Escudier, B

Mickisch, G H J

Nuijten, M

Walzer, S

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G H J Mickisch

B Escudier

S Walzer

M Nuijten

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British Journal of Cancer

Reply: Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-α2a compared with sunitinib

Mickisch, G.H.J.

Escudier, B. (B.)

Walzer, S. (S.)

Nuijten, M.J.C. (Mark)

Erasmus University Digital Repository

Letter to the EditorReply: Costs of managing adverse events in the treatmentof first-line metastatic renal cell carcinoma: bevacizumabin combination with interferon-a2a compared with sunitinibGHJ Mickisch*,1, B Escudier2, S Walzer3 and M Nuijten41Center of Operative Urology, Bremen 28277, Germany; 2Institut Gustave Roussy, Villejuif 94805, France; 3F Hoffmann-La Roche Ltd., Basel CH-4070,Switzerland; 4Erasmus University, Rotterdam 1546 LG, The NetherlandsBritish Journal of Cancer (2010) 103, 1309 – 1310. doi:10.1038/sj.bjc.6605887 www.bjcancer.com& 2010 Cancer Research UKSir,We welcomed the response and debate regarding treatment-related costs in metastatic renal cell carcinoma (RCC) providedby Charbonneau (Pfizer, USA) and Sandin (Pfizer, Sweden)(Charbonneau and Sandin, 2010). However, there are severalpoints in their letter we would like to address.Novel therapies for the treatment of metastatic RCC havedifferent tolerability profiles, which are largely based on differ-ences in mechanism of action (Schmidinger and Zielinski, 2009).Side effects of therapy may have a different impact on individualpatients, with the potential to disrupt well-being, daily activities/function and overall quality of life. The management of side effectsis a concern for physicians due to the potential for temporary orpermanent withdrawal of therapy to manage side effects, meaningthat patients may receive a suboptimal treatment benefit. Themanagement of side effects also represents additional costs forpayers and contributes to the total cost of therapy.Two of the standard first-line treatment options for patientswith metastatic RCC, bevacizumabþ IFN and sunitinib, havelargely different safety profiles. Vascular endothelial growth factor(VEGF)-related side effects such as hypertension are observed withboth therapies, but non-VEGF-related side effects such as hand-foot syndrome are also seen in patients treated with sunitinib(Escudier et al, 2007; Motzer et al, 2007). Our original paperoutlined that bevacizumabþ IFN is associated with lower adverseevent management costs than sunitinib, largely based on thedifference in tolerability profiles. These data are supported byanother recent analysis of healthcare costs in the United States thatreported that the adverse event management costs for bevacizumabare 2–3 times lower than those for sunitinib (Oh et al, 2010).One point that we would like to reiterate is that there is strongevidence to indicate that bevacizumabþ IFN has similar efficacyto sunitinib in patients with metastatic RCC. The two pivotaltrials for these therapies in metastatic RCC showed that bothbevacizumabþ IFN and sunitinib significantly improved progres-sion-free survival (PFS) compared with IFN, with a median PFSof 10.2 and 11.0 months, respectively. Furthermore, a robustmeta-analysis performed by the Cochrane Collaboration concludedthat bevacizumabþ IFN provides similar efficacy to sunitinib inuntreated patients with metastatic RCC (Coppin et al, 2008).In our original publication, we addressed the papers byThompson-Coon et al and Mills et al, both of which suggestedthat sunitinib is significantly more efficacious than bevacizumabþIFN (Mills et al, 2009; Thompson Coon et al, 2009). A signi-ficant limitation of these analyses is the inclusion of data forbevacizumabþ IFN from CALGB 90206, an open-label phase III trialwith some important differences in patient demographics comparedwith AVOREN. We argue that a valid indirect comparison of PFSshould only use the pivotal trial data, performed under the sameconditions and providing the same quality of data (independentradiology review of PFS from controlled, blinded studies that are notcomparable to open-label studies). Furthermore, a recent analysis ofindependently assessed PFS data from AVOREN and the phase IIIsunitinib trials reported that there is no significant difference infirst-line