-third decline in benefit in years 3 to 5 and an additional but persistent benefit from years 6 to 10 to us appears excessively optimistic. The reports differed slightly in the risk of systemic recurrences beyond 5 years but this had little impact on the results.
The models took markedly different approaches in estimating the costs and prognosis of women if systemic recurrences did occur. Liberato et al assumed that only women initially not receiving adjuvant trastuzumab would get late trastuzumab and their survival with metastatic disease would be longer than those getting adjuvant trastuzumab. In contrast, the model of Kurian et al assumed that both cohorts would get late trastuzumab and it would be given until death. In our opinion, the approach of Liberato et al makes more scientific sense, but the Kurian et al model represents what is most likely being done. Lastly, the time frame for the long-term benefits of trastuzumab to accrue markedly differed. Each model considered that the starting age of their cohort was age 50, but the Liberato et al model's base case used a 15-year time frame while Kurian et al used a lifetime (40+ year) time frame. Only Liberato et al assessed the impact of different time frame assumptions on the cost-effectiveness ratios. Neither report extensively explored the impact of trastuzumab's price or the impact from dosing women with larger body mass (Italian women weighed only 60 kgs). Despite these differences, the two reports, as well as two other preliminary models,6,7 come to the same primary conclusions—adjuvant trastuzumab is projected to improve long-term survival by at least 1 year, the impact of trastuzumab's cardiac toxicity has little effect on the long-term results, and the base case cost-effectiveness ratios are comparable or less than that of other widely accepted therapies. Stated another way, the high costs of trastuzumab are justifiable given the large benefits. In our opinion, what are equally important to the primary conclusions are the insights from the uncertainties. The cost-effectiveness ratios will be markedly higher if trastuzumab is less effective than the average point estimate or if the duration of benefit from trastuzumab is fewer than 5 years. Differences in patient age have little impact except for the most elderly, and cardiac toxicity has minimal impact on the overall conclusions. Updating these models after further clinical follow-up should be expected of the authors and the Journal given the importance of the conclusions. The primary conclusion that adjuvant trastuzumab is cost effective likely represents icing on the cake to US oncologists who have rapidly embraced trastuzumab. Adjuvant trastuzumab has also been approved in Australia and the United Kingdom in 2006. From early 2005 to mid-2006, sales of trastuzumab in the United States have increased by 250% or an additional approximately $750 million per year.8 The absolute increase in annual sales approximates our estimate of treating all new cases of node-positive, HER2-positive breast cancer. In conclusion, the cost-benefit ratio of adjuvant trastuzumab when used in women with HER2-positive, node-positive disease is comparable to other widely adopted cancer and noncancer interventions in the United States and most Western affluent countries. It is important to remember that these are additional health care costs: money spent on adjuvant trastuzumab cannot be spent on other treatments or for other forms of health care without raising taxes, raising copays dramatically, or restricting access. An acceptable cost-effectiveness ratio should not be viewed as justifying a new therapies price especially when the evidence supporting its use was predominantly done using public (National Cancer Institute) funds. The ongoing debate about if the biotechnology industry is acting in a socially and morally responsible manner should continue.9,10 The perfect storm concerns about the escalating costs of cancer therapies will continue to escalate, particularly for patients with advanced disease, where the benefits may be measured in weeks, and treatment requires frequent expensive supportive care.11 So far, there has been no effective movement to reduce the prices of new drugs, even when there are several competing alternatives in the marketplace.12 Reducing drug costs by negotiating a lower price for trastuzumab (which has been relatively stable world-wide) or a shorter duration (an indirect inference from the 9-week schedule used in the Finnish trial13) would lower the cost-effectiveness ratios. We are disappointed that in the United States there are no current plans to address the duration of therapy question. Fortunately, the French have initiated a trial comparing 6 months to 12 months of trastuzumab.14 We should all be rejoicing that the breast cancer death rates will fall further in Western countries with trastuzumab. We must remember that everyone is not as affluent as us and/or as willing to devote increasingly amounts of their economic resources to health care. Let's hope that the translational scientific community will hit more home runs. In our opinion, there have been only two walk-off home run oncology products or strategies in the last 20 years—ones that provided relative reductions exceeding 50% compared with the best current care—imatinib and trastuzumab. Unless we want to bankrupt future generations, cost-effectiveness assessments will have an increasing role in determining value and how we spend or allocate our precious health care dollars.15-17 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors 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: N/A Honoraria: N/A Research Funds: Bruce E. Hillner, American Cancer Society Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: Bruce E. Hillner Collection and assembly of data: Bruce E. Hillner, Thomas J. Smith Data analysis and interpretation: Bruce E. Hillner, Thomas J. Smith Manuscript writing: Bruce E. Hillner, Thomas J. Smith Final approval of manuscript: Bruce E. Hillner, Thomas J. Smith
REFERENCES 1. 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 randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 2. Kievit W, Bolster MJ, van der Wilt GJ, et al: Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer. Ann Oncol 16:1874-1881, 2005 3. World Health Organization.Macroeconomics and Health: Investing in Health for Economic Development: Report of the Commission on Macroeconomics and Health. Geneva, World Health Organization, 2001 4. Kurian AW, Thompson RN, Gaw AF, et al: Cost effectiveness analysis of adjuvant trastuzumab regimens in early HER-2/neu-positive breast cancer. J Clin Oncol 25:634-641, 2007 5. Liberato NL, Marchetti M, Barosi G: Cost effectiveness of adjuvant trastuzumab in HER2-positive breast cancer. J Clin Oncol 25:625-633, 2007 6. Hillner BE: Clinical and cost-effectiveness implications of the adjuvant trastuzumab in HER2+ breast cancer trials. Breast Cancer Res Trt 94S:S5040, 2005 7. Garrison L, Perez EA, Dueck A, et al: Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2+ breast cancer. J Clin Oncol 24:306s, 2006 (abstr 6023) 8. Genentech: Investor relations: Financials. http://www.gene.com/gene/ir/financials/ 9. Vanchieri C: When will the U.S. flinch at cancer drug prices? J Natl Cancer Inst 97:624-626, 2005 10. Carreyrou J, Anand G: Wary of backlash, cancer-drug makers weigh price limits. Wall Street Journal, May 10, 2006 11. Schrag D: The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med 351:317-319, 2004 12. Berenson A: Hope, at $4,200 a dose. New York Times, October 2, 2006 13. 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 14. National Institutes of Health: Clinical trials: Trastuzumab for 6 Months or 1 year in treating women with nonmetastatic breast cancer that can be removed by surgery. http://clinicaltrials.gov/show/NCT00381901 15. Garber AM: Cost-effectiveness and evidence evaluation as criteria for coverage policy. Health Aff (Millwood) Jan-Jun, 2004 (suppl; Web Exclusives W4-284-96) 16. Goldman L: Cost-effectiveness in a flat world: Can ICDs help the United States get rhythm? N Engl J Med 353:1513-1515, 2005 17. Neumann PJ, Rosen AB, Weinstein MC: Medicare and cost-effectiveness analysis. N Engl J Med 353:1516-1522, 2005
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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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