To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population.
Methods
Controlled, nonrandomized retrospective observational study. Treatment-naïve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007-December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). Statistical analysis: median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test).
Results
In all, 69 patients were included: 32 (57.2 years –95%CI: 54.0–60.5–, 65.6% men) in CPT-FUFA group and 37 (68.1 years – 95%CI: 65.5–70.7–, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1–12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6–12.6) in bevacizumab_CPT-FUFA (hazard ratio = 1.22; 95%CI: 0.7–2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4–20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8–35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4–50) in 20/37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8–14,532.1) euros/patient.
Conclusion
The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progression-free survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.
JemalABrayFCenterMM. Global cancer statistics. CA Cancer J Clin2011; 61: 69–90.
2.
FerlayJAutierPBoniolM. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol2007; 18: 581–592.
3.
SiegelRNaishadhamDJemalA. Cancer statistics, 2012. CA Cancer J Clin2012; 62: 10–29.
4.
National Statistics Institute. [Deaths by cause of death. Year 2010]. Madrid: INE. http://www.ine.es/prensa/prensa. htm (2012, accessed 6 July 2012).
5.
EdwardsBKWardEKohlerBA. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer2010; 116: 544–573.
6.
Lopez-AbenteGArdanazETorrella-RamosA. Changes in colorectal cancer incidence and mortality trends in Spain. Ann Oncol2010; 21: iii76–iii82.
7.
MitryEGuiuBCosconeaS. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut2010; 59: 1383–1388.
8.
Howlader NNA, Krapcho M, Neyman N, et al. SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute Bethesda, MD, 2011.
9.
OkenMMCreechRHTormeyDC. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol1982; 5: 649–655.
10.
Van CutsemENordlingerBCervantesA. Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol2010; 21: v93–v97.
Garcia-CarboneroRGomez EspanaMACasado SaenzE. SEOM clinical guidelines for the treatment of advanced colorectal cancer. Clin Transl Oncol2010; 12: 729–734.
14.
DouillardJYCunninghamDRothAD. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet2000; 355: 1041–1047.
15.
SaltzLBCoxJVBlankeC. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med2000; 343: 905–914.
16.
AndreTLouvetCMaindrault-GoebelF. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer1999; 35: 1343–1347.
17.
Van CutsemEPozzoCStarkhammarH. A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer. Ann Oncol1998; 9: 1199–1204.
18.
KohneCHvan CutsemEWilsJ. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol2005; 23: 4856–4865.
19.
BouzidKKhalfallahSTujakowskiJ. A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer. Ann Oncol2003; 14: 1106–1114.
20.
FuchsCSMarshallJMitchellE. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol2007; 25: 4779–4786.
21.
RothenbergMLMeropolNJPoplinEA. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol2001; 19: 3801–3807.
22.
GoldbergRMSargentDJMcLeodH. Leveraging learning from a phase III colorectal cancer clinical trial: outcomes, methodology, meta-analysis and pharmacogenetics. Trans Am Clin Climatol Assoc2010; 121: 21–32. discussion 3.
23.
Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group In Cancer. J Clin Oncol1998; 16: 301–308.
24.
DelaunoitTGoldbergRMSargentDJ. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer2004; 101: 2170–2176.
HurwitzHFehrenbacherLNovotnyW. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med2004; 350: 2335–2342.
27.
GiantonioBJLevyDEO'DwyerPJ. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol2006; 17: 1399–1403.
28.
FuchsCSMarshallJBarruecoJ. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol2008; 26: 689–690.
29.
KopetzSHoffPMMorrisJS. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol2010; 28: 453–459.
30.
SobreroAAcklandSClarkeS. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology2009; 77: 113–119.
31.
KozloffMYoodMUBerlinJ. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist2009; 14: 862–870.
32.
Van CutsemERiveraFBerryS. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol2009; 20: 1842–1847.
33.
JansmanFGPostmaMJBrouwersJR. Cost considerations in the treatment of colorectal cancer. Pharmacoeconomics2007; 25: 537–562.
34.
ShiroiwaTFukudaTTsutaniK. Cost-effectiveness analysis of bevacizumab combined with chemotherapy for the treatment of metastatic colorectal cancer in Japan. Clin Ther2007; 29: 2256–2267.
35.
LymanGH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw2009; 7: 99–108.
36.
WildiersHReiserM. Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol2011; 77: 221–240.
37.
Food and Drug Administration. Guidance for industry. Clinical trial endpoints for the approval of cancer drugs and biologics. Rockville: FDA. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf (2007, accessed 18 August 2011).
38.
European Medicines Agency. Methodological considerations for using progression-free survival (PFS) as primary endpoint in confirmatory trials for registration. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man. London: EMA. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/12/WC500017736.pdf (2007, accessed 18 August 2011).
39.
TherassePArbuckSGEisenhauerEA. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst2000; 92: 205–216.
40.
KabbinavarFFHurwitzHIYiJ. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol2009; 27: 199–205.
41.
BuyseMBurzykowskiTCarrollK. Progression free survival is a surrogate for survival in advanced colorectal cancer. J Oncol2007; 25: 5218–5224.
42.
National Institute for Health and Clinical Excellence. Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. NICE technology appraisal guidance 118. London: NICE. http://www.nice.org.uk/nicemedia/pdf/TA118Guidance.pdf (2009, accessed 24 May 2011).
43.
TappendenPJonesRPaisleyS. The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales. Eur J Cancer2007; 43: 2487–2494.
44.
Gil-BazoIParamoJAGarcia-FoncillasJ. [New prognostic and predictive factors in advanced colorectal cancer]. Med Clin (Barc)2006; 126: 541–548.
45.
RonzoniMManzoniMMariucciS. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol2010; 21: 2382–2389.
46.
PohlMWernerNMundingJTannapfelA. Biomarkers of anti-angiogenic therapy in metastatic colorectal cancer (mCRC): original data and review of the literature. Z Gastroenterol2011; 49: 1398–1406.