PFS between sunitinib and bevacizumabþ IFN (HR¼ 0.94(95% CI: 0.69–1.29; P¼ 0.709)) (Mickisch et al, 2010a, b).Additionally, repeating the Mills et al, analysis, which is moreconservative than the Thompson Coon analysis, with theinvestigator assessing data from the pivotal trials of sunitiniband bevacizumabþ IFN results in a non-significant PFS HR of 0.83(95% CI: 0.64–1.06; P¼ 0.13) (Mickisch et al, 2009a, b).It is well recognised that non-VEGF-related side effects such asfatigue, GI events, HFSR, myelosuppression, diarrhoea, mucositisand rash, although often not severe, can have an impact on thepatient’s quality of life (Porta and Szczylik, 2009). Therefore, anability to effectively manage side effects and get patients and/orcarers back to work may represent a hidden cost benefit that hasnot been addressed in cost-related analyses to date and should helpto reduce health-related costs.As we outlined in our paper, adverse event management costsvary for each country and for each side effect. For example,haematological adverse events, which are reported more frequentlywith sunitinib than with bevacizumab, are likely to have thehighest management costs and therefore a greater impact on thetotal adverse event management costs. Another consideration isthat some adverse events may be experienced for prolongedperiods and may require repeated treatment measures, which maynot be captured by an analysis such as ours.*Correspondence: Professor GHJ Mickisch;E-mail: gerald.mickisch@coub.deBritish Journal of Cancer (2010) 103, 1309 – 1310& 2010 Cancer Research UK All rights reserved 0007 – 0920/10www.bjcancer.comCharbonneau and Sandin stated that our analysis may haveoverestimated the costs associated with the management of someadverse events, based on a lower cost for the treatment of grade 3/4thrombocytopenia reported in the latest UK National HealthService costs (2010). This observation is correct as we used anolder version of the UK National Health Service costs (NHSreference costs 2006–2007), based on the timing for developmentand submission of our original paper. However, the reportedincidence of grade 3/4 thrombocytopenia with sunitinib is higherthan that seen with bevacizumabþ IFN and therefore theproportional cost for this side effect will remain higher forpatients treated with sunitinib.Overall, treatment-related costs are likely to include acquisitioncosts, administration costs and costs related to the management ofadverse events. Drug acquisition costs will evidently vary due tocountry-specific initiatives agreed between the healthcare autho-rities and pharmaceutical companies. In consequence, overalltreatment costs are not a primary consideration if looking at cross-country trends and differences as a scientific objective. In contrast,secondary costs such as costs associated with the treatment ofadverse events are directly related to the drug involved and largelyindependent of the pricing strategies of the manufacturer. Weagree that the management of adverse event costs is comparativelysmall compared with that of acquisition costs. However, adverseevents and their management may substantially impact on patientquality of life, remain independent of the acquisition costs andhinder physician care. This is most important from a clinician’spoint of view.Taking into account all healthcare-related costs, including anydifferences in drug acquisition costs and costs related to themanagement of adverse events, an analysis of healthcare costsbased on the Italian healthcare system reported comparable annualcosts for bevacizumabþ IFN and sunitinib (Ravasio, 2009). Moreover,an analysis based on healthcare costs in the United Kingdom bythe National Institute of Clinical Excellence (NICE) reported thatbevacizumabþ IFN and sunitinib had comparable incremental cost-effectiveness ratios: d53 820 and d50 000, respectively (NICE, 2009).The management of adverse events has important implicationsfor patients, physicians and payers. In the absence of direct head-to-head clinical assessment, a model such as ours is currentlythe only available way to assess the costs associated with themanagement of adverse events, which may help to facilitate thedecision-making process.ACKNOWLEDGEMENTSMedical writing support was provided by Gardiner-CaldwellCommunications, Macclesfield, UK, and