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International Journal of Colorectal Disease

, Volume 33, Issue 11, pp 1505–1516 | Cite as

First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs

  • Jacopo Giuliani
  • Andrea Bonetti
Review
  • 171 Downloads

Abstract

Purpose

In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC).

Methods

Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs.

Results

Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € (FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases), of € 15,822 (FOLFOX with panitumumab in KRAS wild type), and of 13,383 € (FOLFOX with bevacizumab). According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3.

Conclusions

Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.

Keywords

Metastatic colorectal cancer Randomized phase III trials First-line therapy Costs of drugs ESMO-MCBS 

Notes

Authorship

Jacopo Giuliani and Andrea Bonetti contributed equally in the conception and design, acquisition of data, or analysis and interpretation of data; drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Compliance with ethical standards

Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. In particular:

• Jacopo Giuliani, M.D., has no conflict of interest.

• Andrea Bonetti, M.D., has no conflict of interest.

Disclosure

No founds were received to support this article.

References

  1. 1.
    Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E (2013) European cancer mortality predictions for the year 2013. Ann Oncol 24:792–800CrossRefGoogle Scholar
  2. 2.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefGoogle Scholar
  3. 3.
    Gruenberger B, Tamandl D, Schueller J, Scheithauer W, Zielinski C, Herbst F, Gruenberger T (2008) Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 26:1830–1835CrossRefGoogle Scholar
  4. 4.
    Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671CrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417CrossRefGoogle Scholar
  6. 6.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705CrossRefGoogle Scholar
  7. 7.
    Bonetti A, Giuliani J, Muggia F (2014) Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. Anticancer Res 34:423–434PubMedGoogle Scholar
  8. 8.
    Schrag D (2004) The price tag on progress-chemotherapy for colorectal cancer. N Engl J Med 351:317–319CrossRefGoogle Scholar
  9. 9.
    Kriza C, Emmert M, Wahlster P, Niederländer C, Kolominsky-Rabas P (2013) Cost of illness in colorectal cancer: an international review. Pharmacoeconomics 31:577–588CrossRefGoogle Scholar
  10. 10.
    Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, de Vries EG, Piccart MJ (2015) A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 26:1547–1573CrossRefGoogle Scholar
  11. 11.
    Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047CrossRefGoogle Scholar
  12. 12.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947CrossRefGoogle Scholar
  13. 13.
    Twelves C, Boyer M, Findlay M, Cassidy J, Weitzel C, Barker C, Osterwalder B, Jamieson C, Hieke K, Xeloda Colorectal Cancer Study Group (2001) Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer 37:597–604CrossRefGoogle Scholar
  14. 14.
    Blanke CD, Shultz J, Cox J, Modiano M, Isaacs R, Kasimis B, Schilsky R, Fleagle J, Moore M, Kemeny N, Carlin D, Hammershaimb L, Haller D (2002) A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. Ann Oncol 13:87–91CrossRefGoogle Scholar
  15. 15.
    Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur R (2002) Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol 20:1519–1526CrossRefGoogle Scholar
  16. 16.
    Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237CrossRefGoogle Scholar
  17. 17.
    Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30CrossRefGoogle Scholar
  18. 18.
    Comella P, Massidda B, Filippelli G, Palmeri S, Natale D, Farris A, De Vita F, Buzzi F, Tafuto S, Maiorino L, Mancarella S, Leo S, Lorusso V, De Lucia L, Roselli M (2005) Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial. Ann Oncol 16:878–886CrossRefGoogle Scholar
  19. 19.
    Colucci G, Gebbia V, Paoletti G, Giuliani F, Caruso M, Gebbia N, Cartenì G, Agostara B, Pezzella G, Manzione L, Borsellino N, Misino A, Romito S, Durini E, Cordio S, Di Seri M, Lopez M, Maiello E, Montemurro S, Cramarossa A, Lorusso V, Di Bisceglie M, Chiarenza M, Valerio MR, Guida T, Leonardi V, Pisconti S, Rosati G, Carrozza F, Nettis G, Valdesi M, Filippelli G, Fortunato S, Mancarella S, Brunetti C, Dell'Italia Meridionale GO (2005) Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 23:4866–4875CrossRefGoogle Scholar
  20. 20.
    Hospers GA, Schaapveld M, Nortier JW, Wils J, van Bochove A, de Jong RS, Creemers GJ, Erjavec Z, de Gooyer DJ, Slee PH, Gerrits CJ, Smit JM, Mulder NH (2006) Randomised phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer. Ann Oncol 17:443–449CrossRefGoogle Scholar
  21. 21.
    Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G, Ovest GON (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25:1670–1676CrossRefGoogle Scholar
