Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Management of acute chemotherapy-related diarrhea

Smitha S Krishnamurthi, MD
Carole Macaron, MD
Section Editor
Reed E Drews, MD
Deputy Editor
Diane MF Savarese, MD


Most chemotherapeutic agents target rapidly dividing cells, and effects on these cells within the gastrointestinal tract can lead to a variety of symptoms. Diarrhea caused by chemotherapy, referred to here as chemotherapy-related diarrhea (CRD), is a common problem in cancer patients and is most often described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is often the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with irinotecan. The frequency of severe (grade 3 or 4 (table 1)) diarrhea with these agents ranges from 5 to 44 percent, and rates vary according to the dose, the specific agents administered, and the schedule of administration. (See "Enterotoxicity of chemotherapeutic agents", section on 'Fluorouracil' and "Enterotoxicity of chemotherapeutic agents", section on 'Irinotecan'.)

In addition to conventional cytotoxic drugs, such as fluoropyrimidines and irinotecan, several molecularly targeted agents are also associated with CRD:

For many tyrosine kinase inhibitors (TKIs), such as afatinib, ceritinib, erlotinib, lapatinib, sorafenib, and sunitinib, diarrhea is second only to rash as the most common toxicity. Diarrhea develops in approximately one-half of treated patients, although the incidence of severe (grade 3 or 4) diarrhea is lower than with conventional cytotoxic agents. Diarrhea is especially common with ceritinib and afatinib, occurring in 75 to 86 percent of treated patients, but severe in only 6 to 16 percent. (See "Enterotoxicity of chemotherapeutic agents", section on 'Small molecule EGFR inhibitors' and "Enterotoxicity of chemotherapeutic agents", section on 'Small molecule inhibitors of VEGFR' and "Enterotoxicity of chemotherapeutic agents", section on 'Lapatinib and pertuzumab' and "Enterotoxicity of chemotherapeutic agents", section on 'ALK inhibitors'.)

Monoclonal antibodies directed against the epidermal growth factor receptor (EGFR) rarely cause severe diarrhea when used as monotherapy but can increase the incidence of severe diarrhea when combined with cytotoxic chemotherapy. (See "Enterotoxicity of chemotherapeutic agents", section on 'Anti-EGFR monoclonal antibodies'.)

