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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2226-2227 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.4244
To the EditorDepartment of Medical Oncology, Cancer Research UK, University of Glasgow, Glasgow, Scotland
Martin Luther University, Halle, Germany
University Hospital Gasthuisberg, Leuven, Belgium We read with interest the recent editorial by Dr Mayer1 published in the Journal of Clinical Oncology, which questioned whether capecitabine should replace infusional fluorouracil (FU) and leucovorin when combined with oxaliplatin in metastatic colorectal cancer. The author quite rightly points out that given the equal efficacy of capecitabine/oxaliplatin (XELOX) and oxaliplatin/infusional FU regimens as reported in phase II/III trials,2-6 tolerability, patient convenience, and cost need to be considered. In terms of safety, it is true that single-agent capecitabine was initially compared with bolus FU and was shown to be better tolerated.7,8 However, more recent data show quite clearly that combinations of capecitabine and oxaliplatin are as well tolerated as infusional FU/oxaliplatin regimens.2-5 We were particularly interested in the cost analysis presented toward the end of the editorial. In his analysis, Dr Mayer compares the XELOX regimen with various infusional regimens of FU and oxaliplatin, and concludes that XELOX is more costly than the FU-based comparators. We would like to challenge this assertion on several grounds. First, from our perspective, the pricing in Europe differs markedly from that in the United States and has significant implications for the cost of therapy. For the purposes of comparison, we estimated the costs of the regimens discussed by Dr Mayer, as well as two other regimens commonly used in Europe (FU, oxaliplatin, and leucovorin [FOLFOX-6 and FUFOX]). These cost estimates, which are based on publicly listed prices in Europe, are presented in Table 1 alongside Dr Mayer's estimates from his editorial. Though in the US the cost of the XELOX regimen was considerably higher than the FU-based regimens, in Europe it was consistently the lowest or second lowest-priced regimen (Table 1). The exact price differentials varied among European countries, but the ranking of XELOX in terms of cost was consistently lower than the data used by Dr Mayer.
Second, assumptions and cost estimates of any pharmacoeconomic analysis should be tested in a sensitivity analysis. As a reader, it appears that key assumptions made in the analysis described by Dr Mayer presuppose the worst scenario for XELOX and the best scenario for FU-based regimens. For example, it is assumed that a central venous access device (CVAD) is used for all patients receiving XELOX. Despite Dr Mayer's justification for this practice, prospective data show that this does not happen in the clinic. In NO16966, a phase III study involving more than 2,000 patients from 32 different countries, only 20% of the patients receiving XELOX had CVAD placements, whereas 100% of those receiving FU, oxaliplatin, and leucovorin (FOLFOX) had CVAD placements. It was also assumed that all patients receiving intravenous FU do not need to return to the clinic at the conclusion of their infusion for flushing the infusion line and disconnecting the pump. Again, we do not believe that this represents actual clinical practice in many institutions worldwide. We would like to draw readers’ attention to recently presented data from a cost analysis comparing XELOX with FOLFOX-4 based on prospective medical resource utilization data from NO16966.12 The analysis, which was performed from the perspective of a United States third-party payer, reported total direct medical cost estimates of US $45,800 for FOLFOX-4 and US $44,500 for XELOX. The costs considered in this analysis were drug acquisition; drug infusion and pump refill/maintenance; CVAD placement, removal, and maintenance; and the costs of treating adverse events (ie, hospitalization, ambulatory encounters, and concomitant medications). Furthermore, a French analysis, which considered hospitalization costs for drug administration only, showed that XELOX cost less than FOLFOX-6.13 The findings from these analyses should be considered alongside those reported in Dr Mayer's editorial before readers make a final decision about the relative cost of XELOX versus FU-based regimens. Third, we believe that important design features are missing from the cost analysis described by Dr Mayer. The perspective of any pharmacoeconomic analysis (for example, payer, patient, or society) should be clearly defined as it dictates the types of costs to be included (eg, direct costs, indirect costs, medical direct costs, and so on). This was not specified in the analysis described by Dr Mayer. Also, several important and relevant direct costs, (eg, specialist and physician