funded by F Hoffmann-LaRoche Ltd.REFERENCESCharbonneau C, Sandin R (2010) Comment on ‘Costs of managing adverseevents in the treatment of first-line metastatic renal cell carcinoma:bevacizumab in combination with interferon-a2a compared withsunitinib’. Br J Cancer 103: 1307–1308Coppin C, Le L, Porzsolt F, Wilt T (2008) Targeted therapy for advancedrenal cell carcinoma. Cochrane Database Syst Rev, (2): Art. No. CD006017Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C,Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO,Bodrogi I, Jagiello-Gruszfeld A, Moore N, AVOREN Trial investigators(2007) Bevacizumab plus interferon alfa-2a for treatment of metastaticrenal cell carcinoma: a randomised, double-blind phase III trial. Lancet370: 2103–2111Mickisch GH, Schwander B, Escudier BJ, Bellmunt J, Maroto JP, Porta C,Walzer S, Nuijten M (2010a) Indirect comparison of two targetedtherapies in first-line metastatic renal cell carcinoma therapy: aninvestigation of the influence of patient compliance and down-dosingon the progression-free survival. Presented at the 2010 GenitourinaryCancers Symposium; 5–7 March 2010; San Francisco, CA. Abstract 403.Available at: http://www.asco.orgMickisch GH, Schwander B, Escudier B, Bellmunt J, Maroto P, Porta C,Walzer S, Siebert U (2009b) A comparative effectiveness assessment offirst-line bevacizumab + interferon alpha-2 vs sunitinib in metastaticrenal cell carcinoma. Value Health 12: A528 (abstract PCN13)Mickisch GH, Schwander B, Walzer S (2009a) Metastatic renal cell carcinoma: acomparative effectiveness assessment of first-line bevacizumab + interferonalpha-2a vs sunitinib. Eur J Cancer, 4(Suppl 1): 437 (abstract 7146)Mickisch GH, Schwander B, Escudier BJ, Bellmunt J, Maroto PJ, Porta C,Walzer S, Nuijten M (2010b) Indirect comparison of bevacizumab plusinterferon-alpha-2a versus tyrosine kinase inhibitors in first-line metastaticrenal cell carcinoma therapy. J Clin Oncol 28(Suppl): 369s (abstract 4612)Mills EJ, Rachlis B, O’Regan C, Thabane L, Perri D (2009) Metastatic renal cellcancer treatments: an indirect comparison meta-analysis. BMC Cancer 9: 34Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O,Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM,Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cellcarcinoma. N Engl J Med 356: 115–124National Health Service reference costs 2006–2007 Published 1 February 2008http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_082571NICE guidance on RCC. http://guidance.nice.org.uk/TA178Oh WK, McDermott DF, Duh MS, Antra`s L, Chen K, Sarda SP, Luka A,Neary M, Choueiri TK (2010) Healthcare costs in patients (pts) withmetastatic renal cell carcinoma treated with angiogenesis inhibitors.Presented at the 2010 Genitourinary Cancers Symposium; 5–7 March2010; San Francisco, CA. Abstract 356. Available at: http://www.asco.orgPorta C, Szczylik C (2009) Tolerability of first-line therapy for metastaticrenal cell carcinoma. Cancer Treat Rev 35: 297–307Ravasio R (2009) Economic evaluation of bevacizumabþ interferon vssunitinib in the first line treatment of metastatic renal cell carcinoma inview of the AIFA cost-slanting agreements. 8th National Convention‘Economics of Drugs and Health Technologies’; 21–22 May 2009; MilanSchmidinger M, Zielinski CC (2009) Novel agents for renal cell carcinomarequire novel selection paradigms to optimise first-line therapy. CancerTreat Rev 35: 289–296Thompson Coon JS, Liu Z, Hoyle M, Rogers G, Green C, Moxham T,Welch K, Stein K (2009) Sunitinib and bevacizumab for first-linetreatment of metastatic renal cell carcinoma: a systematic review andindirect comparison of clinical effectiveness. Br J Cancer 101: 238–243This work is licensed under the Creative CommonsAttribution-NonCommercial-Share Alike 3.0 UnportedLicense. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Letter to the Editor1310British Journal of Cancer (2010) 103(8), 1309 – 1310 & 2010 Cancer Research UK

Reply: Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: Bevacizumab in combination with interferon-α2a compared with sunitinib

Comment on ‘Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-a2a compared with sunitinib’.

Reply: Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-α2a compared with sunitinib

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