  22. 22.
    Souglakos A, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis C, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V (2007) FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research group (HORG). Br J Cancer 94:798–805CrossRefGoogle Scholar
  23. 23.
    Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019CrossRefGoogle Scholar
  24. 24.
    Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG (2009) A randomized phase IIIB trial of chemotherapy, bevacizumab and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 27:672–680CrossRefGoogle Scholar
  25. 25.
    Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Börger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360:563–572CrossRefGoogle Scholar
  26. 26.
    Hecht JR, Trarbach T, Hainsworth JD, Major P, Jäger E, Wolff RA, Lloyd-Salvant K, Bodoky G, Pendergrass K, Berg W, Chen BL, Jalava T, Meinhardt G, Laurent D, Lebwohl D, Kerr D (2011) Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J Clin Oncol 29:1997–2003CrossRefGoogle Scholar
  27. 27.
    Fischer von Weikersthal L, Schalhorn A, Stauch M, Quietzsch D, Maubach PA, Lambertz H, Oruzio D, Schlag R, Weigang-Köhler K, Vehling-Kaiser U, Schulze M, Truckenbrodt J, Goebeler M, Mittermüller J, Bosse D, Szukics B, Grundeis M, Zwingers T, Giessen C, Heinemann V (2011) Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer 47:206–214CrossRefGoogle Scholar
  28. 28.
    Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP, Trial Investigators MRCCOIN (2011) Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377:2103–2114CrossRefGoogle Scholar
  29. 29.
    Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Rittweger K, Gilberg F, Saltz L (2011) XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. Br J Cancer 105:58–64CrossRefGoogle Scholar
  30. 30.
    Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T (2012) Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 30:1755–1762CrossRefGoogle Scholar
  31. 31.
    Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E (2012) Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 30:3588–3595CrossRefGoogle Scholar
  32. 32.
    Primrose JN, Falk S, Finch-Jones M, Valle JW, Sherlock D, Hornbuckle J, Gardner-Thorpe J, Smith D, Imber C, Hickish T, Davidson B, Cunningham D, Poston GJ, Maughan T, Rees M, Stanton L, Little L, Bowers M, Wood W, Bridgewater JA (2013) A randomized clinical trial of chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: the new EPOC study. J Clin Oncol 31:abstr 3504Google Scholar
  33. 33.
    Falcone A, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Trenta L, Tomasello G, Ronzoni M, Ciuffreda L, Zaniboni A, Tonini G, Buonadonna A, Valsuani C, Chiara S, Carlomagno C, Boni C, Marcucci L, Boni L, Loupakis F (2013) FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol 31:abstr 3505Google Scholar
  34. 34.
    Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J (2013) Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 31:1931–1938CrossRefGoogle Scholar
  35. 35.
    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S (2014) 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 15:1065–1075CrossRefGoogle Scholar
  36. 36.
    Bokemeyer C, Kohne C, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, Beier F, Duecker K, Tejpar S (2014) Treatment outcome according to tumor RAS mutations status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX 4 with/without cetuximab. J Clin Oncol 32:abstr 3505Google Scholar
  37. 37.
    Ciardiello F, Lenz H, Kohne C, Heinemann V, Tejpar S, Melezinek I, Beier F, Stroh C, Van Cutsem E (2014) Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol 32:abstr 3506CrossRefGoogle Scholar
  38. 38.
    Shi Q, de Gramont A, Grothey A, Zalcberg J, Chibaudel B, Schmoll HJ, Seymour MT, Adams R, Saltz L, Goldberg RM, Punt CJ, Douillard JY, Hoff PM, Hecht JR, Hurwitz H, Díaz-Rubio E, Porschen R, Tebbutt NC, Fuchs C, Souglakos J, Falcone A, Tournigand C, Kabbinavar FF, Heinemann V, Van Cutsem E, Bokemeyer C, Buyse M, Sargent DJ (2015) Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol 33:22–28CrossRefGoogle Scholar
  39. 39.
    Olchanski N, Zhong Y, Cohen JT, Saret C, Bala M, Neumann PJ (2015) The peculiar economics of life-extending therapies: a review of costing methods in health economic evaluations in oncology. Expert Rev Pharmacoecon Outcomes Res 15:931–940CrossRefGoogle Scholar
  40. 40.
    Cohn DE, Kim KH, Resnick KE, O'Malley DM, Straughn JM Jr (2011) At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. J Clin Oncol 29:1247–1951CrossRefGoogle Scholar
  41. 41.
    Lindgren P, Jönsson B, Wilking N (2015) Assessing the Esmo Magnitude of Clinical Benefit Scale from a health economics perspective. Value Health 18:A569CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OncologyMater Salutis Hospital—Az. ULSS 9 ScaligeraLegnagoItaly

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