Multicentre randomized controlled trial comparing ferric(III)carboxymaltose infusion with oral iron supplementation in the treatment of preoperative anaemia in colorectal cancer patients

W A A Borstlap, C J Buskens, K M A J Tytgat, J B Tuynman, E C J Consten, R C Tolboom, G Heuff, N van Geloven, B A van Wagensveld, C A C A Wientjes, M F Gerhards, S M M de Castro, J Jansen, A W H van der Ven, E van der Zaag, J M Omloo, H L van Westreenen, D C Winter, R P Kennelly, M G W Dijkgraaf, P J Tanis, W A Bemelman, W A A Borstlap, C J Buskens, K M A J Tytgat, J B Tuynman, E C J Consten, R C Tolboom, G Heuff, N van Geloven, B A van Wagensveld, C A C A Wientjes, M F Gerhards, S M M de Castro, J Jansen, A W H van der Ven, E van der Zaag, J M Omloo, H L van Westreenen, D C Winter, R P Kennelly, M G W Dijkgraaf, P J Tanis, W A Bemelman

Abstract

Background: At least a third of patients with a colorectal carcinoma who are candidate for surgery, are anaemic preoperatively. Preoperative anaemia is associated with increased morbidity and mortality. In general practice, little attention is paid to these anaemic patients. Some will have oral iron prescribed others not. The waiting period prior to elective colorectal surgery could be used to optimize a patients' physiological status. The aim of this study is to determine the efficacy of preoperative intravenous iron supplementation in comparison with the standard preoperative oral supplementation in anaemic patients with colorectal cancer.

Methods/design: In this multicentre randomized controlled trial, patients with an M0-staged colorectal carcinoma who are scheduled for curative resection and with a proven iron deficiency anaemia are eligible for inclusion. Main exclusion criteria are palliative surgery, metastatic disease, neoadjuvant chemoradiotherapy (5 × 5 Gy = no exclusion) and the use of Recombinant Human Erythropoietin within three months before inclusion or a blood transfusion within a month before inclusion. Primary endpoint is the percentage of patients that achieve normalisation of the haemoglobin level between the start of the treatment and the day of admission for surgery. This study is a superiority trial, hypothesizing a greater proportion of patients achieving the primary endpoint in favour of iron infusion compared to oral supplementation. A total of 198 patients will be randomized to either ferric(III)carboxymaltose infusion in the intervention arm or ferrofumarate in the control arm. This study will be performed in ten centres nationwide and one centre in Ireland.

Discussion: This is the first randomized controlled trial to determine the efficacy of preoperative iron supplementation in exclusively anaemic patients with a colorectal carcinoma. Our trial hypotheses a more profound haemoglobin increase with intravenous iron which may contribute to a superior optimisation of the patient's condition and possibly a decrease in postoperative morbidity.

Trial registration: ClincalTrials.gov: NCT02243735 .

