Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m2 as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m2 as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m2) and raltitrexed (3 mg/m2) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.

Midgley R, Kerr D: Colorectal cancer. Lancet 1999;353:391–399.
Armand JP, Ducreux M, Mahjoubi M, Abigerges D, Bugat R, Chabot G, Herait P, de Forni M, Rougier P: CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J Cancer 1995;31A: 1283–1287.
Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou T-C, Sun M, Pulliam S, Gonzalez C: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996;14:709–715.
Rothenberg ML, Eckardt JR, Kuhn JG, Burris III HA, Nelson J, Hilsenbeck SG, Rodriguez GI, Thurman AM, Smith LS, Eckhardt SG, Weiss GR, Elfring GL, Rinali DA, Scaaf LJ, Von Hoff DD: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996;14:1128–1135.
Rougier P, Bugat E, Douillard JY, Culine S, Suc E, Brunet P, Becouarn M, Ychou M, Marty M, Extra JM, Bonneterre J, Adenis A, Seitz JF, Ganem G, Namer M, Conroy T, Negrier S, Merrouche Y, Burki F, Mousseau M, Herait P, Mahjoubi M: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997;15:251–260.
Cunningham D, Pyrhönen S, James RD, Punt CJA, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413–1418.
Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, Navarro M, Morant R, Bleiberg H, Wils J, Awad L, Herait P, Jacques C: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998;352:1407–1412.
Zalcberg JR, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M: Seymour I for the Tomudex Colorectal Study Group. ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. J Clin Oncol 1996;14:716–721.
Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G and the ‘Tomudex’ Colorectal Cancer Study Group: Final results of a randomised trial comparing Tomudex (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. Ann Oncol 1996;7:961–965.
Aschele C, Baldo C, Sobrero AF, Debernardis D, Bornmann WG, Bertino JR: Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. Clin Cancer Res 1998;4:1323–1330.
Wadler S, Benson III AB, Englelking C, Catalano R, Field M, Kornblau SM, Mitchell E, Rubin J, Trotta P, Vokes E: Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 1998;16:3169–3178.
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 1981;47:207–214.
Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481.
Kimbell R, Jackman AL: Combination studies with ‘Tomudex’ and SN-38 (CPT-11) in a panel of human tumor cell lines. Br J Cancer 1997;75 (suppl 1): P23 (abstr).
Ford HER, Cunningham D, Ross PJ, Rao S, Aherne GW, Benepal TS, Price T, Massey A, Vernillet L, Gruia G: Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma. Br J Cancer 2000;83:146–152.
Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S, Rustum YM: Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol 2001;19:1501–1518.
Van Cutsem E, Cunningham D, Ten Bokkel Huinink WW, Punt CJA, Alexopoulos CG, Dirix L, Symann M, Blijham GH, Cholet P, Fillet G, Van Groeningen C, Vannetzel JM, Levi F, Panagos G, Unger C, Wils J, Cote C, Blanc C, Hérait P, Bleiberg H: Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU). Eur J Cancer 1999;35:54–59.
de Gramont A, Figer A, Seymur 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: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–2947.
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: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 2000;355:1041–1047.
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL, for the Irinotecan Study Group: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905–914.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.