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PharmacoEconomics

, Volume 36, Issue 7, pp 837–851 | Cite as

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England

  • Irina A. Tikhonova
  • Nicola Huxley
  • Tristan Snowsill
  • Louise Crathorne
  • Jo Varley-Campbell
  • Mark Napier
  • Martin Hoyle
Original Research Article

Abstract

Background

Combination therapies with cetuximab (Erbitux®; Merck Serono UK Ltd) and panitumumab (Vectibix®; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family.

Objective

The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective.

Methods

We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum.

Results

Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence’s end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence’s threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments.

Conclusion

Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Notes

Acknowledgements

The authors thank Mrs. Sue Whiffin and Ms. Jenny Lowe for the excellent administrative support.

Author Contributions

IAT drafted the final version of the manuscript; NH, TS, LC, JVC, MN and MH revised the manuscript prior to submission. MH is the overall guarantor of the content.

Funding

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (14/65/01). The original report submitted by the Peninsula Technology Assessment Group to the National Institute for Health and Care Excellence on 7 August, 2015 was published in full in Health Technology Assessment [48]. Visit the HTA Programme website for further information [18]. This report presents independent research commissioned by the NIHR. The views and opinions expressed by the authors in this publication are those of the authors and do not necessarily reflect those of the National Health Service, the NIHR, Medical Research Council, the NIHR HTA Programme or the Department of Health.

Compliance with Ethical Standards

Conflict of interest

Irina A. Tikhonova, Nicola Huxley, Tristan Snowsill, Louise Crathorne, Jo Varley-Campbell, Mark Napier and Martin Hoyle have no conflicts of interest directly relevant to the content of this article.

Supplementary material

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Supplementary material 1 (PDF 137 kb)
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Supplementary material 2 (PDF 365 kb)
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Supplementary material 3 (PDF 40 kb)
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Supplementary material 4 (PDF 176 kb)
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Supplementary material 5 (PDF 437 kb)
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Supplementary material 6 (PDF 27 kb)
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Supplementary material 7 (PDF 76 kb)

