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Originally published as JCO Early Release 10.1200/JCO.2006.05.6812 on May 8 2006 © 2006 American Society of Clinical Oncology.
When the Risk of Febrile Neutropenia Is 20%, Prophylactic Colony-Stimulating Factor Use Is Clinically Effective, but Is It Cost-Effective?Dartmouth University, Hanover, NH
Northwestern University, Chicago, IL A major change in the 2006 American Society of Clinical Oncology (ASCO) guidelines for white-cell growth factors is to recommend use of granulocyte colony-stimulating factor (GSCF) or granulocyte-macrophage colony-stimulating factor when the risk of febrile neutropenia (FN) is approximately 20%, rather than 40% as in the 1996, 1997, and 2000 guidelines.1 The National Comprehensive Cancer Center Network (NCCN) also recently revised their own guidelines in favor of a 20% FN threshold for a definite indication of colony-stimulating factor (CSF) prophylaxis and a 10% to 20% FN threshold range indicating optional CSF prophylaxis.2 This change is based largely on two new phase III clinical trials that show CSFs are effective when the risk of FN is approximately 20%.3,4 In the first study, Vogel et al3 compared patients with breast cancer who received docetaxel 100 mg/m2 with or without pegylated GCSF; the risk of FN was reduced from 17% without to 1% with GCSF, and the risk of hospitalization for FN was reduced from 14% without to 1% with GCSF. A second study by Timmer-Bonte et al4 showed that the risk of FN in small-cell lung cancer (SCLC) patients at high risk of FN could be reduced from 24% to 10% in cycle 1 by adding CSF. Although this regimen is not widely used in the United States, the SCLC trial supports the results of the breast cancer trial: CSFs reduce the risk of FN, even when that risk is relatively low. Previous studies had shown both clinical efficacy and cost neutrality with CSF use after intense chemotherapy regimens with FN risks of 40% or higher.5,6 We question the cost implications of the 2006 ASCO recommendation to decrease the threshold to 20% rates of FN. The revised ASCO guideline is likely to have its largest effect on reimbursement decisions for CSFs by third-party payers. The prior CSF guideline had only modest impact on physician behavior, as prophylactic CSF use varies greatly among and within practices.7-10 One reason for wide practice variations may be the uncertainty of cost-effectiveness of CSFs.5 For example, the study by Timmer-Bonte et al4 found benefit even when compared with antibiotic prophylaxis alone. However, the benefit of CSF prophylaxis decreased in later chemotherapy cycles, primarily because of lower rates of FN in the arm that did not receive CSF. Incorporating prospective economic analyses alongside phase III clinical trials is a positive new trend; in this issue of the Journal of Clinical Oncology, Timmer-Bonte et al11 add to the debate about whether the reduction of FN by 14% in the first cycle is worth the additional cost of CSF for all patients. Cost-effectiveness analyses, both trial-based and model-based, have become increasingly accepted by and important for reimbursement consideration in federal health systems, managed care organizations, and private health insurers.12 Trial-based analyses rely on data collected within a clinical trial, whereas model-based analyses make assumptions by collecting clinical and economic data from many sources. Trial-based analyses may be prospective, which are built into the data collection protocol, or retrospective, which are initiated after the results are known. Prospective trial-based cost-effectiveness analyses offer some advantages over other economic analyses. By initiating the analysis prospectively, Timmer-Bonte et al11 avoid a main criticism of retrospective analyses—biased selection of clinical effectiveness data.13,14 Prospective trial-based cost-effectiveness analyses offer an advantage over model-based cost-effectiveness analyses as well; model-based analyses rely on expert opinions and assumptions, and they may omit important costs. For the same reason, prospective analyses of clinical trials reporting intention-to-treat analysis can yield more complete economic pictures. For example, although Timmer-Bonte et al11 were unable to identify significant differences in non–FN-related adverse events between arms, the benefit of CSF use increased substantially when they included non-FN toxicity cost data. This may support unpublished findings that FN events, although not directly causing new toxicity, may exacerbate the severity of other chemotoxic events.15 Economic models of CSF in SCLC have historically omitted non–FN-related costs.5 There are normative reasons for including societal costs in cost-effectiveness analyses.13 Inclusion of societal costs, such as loss of productivity, can double the total costs of an episode of FN, shifting the cost-effectiveness decision in favor of CSF use.16,17 Timmer-Bonte et al11 do not include these costs in their analysis; however, many organizations will prefer a third-party payer perspective, so this is not a critical omission. Moreover, it is unlikely that productivity losses in this clinical trial would be large, given the old age and extent of severe comorbidity of the trial participants. Despite similar recommendations, there are important distinctions in the supporting text of the 2005 NCCN guidelines and the 2006 ASCO guidelines, primarily related to cost considerations. As noted in the NCCN guidelines, when societal costs are considered, the economic impact of FN becomes greater, and the cost-saving benefits of CSF are more apparent. The Timmer-Bonte et al11 economic analysis in this issue of the Journal of Clinical Oncology confirms the NCCN economic assessments of CSF use. Adding CSF to antibiotic prophylaxis increased per-patient cost in the European setting by $650 (US) in the first cycle and $5,000 overall. However, prophylactic regimens and reduced toxicity appear more cost effective in the United States, where costs of each episode of FN can be four times greater than in Europe because of markedly greater healthcare and hospital expenditures.18 In addition, the indirect costs of FN can be substantial. It is entirely possible that, in the United States, CSF use for primary prophylaxis in the setting of cancer chemotherapies associated with a 20% rate of FN may be both clinically effective and cost effective. Clinical guidelines are important in summarizing evidence, but they have had only marginal effect on physician practice with respect to CSF use.7,19 Formulary managers and insurers have important roles in affecting CSF use, and academic researchers have an obligation to provide high-quality economic information.20 Societal costs, out-of-pocket expenses, and indirect costs factor largely into the cost of cancer care and are significant burdens to patients.21 Ultimately, clinical benefits of CSF use are now evident at a 20% threshold rate of FN. Extrapolation of the study by Timmer-Bonte et al11 to the United States, with inclusion of a societal perspective and domestic estimates of resource costs, may find that this practice is cost neutral. As with the 40% FN threshold originally supported in the 1996 ASCO guidelines, current, detailed information on the economic implications of a 20% FB threshold for CSF is necessary. Although the Timmer-Bonte et al11 cost study from Europe provides an important template for this analysis, an economic modeling effort of cost implications of this important study for the United States would be helpful. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES
1. Smith TJ, Khatcheressian J, Lyman GH: 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based, clinical practice guideline. J Clin Oncol 24:3187-3205, 2006 2. NCCN Releases New Myeloid Growth Factors Clinical Practice Guidelines. http://www.nccn.org/about/news/newsinfo.asp?NewsID=50 3. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178-1184, 2005 4. Timmer-Bonte JN, De Boo TM, Smit HJ, et al: Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: A Dutch randomized Phase III study. J Clin Oncol 23:7974-7984, 2005 5. Adams JR, Lyman GH, Djubegovic B, et al: G-CSF as prophylaxis of febrile neutropenia in SCLC. Expert Opin Pharmacother 3:1273-1281, 2002[CrossRef][Medline] 6. Lyman GH: Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: A review of the evidence. J Natl Compr Canc Netw 3:557-571, 2005[Medline] 7. Swanson G, Bergstrom K, Stump E, et al: Growth factor usage patterns and outcomes in the community setting: Collection through a practice-based computerized clinical information system. J Clin Oncol 18:1764-1770, 2000 8. Bennett CL, Weeks JA, Somerfield MR, et al: Use of hematopoietic colony-stimulating factors: Comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. J Clin Oncol 17:3676-3681, 1999 9. Bach PB: Using Practice Guidelines to Assess Cancer Care Quality. J Clin Oncol 23:9041-9043, 2005 10. Harlan L, Greene AL, Limin X, et al: Insurance status and the use of guideline therapy in the treatment of selected cancers. J Clin Oncol 23:9079-9088, 2005 11. Timmer-Bonte JN, Adang EM, Smit HM, et al: Cost-effectiveness of adding ganulocyte-colony stimulating factor to pimary prophylaxis with antibiotics in small-cell lung cancer. J Clin Oncol 24:2991-2997, 2006 12. Glandon GL, Shapiro RJ: Economic and quality of life outcomes: managed care perspectives. Oncology 9:111-119, 1995 (suppl 11)[Medline] 13. Drummond M, Sculpher M. Common methodological flaws in economic evaluations. Med Care 43:5-14, 2005 (suppl 7)[Medline] 14. Friedberg M, Saffran B, Stinson TJ, et al: Evaluation of conflict of interest in economic analyses of new drugs used in oncology. JAMA 282:1453-1457, 1999 15. Glaspy J, Hackett J, Flyer P, et al: Febrile neutropenia is associated with an increase in the incidence, duration, and severity of chemotherapy toxicities. Blood 98:432a, 2001 16. Calhoun EA, Schumock GT, McKoy JM, et al: Granulocyte colony–stimulating factor for chemotherapy-induced neutropenia in patients with small cell lung cancer: The 40% rule revisited. Pharmacoeconomics 23:767-775, 2005[CrossRef][Medline] 17. Cosler LE, Calhoun EA, Agboola O, et al: Effects of indirect and additional direct costs on the risk threshold for prophylaxis with colony-stimulating factors in patients at risk for severe neutropenia from cancer chemotherapy. Pharmacotherapy 24:488-494, 2004[CrossRef][Medline] 18. Smith DH, Adams JR, Johnston SR, et al: A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the United States and the United Kingdom. Ann Oncol 13:1590-1597, 2002 19. Bennett CL, Stinson TJ, Laver JH, et al: Cost analyses of adjunct colony stimulating factors for acute leukemia: Can they improve clinical decision making. Leuk Lymphoma 37:65-70, 2000[Medline] 20. Bennett CL, Armitage JL, LeSage S, et al: Economic analyses of clinical trials in cancer: Are they helpful to policy makers? Stem Cells 12:424-429, 1994[Abstract] 21. Calhoun EA, Chang CH, Welshman EE, et al. Evaluating the total costs of chemotherapy-induced toxicity: Results from a pilot study with ovarian cancer patients. Oncologist 6:441-445, 2001
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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