Journal Mobile Options
Table of Contents
Vol. 69, No. 1, 2005
Issue release date: August 2005

A Phase II Trial of Irinotecan, 5-Fluorouracil and Leucovorin Combined with Celecoxib and Glutamine as First-Line Therapy for Advanced Colorectal Cancer

Pan C.-X. · Loehrer P. · Seitz D. · Helft P. · Juliar B. · Ansari R. · Pletcher W. · Vinson J. · Cheng L. · Sweeney C.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Objectives: Preclinical and clinical data indicate that cyclooxygenase-2 (COX-2) is a bona fide molecular target for colorectal cancer (CRC). Glutamine may decrease chemotherapy-associated diarrhea. This study was designed to address whether the addition of celecoxib, a COX-2 inhibitor, and glutamine would improve the efficacy and decrease the toxicities of the irinotecan, fluorouracil and leucovorin (IFL) regimen. Methods: All patients received the original IFL regimen plus celecoxib (400 mg, po, every 12 h continuously while on trial) and glutamine (10 g, po, every 8 h continuously while on chemotherapy). Results: Of the 41 patients enrolled, 40 patients received between 1 and 6 cycles of treatment. This regimen was associated with significant toxicities: 45.0% had grade 3 diarrhea, 35.0% grade 3/4 neutropenia, 22.5% hospitalization, 10.0% deep vein thrombosis and 2 treatment-related deaths. The overall response rate was 47.2%. The median progression-free survival was 6.7 months. The median overall survival was 16.3 months. The 12-month overall survival rate was 54.8%. COX-2 expression was present in 63.2% of the specimens evaluated. There was no significant correlation between COX-2 expression and response to chemotherapy (p = 0.739). Conclusion: The addition of celecoxib and glutamine appears not to improve the efficacy or decrease the toxicities of IFL for the treatment of metastatic CRC.

Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.


