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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4506-4507 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.0401
Does a Statistically Significant Survival Benefit of Erlotinib Plus Gemcitabine for Advanced Pancreatic Cancer Translate Into Clinical Significance and Value?Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Hospital, Harvard Medical School; and the Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA
Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA To the Editor: While survival improvements are needed for patients with advanced pancreatic cancer, quality of life remains an important goal.1 Moore and colleagues2 report a statistically significant overall survival benefit of 0.33 months for erlotinib plus gemcitabine compared with gemcitabine alone for first-line treatment of advanced pancreatic cancer (National Institute of Canada PA.3 trial). However, the small size of the survival gain and the increased risk of toxicities (diarrhea, interstitial lung disease, and treatment-related death) suggest that the clinical value of erlotinib may be limited. In addition, the high cost of erlotinib raises concerns about its value in this setting. To estimate the magnitude of the cost per quality-adjusted life year (QALY) gained by adding erlotinib to gemcitabine, we performed a posthoc, informal cost-effectiveness analysis. The median survival, time to progression, and proportion of patients who had dose reduction, stopped erlotinib early, and experienced excess adverse effects were obtained from the PA.3 trial.2 Oncology and pharmacy experts at our institution estimated resource utilization for adverse effects and treatment-related deaths. Drug and inpatient medical care costs were estimated using 2007 average wholesale price3 and 2007 Medicare reimbursements rates,4 respectively. Time spent with diarrhea, the only significant quality-of-life domain (P < .0001),2 was adjusted for quality of life loss. Because there are limited quality-of-life data for pancreatic cancer, a sensitivity analysis was performed using estimates for colon5 and prostate cancer6: diarrhea lowered quality of life by 0.07 (low impact)5 or 0.29 (high impact)6 on a zero to one scale (1 = perfect health and 0 = death). Analysis assumptions were conservative in order to avoid bias against erlotinib. Treatment course assumptions were: starting erlotinib dose of 100 mg by mouth daily; average length of treatment equal to median time to progression (3.75 months); if the dose of erlotinib was reduced, this occurred at the end of the first month of treatment and the new dose was 75 mg daily; if erlotinib was discontinued early, this occurred after half of the treatment course was completed; and the course of patients after first-line treatment failure was the same in both arms. Toxicity assumptions were: toxicities requiring hospitalization occurred once, while rash and grade 1/2 diarrhea were present for half of the treatment period; and no additional outpatient visits occurred due to excess toxicities. Additional model assumptions were: the time frame was lifetime; the perspective was third-party payer; medical costs associated with extra days lived was equivalent to third party payer palliative care costs obtained from the literature.7 Because the vast majority of patients died within 1 year, costs and benefits were assumed to occur within 1 year and were not discounted. All costs are reported in 2007 US dollars ($). Compared with gemcitabine alone, the average incremental cost of adding erlotinib was $15,194 per patient: $10,293 for erlotinib (weighted for dose reductions and discontinuations), $780 for toxicities (weighted by frequency of events), and $4,101 for third-party payer costs for extended life (Table 1) . Quality-of-life adjustments reduced the survival gain by 5% to 20% when the impact of grade 1/2 diarrhea is considered low or high, respectively.
Based on our informal analysis, the incremental cost-effectiveness ratio of adding erlotinib to gemcitabine was $410,000 per year of life saved ($7,885 per week of life saved). When adjusted for the quality-of-life impact of diarrhea, the incremental cost-effectiveness ratio rose to $430,000 (low impact of diarrhea) and $510,000 (high impact of diarrhea) per QALY. These results are far above the commonly accepted cost-effectiveness threshold of $50,000 to $100,000 per QALY ($962 to $1,923 per quality-adjusted life week).5 The primary cost component is the cost of erlotinib. To be cost effective at threshold of $100,000 per QALY, the cost of an erlotinib course must be $2,500 (75% reduction). Or, given current costs and toxicity profile, erlotinib needs to provide a 50-day survival benefit (a five-fold increase). The results of this analysis must be considered within the context of the study. Although diarrhea was the only positive domain on the quality-of-life component of the PA.3 trial, it is possible that the impact of some adverse effects or adverse effect combinations were not captured. The results were robust to a sensitivity analysis on quality-of-life value for diarrhea. Because less than 15% of patients were alive at the time of PA.3's analysis, toxicities and benefits were not modeled beyond the time horizon of the trial. Although this analysis may not be generalizable outside of the trial setting, it is unlikely that the efficacy of erlotinib is superior in a community setting. Out-of-pocket expenses and time costs for patients and caregivers were not included in this analysis, biasing estimates in favor of erlotinib. This analysis suggests that the clinical significance and value of erlotinib's small survival benefit may be limited. In order to increase the value derived from adding erlotinib to gemcitabine, the survival benefit must increase dramatically or the cost of erlotinib must fall significantly. To our knowledge, this is the first cost-effectiveness analysis of erlotinib in advanced pancreatic cancer, which is already approved by the Food and Drug Administration.8 The results are consistent with those obtained in a study of the value of erlotinib in non–small-cell lung cancer.9 While the primary end point in the PA.3 trial reached statistical significance, it is important to place this finding in the context of the small size of the survival benefit afforded by erlotinib, the quality of life implications of treatment toxicities, and the lack of cost effectiveness. This analysis emphasizes the usefulness of cost-effectiveness analyses of novel targeted therapies in order to better understand the value of potential treatment options. In an ideal setting, the cost of novel antineoplastic therapies would be linked to the positive impact they exert on the disease process in question. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS Supported in part by the National Institutes of Health Grant No. R25 CA92203 (R.A.M.). REFERENCES 1. Li D, Xie K, Wolff R, et al: Pancreatic cancer. Lancet 363:1049-1057, 2004[CrossRef][Medline] 2. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007 3. Murray L: 2007 Red Book (ed 111). Montvale, NJ, Thomson Healthcare Inc, 2007 4. Centers for Medicare and Medicaid Services: DRG Relative Weights: FY07 Proposed Notice Data. Washington DC, United States Government, 2006 5. Earle CC, Chapman RH, Baker CS, et al: Systematic overview of cost-utility assessments in oncology. J Clin Oncol 18:3302-3317, 2000 6. Stewart ST, Lenert L, Bhatnagar V, et al: Utilities for prostate cancer health states in men aged 60 and older. Med Care 43:347-355, 2005[CrossRef][Medline] 7. Chang S, Long SR, Kutikova L, et al: Burden of pancreatic cancer and disease progression: Economic analysis in the US. Oncology 70:71-80, 2006[CrossRef][Medline] 8. National Cancer Institute: FDA approval for erlotinib hydrochloride.http://www.cancer.gov/cancertopics/druginfo/fda-erlotinib-hydrochloride#Anchor-Pancreati-44285 9. National Institute for Health and Clinical Excellence: Erlotinib for non-small-cell lung cancer: Appraisal consultation document.http://www.nice.org.uk/page.aspx?o=383603
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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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