References

  1. 1.
    Cancer Research UK. Bowel cancer incidence statistics. London: Cancer Research UK; 2011. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/bowel/incidence/#source23. Accessed 23 Jan 2015.
  2. 2.
    Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, Group EGW. Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl. 3):iii1–9.  https://doi.org/10.1093/annonc/mdu260.CrossRefPubMedGoogle Scholar
  3. 3.
    National Cancer Intelligence Network. Colorectal cancer. 2009. http://www.ncin.org.uk/cancer_type_and_topic_specific_work/cancer_type_specific_work/colorectal_cancer/. Accessed 5 Jun 2017.
  4. 4.
    Adam R, Wicherts DA, de Haas RJ, Ciacio O, Levi F, Paule B, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27(11):1829–35.  https://doi.org/10.1200/JCO.2008.19.9273.CrossRefPubMedGoogle Scholar
  5. 5.
    National Institute for Health and Care Excellence. Colorectal cancer: diagnosis and management. 2014. https://www.nice.org.uk/guidance/cg131. Accessed 9 May 2017.
  6. 6.
    Merck Serono. Summary of product characteristics: Erbitux (cetuximab). Feltham, UK: Merck Serono; 2014.Google Scholar
  7. 7.
    Amgen Ltd. Summary of product characteristics: Vectibix (panitumumab). Cambridge: Amgen Ltd; 2014.Google Scholar
  8. 8.
    Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22.  https://doi.org/10.1038/nrc969.CrossRefPubMedGoogle Scholar
  9. 9.
    Goodsell DS. The molecular perspective: the ras oncogene. Oncologist. 1999;4(3):263–4.PubMedGoogle Scholar
  10. 10.
    Bokemeyer C, Bondarenko I, Hartmann JT, Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22(7):1535–46.  https://doi.org/10.1093/annonc/mdq632.CrossRefPubMedGoogle Scholar
  11. 11.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25:1346–55.CrossRefPubMedGoogle Scholar
  12. 12.
    Heinemann V, Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–75.  https://doi.org/10.1016/S1470-2045%2814%2970330-4.CrossRefPubMedGoogle Scholar
  13. 13.
    Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:2240–7.CrossRefPubMedGoogle Scholar
  14. 14.
    European Medicines Agency. Cetuximab (Erbitux): summary of opinion (post authorisation). London: European Medicines Agency; 2011.Google Scholar
  15. 15.
    European Medicines Agency. Panitumumab (Vectibix): summary of opinion (post authorisation). London: European Medicines Agency; 2011.Google Scholar
  16. 16.
    European Medicines Agency. Cetuximab (Erbitux) assessment report (variation assessment report; EMEA/h/C/000558/II/0062). London: European Medicines Agency; 2013.Google Scholar
  17. 17.
    European Medicines Agency. Panitumumab (Vectibix) assessment report (variation assessment report; EMEA/H/C/000741/II/0050). London: European Medicines Agency; 2013.Google Scholar
  18. 18.
    National Institute for Health Research. Health Technology Assessment (HTA) programme. 2016. http://www.hta.ac.uk. Accessed 8 Apr 2016.
  19. 19.
    National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. 2013. http://www.nice.org.uk/article/pmg9/chapter/foreword. Accessed 20 Feb 2018.
  20. 20.
    National Institute for Health and Care Excellence. Technology appraisal 176 (TA176): cetuximab for the first-line treatment of metastatic colorectal cancer. London: NICE; 2009.Google Scholar
  21. 21.
    NHS England. Cancer drugs fund decision summary: panitumumab: treatment of adult patients with wild-type RAS (KRAS and NRAS) metastatic colorectal cancer (mCRC) in first-line in combination with FOLFOX. London: NHS England; 2014. Available from: https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&ved=0ahUKEwjV8v2m4rPVAhVpJcAKHXWCBVgQFggwMAI&url=https%3A%2F%2Fwww.nice.org.uk%2Fguidance%2Fta240%2Fdocuments%2Fcolorectal-cancer-metastatic-panitumumab-terminated-appraisal-appendix-b-ge-proposal-paper-january-20152&usg=AFQjCNFLNQSDzjhnmBQESt9XA7YRfoT9hg. Accessed 20 Feb 2018.Google Scholar
  22. 22.
    National Institute for Health and Care Excellence. Cetuximab (review of TA176) and panitumumab (partial review of TA240) for the first line treatment of metastatic colorectal cancer [ID794]. 2017. https://www.nice.org.uk/guidance/ta439/evidence. Accessed 9 Aug 2017.
  23. 23.
    PROSPERO international prospective register of systematic reviews. Cetuximab (review of TA176) and panitumumab (partial review of TA240) for the first line treatment of metastatic colorectal cancer. 2015. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015016111. Accessed 12 Jun 2017.
  24. 24.
    Tejpar S, Kohne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer. 2015;51(10):1243–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692–700.  https://doi.org/10.1200/JCO.2014.59.4812.CrossRefPubMedGoogle Scholar
  26. 26.
    England NHS. Cancer drugs fund decision summary: bevacizumab in combination with 1st line single agent fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. London: NHS England; 2015.Google Scholar
  27. 27.
    National Institute for Health and Care Excellence. National cancer drugs fund list. 2017. https://www.england.nhs.uk/publication/national-cancer-drugs-fund-list/. Accessed 5 Jun 2017.