Figures

Figure 1
Figure 1
Flowchart of FIT-trial
Figure 2
Figure 2
Study follow-up

References

    1. Vlug MS, Wind J, Hollmann MW, Ubbink DT, Cense HA, Engel AF, et al. Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study) Ann Surg. 2011;254(6):868–75. doi: 10.1097/SLA.0b013e31821fd1ce.
    1. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol. 2010;116(3):522–5. doi: 10.1016/j.ygyno.2009.12.004.
    1. Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, et al. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology. 2011;14(3):846–53. doi: 10.1053/j.gastro.2011.06.005.
    1. Krayenbuehl PA, Battegay E, Breymann C, Furrer J, Schulthess G. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood. 2011;118(12):3222–7. doi: 10.1182/blood-2011-04-346304.
    1. Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H, et al. Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency. New Engl J Med. 2009;361(25):2436–48. doi: 10.1056/NEJMoa0908355.
    1. Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, et al. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMJ. 2003;326(7399):1124. doi: 10.1136/bmj.326.7399.1124.
    1. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53(8):1190–7. doi: 10.1136/gut.2003.035758.
    1. Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients. Inflamm Bowel Dis. 2006;12(2):123–30. doi: 10.1097/01.MIB.0000196646.64615.db.
    1. Bruner AB, Joffe A, Duggan AK, Casella JF, Brandt J. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996;348(9033):992–6. doi: 10.1016/S0140-6736(96)02341-0.
    1. Amato AC, Pescatori M. Effect of perioperative blood transfusions on recurrence of colorectal cancer - Meta-analysis stratified on risk factors. Dis Colon Rectum. 1998;41(5):570–85. doi: 10.1007/BF02235262.
    1. Pascual M, Bohle B, Alonso S, Mayol X, Salvans S, Grande L, et al. Preoperative administration of erythropoietin stimulates tumor recurrence after surgical excision of colon cancer in mice by a vascular endothelial growth factor-independent mechanism. J Surg Res. 2013;183(1):270–7. doi: 10.1016/j.jss.2012.12.041.
    1. Bohlius J, Schmidlin K, Brillant C. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials (vol 373, pg 1532, 2009) Lancet. 2009;374(9683):28. doi: 10.1016/S0140-6736(09)61238-1.
    1. Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet. 2011;378(9800):1396–407. doi: 10.1016/S0140-6736(11)61381-0.
    1. Lindsey I. Predicting response to chemoradiotherapy in rectal cancer: Are we there yet? Colorectal Dis. 2013;15(10):1199–200. doi: 10.1111/codi.12429.
    1. Khan AA, Klonizakis M, Shabaan A, Glynne-Jones R. Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long-term outcomes in patients with locally advanced rectal cancers. Colorectal Dis. 2013;15(10):1232–7. doi: 10.1111/codi.12307.
    1. Lee SD, Park JW, Park KS, Lim SB, Chang HJ, Kim DY, et al. Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis. 2009;24(12):1451–8. doi: 10.1007/s00384-009-0762-7.
    1. Cuenca J, Garcia-Erce JA, Martinez F, Perez-Serrano L, Herrera A, Munoz M. Perioperative intravenous iron, with or without erythropoietin, plus restrictive transfusion protocol reduce the need for allogeneic blood after knee replacement surgery. Transfusion. 2006;46(7):1112–9. doi: 10.1111/j.1537-2995.2006.00859.x.
    1. Diez-Lobo AI, Fisac-MartÍN MP, Bermejo-Aycar I, MuÑOz M. Preoperative intravenous iron administration corrects anemia and reduces transfusion requirement in women undergoing abdominal hysterectomy. Transfusion Alternatives in Transfusion Medicine. 2007;9(2):114–9. doi: 10.1111/j.1778-428X.2007.00060.x.
    1. Kotze A, Carter LA, Scally AJ. Effect of a patient blood management programme on preoperative anaemia, transfusion rate, and outcome after primary hip or knee arthroplasty: a quality improvement cycle. Br J Anaesth. 2012;108(6):943–52. doi: 10.1093/bja/aes135.
    1. Edwards TJ, Noble EJ, Durran A, Mellor N, Hosie KB. Randomized clinical trial of preoperative intravenous iron sucrose to reduce blood transfusion in anaemic patients after colorectal cancer surgery. Br J Surg. 2009;96(10):1122–8. doi: 10.1002/bjs.6688.
    1. Lidder PG, Sanders G, Whitehead E, Douie WJ, Mellor N, Lewis SJ, et al. Pre-operative oral iron supplementation reduces blood transfusion in colorectal surgery - a prospective, randomised, controlled trial. Ann R Coll Surg Engl. 2007;89(4):418–21. doi: 10.1308/003588407X183364.
    1. Quinn M, Drummond RJ, Ross F, Murray J, Murphy J, Macdonald A. Short course pre-operative ferrous sulphate supplementation–is it worthwhile in patients with colorectal cancer? Ann R Coll Surg Engl. 2010;92(7):569–72. doi: 10.1308/003588410X12699663904277.
    1. Nederland Z. Ferrofumaraat. . Assessed 15 March 2015.
    1. Seid MH, Derman RJ, Baker JB, Banach W, Goldberg C, Rogers R. Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial. Am J Obstet Gynecol. 2008;199(4):435. doi: 10.1016/j.ajog.2008.07.046.
    1. Slankamenac K, Graf R, Barkun J, Puhan MA, Clavien PA. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg. 2013;258(1):1–7. doi: 10.1097/SLA.0b013e318296c732.
    1. 26.Hakkaart- van Roijen L, Tan SS, Bouwmans CAM. Handleiding voor Kostenonderzoek CVZ 2010.
    1. Lamers LM, Stalmeier PF, McDonnell J, Krabbe PF, van Busschbach JJ. Measuring the quality of life in economic evaluations: the Dutch EQ-5D tariff. Nederlands tijdschrift voor geneeskunde. 2005;149(28):1574–8.
    1. Okuyama M, Ikeda K, Shibata T, Tsukahara Y, Kitada M, Shimano T. Preoperative iron supplementation and intraoperative transfusion during colorectal cancer surgery. Surg Today. 2005;35(1):36–40. doi: 10.1007/s00595-004-2888-0.
    1. Keeler B, Simpson J, Ng S, Tselepis C, Iqbal T. Brookes M, et al. Colorectal Dis: The feasibility and clinical efficacy of intravenous iron administration for preoperative anaemia in patients with colorectal cancer; 2014.
    1. Bisbe E, Garcia-Erce JA, Diez-Lobo AI, Munoz M, Anaemia Working Group E A multicentre comparative study on the efficacy of intravenous ferric carboxymaltose and iron sucrose for correcting preoperative anaemia in patients undergoing major elective surgery. Br J Anaesth. 2011;107(3):477–8. doi: 10.1093/bja/aer242.
    1. Amato A, Pescatori M. Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database of Systematic Reviews. 2006(1).

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir