Mortality Associated With Irinotecan Plus Bolus Fluorouracil/Leucovorin
Authors: Harry Bleiberg, Angelo Di Leo, Mace L. Rothenberg, Neal J. Meropol, Elizabeth A. Poplin, Eric Van Cutsem, Scott Wadler
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.4.1145 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11844840 Mortality Associated With Irinotecan Plus Bolus Fluorouracil/Leucovorin Harry BleibergxHarry BleibergSearch for articles by this author , Angelo Di LeoxAngelo Di LeoSearch for articles by this author Mace L. RothenbergxMace L. RothenbergSearch for articles by this author , Neal J. MeropolxNeal J. MeropolSearch for articles by this author , Elizabeth A. PoplinxElizabeth A. PoplinSearch for articles by this author , Eric Van CutsemxEric Van CutsemSearch for articles by this author , Scott WadlerxScott WadlerSearch for articles by this author Show More Jules Bordet Institute, Brussels, BelgiumVanderbilt-Ingram Cancer Center, Nashville, TNFox Chase Cancer Center, Philadelphia, PACancer Institute of New Jersey, New Brunswick, NJUniversity Hospital Gasthuisberg, Leuven, BelgiumAlbert Einstein College of Medicine, Bronx, NY https://doi.org/10.1200/JCO.2002.20.4.1145 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15022002In Reply:We appreciate Drs Bleiberg and Di Leo raising this important issue. The irinotecan (Camptosar; Pharmacia Corp, Peapack, NJ) NDA supplemental report on the United States Food and Drug Administration Web site actually lists two kinds of vascular events: “thrombosis” and “cardiovascular disorders.”1 As Bleiberg and Di Leo point out, the incidence of grade 3 or 4 events seems to be disproportionately higher in the irinotecan/fluorouracil (5-FU)/leucovorin arms than in the 5-FU/leucovorin arms (Table 1). Incidence of Thromboembolic Events: Infusional 5-FU, Leucovorin, +/− Irinotecan Incidence of Thromboembolic Events: Infusional 5-FU, Leucovorin, +/− IrinotecanIrinotecan + Infusional 5-FU + LeucovorinInfusional 5-FU + LeucovorinFisher’s Exact TestTotal (%)Grade 3/4 (%)Total (%)Grade 3/4 (%)P totalP Grade 3/4Thrombosis1649< 1.064.038Cardiovascular disorders1166< 1.10.0059However, a similar trend was not found in the trial that compared irinotecan plus bolus 5-FU and leucovorin with daily bolus 5-FU and leucovorin. Although detailed data on the incidence of thromboembolism or cardiovascular events in this trial were not included on the Food and Drug Administration’s Web site, we have been provided with the following information from Pharmacia regarding these toxicities in that trial (David Emanuel, MD, Pharmacia Corp, personal communication, November 2001) (Table 2). As can be seen in Table 2, there is no obvious difference between the rates of thromboembolic events in the three-drug regimen compared with the two-drug regimen when 5-FU is administered as a bolus. Incidence of Thromboembolic Events: Bolus 5-FU, Leucovorin +/− Irinotecan Incidence of Thromboembolic Events: Bolus 5-FU, Leucovorin +/− IrinotecanIrinotecan + Bolus 5-FU + Leucovorin (total %)Bolus 5-FU + Leucovorin (total %)Thromboembolism (includes arterial and venous events)9.311.4When large volumes of data are subjected to repeated analyses, differences may appear that are due to chance alone. This may be the case with the data from Douillard et al, as cited by Bleiberg and Di Leo. However, we believe that these data should not be taken lightly and that two issues deserve further consideration. First, the incidence of clinically significant thromboembolic events is not trivial. Physicians and patients must be made aware of this as a risk from the disease, treatment, or both before embarking on a course of therapy. Unfortunately, neither of the original reports of the phase III pivotal studies included information on the rates of arterial or venous thromboembolic events.2,3 This may have conveyed the impression that these events were rare or insignificant. This is clearly not the case. In general, there is considerable variability in reporting thromboembolic events as adverse events in colorectal cancer clinical trials. For example, two recently completed, phase III trials report less than 1% incidence rates of thromboembolic events for the same daily bolus (Mayo Clinic) 5-FU/leucovorin regimen as was used in the control arm for the study reported by Saltz’s group.4,5 This discrepancy is more likely to be due to differing standards for adverse event reporting and attribution than truly differing incidence rates. The second point is that these events have been observed in patients receiving the combination of irinotecan, 5-FU, and leucovorin with the 5-FU administered as either an infusion or as a bolus and do not seem to be limited to one way of giving 5-FU or the other.The hypercoagulability of cancer patients remains a complex and poorly understood area. Activation of factor X, increased fibrinogen and platelet catabolism, decreased protein C, S, and antithrombin, and direct generation of thrombin have been implicated in this process, to one extent or another.6 It is not known to what extent irinotecan, 5-FU, leucovorin, and drug administration schedule may contribute to this phenomenon. This area should be the focus of further study. In the meantime, physicians should remain alert to the serious, and not uncommon, constellation of thromboembolic events in patients with advanced colorectal cancer undergoing chemotherapy.1. Medical Officer Summary: Statement for the Advisory Committee, irinotecan hydrochloride (Camptosar Injection®) for colorectal cancer (application for irinotecan as a component of first-line therapy of patients with metastatic carcinoma of the colon or rectum). Http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3592b1.htm Google Scholar2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 543:: 905,2000-912, Google Scholar3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:: 1041,2000-1047, Crossref, Medline, Google Scholar4. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:: 2282,2001-2292, Link, Google Scholar5. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:: 4097,2001-4106, Link, Google Scholar6. Arnold SM, Lowy AM, Patchell R, et al: Paraneoplastic syndromes, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology ( ed 6 ). Philadelphia, PA, Lippincott, Williams & Wilkins, pp 2511,2001,-2536 Google Scholar