  28. 28.
    Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU technical support document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. Sheffield: National Institute for Health and Care Excellence Decision Support Unit; 2014.Google Scholar
  29. 29.
    National Institute for Health and Care Excellence. Cetuximab and panitumumab for previously untreated metastatic colorectal cancer. 2017. https://www.nice.org.uk/guidance/ta439. Accessed 9 May 2017.
  30. 30.
    Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.CrossRefPubMedGoogle Scholar
  31. 31.
    Woods B, Sideris E, Palmer S, Latimer N, Soares M. NICE DSU TSD19: partitioned survival analysis for decision modelling in health care: a critical review. 2017. http://scharr.dept.shef.ac.uk/nicedsu/wp-content/uploads/sites/7/2017/06/Partitioned-Survival-Analysis-final-report.pdf. Accessed 12 Jun 2017.
  32. 32.
    Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240(4):644–57 (discussion 57–8).PubMedPubMedCentralGoogle Scholar
  33. 33.
    Soares MO, Canto ECL. Continuous time simulation and discretized models for cost-effectiveness analysis. Pharmacoeconomics. 2012;30(12):1101–17.  https://doi.org/10.2165/11599380-000000000-00000.CrossRefPubMedGoogle Scholar
  34. 34.
    Adam R, De Gramont A, Figueras J, Guthrie A, Kokudo N, Kunstlinger F, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist. 2012;17(10):1225–39.  https://doi.org/10.1634/theoncologist.2012-0121.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229–37.  https://doi.org/10.1200/JCO.2004.05.113.CrossRefPubMedGoogle Scholar
  36. 36.
    Bormann I. Digitizer software. 2015. http://www.digitizeit.de/. Accessed 20 Feb 2018.
  37. 37.
    Latimer NR, Abrams KR, Lambert PC, Crowther MJ, Wailoo AJ, Morden JP, et al. Adjusting survival time estimates to account for treatment switching in randomized controlled trials: an economic evaluation context: methods, limitations, and recommendations. Med Decis Making. 2014;34(3):387–402.  https://doi.org/10.1177/0272989X13520192.CrossRefPubMedGoogle Scholar
  38. 38.
    Curtis L. Unit costs of health and social care 2014. Canterbury: Personal Social Services Research Unit, University of Kent; 2014.Google Scholar
  39. 39.
    CCEMG and EPPI-Centre. CCEMG - EPPI-Centre Cost Converter. 2014. https://eppi.ioe.ac.uk/costconversion/default.aspx. Accessed 1 Aug 2015.
  40. 40.
    Hoyle M, Crathorne L, Peters J, Jones-Hughes T, Cooper C, Napier M, et al. The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal no. 150 and part review of technology appraisal no. 118): a systematic review and economic model. Health Technol Assess. 2013;17(14):1–237.  https://doi.org/10.3310/hta17140.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Department of Health, Commercial Medicines Unit. Drugs and pharmaceutical electronic market information (eMIT). 2015. https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit. Accessed 20 Feb 2018.
  42. 42.
    Joint Formulary Committee. British national formulary. 69th ed. London: BMJ Group and Pharmaceutical Press; 2015.Google Scholar
  43. 43.
    Sacco JJ, Botten J, Macbeth F, Bagust A, Clark P. The average body surface area of adult cancer patients in the UK: a multicentre retrospective study. PLoS One. 2010;5(1):e8933.  https://doi.org/10.1371/journal.pone.0008933.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Papaioannou D, Brazier JE, Paisley S. NICE DSU technical support document 9: the identification, review and synthesis of health state utility values from the literature. London: National Institute for Health and Care Excellence; 2010.Google Scholar
  45. 45.
    Ara R, Brazier JE. Using health state utility values from the general population to approximate baselines in decision analytic models when condition-specific data are not available. Value Health. 2011;14(4):539–45.  https://doi.org/10.1016/j.jval.2010.10.029.CrossRefPubMedGoogle Scholar
  46. 46.
    Digital N. Health survey for England 2012. The Health and Social Care Information Centre, London. 2013. https://digital.nhs.uk/catalogue/PUB13218. Accessed 1 Aug 2015.
  47. 47.
    Freeman K, Connock M, Cummins E, Gurung T, Taylor-Phillips S, Court R, et al. Fluorouracil plasma monitoring: the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion. Coventry: Warwick Evidence; 2014.Google Scholar
  48. 48.
    Huxley N, Crathorne L, Varley-Campbell J, Tikhonova I, Snowsill T, Briscoe S, et al. The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation. Health Technol Assess. 2017;21(38):1–294.  https://doi.org/10.3310/hta21380.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Irina A. Tikhonova
    • 1
  • Nicola Huxley
    • 2
  • Tristan Snowsill
    • 1
  • Louise Crathorne
    • 3
  • Jo Varley-Campbell
    • 1
  • Mark Napier
    • 4
  • Martin Hoyle
    • 1
  1. 1.Peninsula Technology Assessment Group (PenTAG), University of ExeterExeterUK
  2. 2.Monash UniversityMelbourneAustralia
  3. 3.Roboleo LtdYorkUK
  4. 4.Royal Devon and Exeter NHS Foundation TrustExeterUK

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