fees, nurse time, laboratory tests, clinical preparatory work, costs of treating adverse events) do not seem to have been considered in the Mayer analysis, and indirect costs were not considered at all. Patient productivity losses and travel requirements are likely to differ markedly among XELOX and FU-based regimens, a point that was well illustrated in a recent medical resource use comparison of XELOX and FOLFOX-4.14 How accurate and generalizable is the estimate of US $275 (Table 21) for the cost of a newly attached pump and a visit to the clinic infusion room? Does the estimate include labor costs for nurse time and physician consult fees? Costs for clinic visits and this type of resource use are generally much higher than this, which would have increased the cost of the FU-based regimens considerably more than the estimates given. Fourth, intravenous drug administration charges from the Dana-Farber Cancer Institute were considered alongside the average wholesale price (AWP), which was used to estimate drug acquisition costs, but it is not clear exactly who would pay these costs. We believe that the choice of AWP needs to be reconsidered as it is not the best proxy for estimating drug acquisition cost. There is often a wide disparity between AWP and the actual selling price of pharmaceutical products,15 which can include rebates or discounts. Dr Mayer's decision to use AWP rather than Medicare reimbursement rates, for example, has profound implications for the final cost outcome as the analysis was highly sensitive to this input. In our experience, differences in the calculations and the region in which a pharmacoeconomic analysis is performed can lead to regional-specific conclusions. We believe that this point should be borne in mind when interpreting Dr Mayer's editorial. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Jim Cassidy, Roche (C), Sanofi-aventis (C); Hans-Joaquim Schmoll, Roche (C), Sanofi-aventis (C); Eric Van Cutsem, Roche (C) Stock Ownership: None Honoraria: Jim Cassidy, Roche, Sanofi-aventis; Hans-Joaquim Schmoll, Roche, Sanofi-aventis Research Funding: Jim Cassidy, Roche, Sanofi-aventis; Eric Van Cutsem, Roche, Sanofi-aventis Expert Testimony: None Other Remuneration: None
REFERENCES
1. Mayer RJ: Should capecitabine replace infusional fluorouracil and leucovorin when combined with oxaliplatin in metastatic colorectal cancer? J Clin Oncol 25:4165-4167, 2007 2. Cassidy J, Clarke S, Diaz Rubio E, et al: XELOX compared to FOLFOX4: Survival and response results from XELOX-1/NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25:171s, 2007 (suppl, abstr 4030)[CrossRef] 3. Ducreux M, Bennouna J, Hebbar M, et al: Efficacy and safety findings from a randomized phase III study of capecitabine (X) + oxaliplatin (O) (XELOX) vs. infusional 5- FU/LV + O (FOLFOX-6) for metastatic colorectal cancer (MCRC). J Clin Oncol 25:170s, 2007 (suppl, abstr 4029) 4. Porschen R, Arkenau H-T, Kubicka S, et al: Capecitabine plus oxaliplatin versus fluorouracil/leucovorin plus oxaliplatin: A randomized comparison in metastatic colorectal cancer. J Clin Oncol 25:4217-4223, 2007 5. Díaz-Rubio E, Tabernero J, Gómez-España A, et al: Phase III trial of capecitabine and oxaliplatin (XELOX) vs continuous infusion fluorouracil plus oxaliplatin (FUOX) as first-line therapy in metastatic colorectal cancer: Final report of the Spanish TTD group trial. J Clin Oncol 25:4224-4230, 2007 6. Rothenberg ML, Navarro M, Butts C, et al: Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25:171s, 2007 (suppl; abstr 4031)[CrossRef] 7. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001 8. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001 9. Healthcare Republic: MIMS Database. http://www.mims.co.uk 10. Rote Liste: Rote Liste Online. http://www.roteliste.de 11. Institut national d'assurance maladie-invalidité: Honoraires, prix et remboursements. http://www.inami.be 12. Garrison L, Cassidy J, Saleh M, et al: Cost comparison of XELOX compared to FOLFOX4 with or without bevacizumab (bev) in metastatic colorectal cancer. J Clin Oncol 25:182s, 2007 (suppl, abstr 4074) 13. Perrocheau G, Ducreux M, Hebbar M, et al: Cost-minimization analysis of capecitabine + oxaliplatin (XELOX) vs. Infusional 5-fu/lv + oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer (MCRC) in the French setting. Proc ISPOR 10th Annual European Congress, Dublin, Ireland, October 20-23, 2007 (abstr EC3) 14. Scheithauer W, Cassidy J, Figer A, et al: A comparison of medical resource use for 4 chemotherapy regimens as first-line treatment for metastatic colorectal cancer (MCRC): XELOX vs. FOLFOX4 ± bevacizumab (A). J Clin Oncol 25:188s, 2007 (suppl, abstr 4098) 15. Kolassa EMM: Elements of Pharmaceutical Pricing. New York, NY, The Pharmaceutical Products Press, 1997 Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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