  1. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–914.
  2. Trifan OC, Durham WF, Salazar VS, Horton J, Levine BD, Zweifel BS, Davis TW, Masferrer JL: Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11. Cancer Res 2002;62:5778–5784.
  3. Savarese D, Al-Zoubi A, Boucher J: Glutamine for irinotecan diarrhea. J Clin Oncol 2000;18:450–451.
  4. DuBois RN, Awad J, Morrow J, Roberts LJ 2nd, Bishop PR: Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest 1994;93:493–498.
  5. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR: TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991;266:12866–12872.
  6. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994;107:1183–1188.
  7. Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, Subbaramaiah K: Cyclo-oxygenase 2: A pharmacological target for the prevention of cancer. Lancet Oncol 2001;2:544–551.
  8. Sweeney CJ, Marshall MS, Barnard DS, Heilman DK, Billings SD, Cheng L, Marshall SJ, Yip-Schneider MT: Cyclo-oxygenase-2 expression in primary cancers of the lung and bladder compared to normal adjacent tissue. Cancer Detect Prev 2002;26:238–244.
  9. Yip-Schneider MT, Barnard DS, Billings SD, Cheng L, Heilman DK, Lin A, Marshall SJ, Crowell PL, Marshall MS, Sweeney CJ: Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 2000;21:139–146.
  10. Sheehan KM, Sheahan K, O’Donoghue DP, MacSweeney F, Conroy RM, Fitzgerald DJ, Murray FE: The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA 1999;282:1254–1257.
  11. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946–1952.
  12. Lin E, Miorris J, Chau N: Celecoxib attenuated capecitabine induced hand-and-foot syndrome (HFS) and diarrhea and improved time to tumor progression in metastatic colorectal cancer. Proc Am Soc Clin Oncol 2002;21:138b.
  13. Cunningham D, Pyrhonen S, James RD, Punt CJ, 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.
  14. Kase Y, Hayakawa T, Togashi Y, Kamataki T: Relevance of irinotecan hydrochloride-induced diarrhea to the level of prostaglandin E2 and water absorption of large intestine in rats. Jpn J Pharmacol 1997;75:399–405.
  15. Sakai H, Sato T, Hamada N, Yasue M, Ikari A, Kakinoki B, Takeguchi N: Thromboxane A2, released by the anti-tumour drug irinotecan, is a novel stimulator of Cl secretion in isolated rat colon. J Physiol 1997;505:133–144.
  16. Rhoads JM, Keku EO, Quinn J, Woosely J, Lecce JG: L-glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis. Gastroenterology 1991;100:683–691.
  17. Rhoads JM, Keku EO, Bennett LE, Quinn J, Lecce JG: Development of L-glutamine-stimulated electroneutral sodium absorption in piglet jejunum. Am J Physiol 1990;259:G99–G107.
  18. Fox AD, Kripke SA, De Paula J, Berman JM, Settle RG, Rombeau JL: Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. JPEN J Parenter Enteral Nutr 1988;12:325–331.
  19. Blikslager A, Hunt E, Guerrant R, Rhoads M, Argenzio R: Glutamine transporter in crypts compensates for loss of villus absorption in bovine cryptosporidiosis. Am J Physiol Gastrointest Liver Physiol 2001;281:G645–G653.
  20. Cole J, Blikslager A, Hunt E, Gookin J, Argenzio R: Cyclooxygenase blockade and exogenous glutamine enhance sodium absorption in infected bovine ileum. Am J Physiol Gastrointest Liver Physiol 2003;284:G516–G524.
  21. Hsu S, Rain L, Fanged H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase technique: A comparison between ABC and unlabelled antibody procedures. J Histochem Cytochem 1981;29:577–580.
  22. 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.
  23. Goldberg R, Morton R, Sargent D, Fuchs C, Ramanathan R, Williamson S, Findlay B: N9741: Oxaliplatin (Oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life (QOL) data from an intergroup study. Proc Am Soc Clin Oncol 2003;22:252 (abstr 1009).
  24. Blanke C, Benson A III, Dragovich T, Lenz H-J, Haller D, Robles C, Buckbinder A: A phase II trial of celecoxib (CX), irinotecan (I), 5-fluorouracil (5FU), and leucovorin (LCV) in patients (pts) with unresectable or metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 2002; abstr 505.
  25. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993;328:1313–1316.
  26. Giardiello FM, Yang VW, Hylind LM, Krush AJ, Petersen GM, Trimbath JD, Piantadosi S, Garrett E, Geiman DE, Hubbard W, Offerhaus GJ, Hamilton SR: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 2002;346:1054–1059.
  27. Keller JJ, Offerhaus GJ, Drillenburg P, Caspers E, Musler A, Ristimaki A, Giardiello FM: Molecular analysis of sulindac-resistant adenomas in familial adenomatous polyposis. Clin Cancer Res 2001;7:4000–4007.
  28. Saliba F, Hagipantelli R, Misset JL, Bastian G, Vassal G, Bonnay M, Herait P, Cote C, Mahjoubi M, Mignard D, Cvitkovic E: Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: A prospective assessment. J Clin Oncol 1998;16:2745–2751.
  29. Daniele B, Perrone F, Gallo C, Pignata S, De Martino S, De Vivo R, Barletta E, Tambaro R, Abbiati R, D’Agostino L: Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: A double blind, placebo controlled, randomised trial. Gut 2001;48:28–33.
  30. van Zaanen HC, van der Lelie H, Timmer JG, Furst P, Sauerwein HP: Parenteral glutamine dipeptide supplementation does not ameliorate chemotherapy-induced toxicity. Cancer 1994;74:2879–2884.
  31. Bozzetti F, Biganzoli L, Gavazzi C, Cappuzzo F, Carnaghi C, Buzzoni R, Dibartolomeo M, Baietta E: Glutamine supplementation in cancer patients receiving chemotherapy: A double-blind randomized study. Nutrition 1997;13:748–751.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50