The antiangiogenic agent aflibercept, which is a recombinant fusion protein of the vascular endothelial growth factor (VEGF) binding portions of the VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G1 (IgG1), increased severe diarrhea by 10 percent when added to FOLFIRI (irinotecan plus leucovorin and short-term infusional FU) chemotherapy [1]. When added to FOLFOX (oxaliplatin plus leucovorin and short-term infusional FU) chemotherapy, aflibercept increased the incidence of severe diarrhea by 8 percent [2].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Feb 13, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50:320.
  2. Folprecht G, Pericay C, Saunders MP, et al. Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study. Ann Oncol 2016; 27:1273.
  3. Ikuno N, Soda H, Watanabe M, Oka M. Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J Natl Cancer Inst 1995; 87:1876.
  4. Parnes HL, Fung E, Schiffer CA. Chemotherapy-induced lactose intolerance in adults. Cancer 1994; 74:1629.
  5. Osterlund P, Ruotsalainen T, Peuhkuri K, et al. Lactose intolerance associated with adjuvant 5-fluorouracil-based chemotherapy for colorectal cancer. Clin Gastroenterol Hepatol 2004; 2:696.
  6. Abigerges D, Chabot GG, Armand JP, et al. Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995; 13:210.
  7. Dranitsaris G, Maroun J, Shah A. Estimating the cost of illness in colorectal cancer patients who were hospitalized for severe chemotherapy-induced diarrhea. Can J Gastroenterol 2005; 19:83.
  8. Arbuckle RB, Huber SL, Zacker C. The consequences of diarrhea occurring during chemotherapy for colorectal cancer: a retrospective study. Oncologist 2000; 5:250.
  9. Carlotto A, Hogsett VL, Maiorini EM, et al. The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. Pharmacoeconomics 2013; 31:753.
  10. Elting LS, Shih YC. The economic burden of supportive care of cancer patients. Support Care Cancer 2004; 12:219.
  11. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (Accessed on March 8, 2011).
  12. Benson AB 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 2004; 22:2918.
  13. Mertz HR, Beck CK, Dixon W, et al. Validation of a new measure of diarrhea. Dig Dis Sci 1995; 40:1873.
  14. Andreyev J, Ross P, Donnellan C, et al. Guidance on the management of diarrhoea during cancer chemotherapy. Lancet Oncol 2014; 15:e447.
  15. O'Brien BE, Kaklamani VG, Benson AB 3rd. The assessment and management of cancer treatment-related diarrhea. Clin Colorectal Cancer 2005; 4:375.
  16. Khoshini R, Dai SC, Lezcano S, Pimentel M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci 2008; 53:1443.
  17. Smith GM, Chesner IM, Asquith P, Leyland MJ. Small intestinal bacterial overgrowth in patients with chronic lymphocytic leukaemia. J Clin Pathol 1990; 43:57.
  18. Wedlake L, Thomas K, McGough C, Andreyev HJ. Small bowel bacterial overgrowth and lactose intolerance during radical pelvic radiotherapy: An observational study. Eur J Cancer 2008; 44:2212.
  19. Grace E, Shaw C, Whelan K, Andreyev HJ. Review article: small intestinal bacterial overgrowth--prevalence, clinical features, current and developing diagnostic tests, and treatment. Aliment Pharmacol Ther 2013; 38:674.
  20. Grigg AP, Angus PW, Hoyt R, Szer J. The incidence, pathogenesis and natural history of steatorrhea after bone marrow transplantation. Bone Marrow Transplant 2003; 31:701.
  21. Phillips F, Muls AC, Lalji A, Andreyev HJ. Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy? Colorectal Dis 2015; 17:730.
  22. Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993; 17:109.
  23. Emoto M, Kawarabayashi T, Hachisuga MD, et al. Clostridium difficile colitis associated with cisplatin-based chemotherapy in ovarian cancer patients. Gynecol Oncol 1996; 61:369.
  24. Kamthan AG, Bruckner HW, Hirschman SZ, Agus SG. Clostridium difficile diarrhea induced by cancer chemotherapy. Arch Intern Med 1992; 152:1715.
  25. Husain A, Aptaker L, Spriggs DR, Barakat RR. Gastrointestinal toxicity and Clostridium difficile diarrhea in patients treated with paclitaxel-containing chemotherapy regimens. Gynecol Oncol 1998; 71:104.
  26. Aksoy DY, Tanriover MD, Uzun O, et al. Diarrhea in neutropenic patients: a prospective cohort study with emphasis on neutropenic enterocolitis. Ann Oncol 2007; 18:183.
  27. Krishna SG, Zhao W, Grazziutti ML, et al. Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients: clinical and research implications. Cancer 2011; 117:648.
  28. Ibrahim NK, Sahin AA, Dubrow RA, et al. Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer. Lancet 2000; 355:281.
  29. Kreis W, Petrylak D, Savarese D, Budman D. Colitis and docetaxel-based chemotherapy. Lancet 2000; 355:2164.
  30. Ghiringhelli F, Vincent J, Beltjens F, et al. Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients. Invest New Drugs 2015; 33:1263.
  31. DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1997; 92:1962.
  32. Vinther S, Rumessen JJ, Christensen M. [Pharmaceutical drugs containing lactose can as a rule be used by persons with lactose intolerance]. Ugeskr Laeger 2015; 177.
  33. Eadala P, Waud JP, Matthews SB, et al. Quantifying the 'hidden' lactose in drugs used for the treatment of gastrointestinal conditions. Aliment Pharmacol Ther 2009; 29:677.
  34. Regnard C, Twycross R, Mihalyo M, Wilcock A. Loperamide. J Pain Symptom Manage 2011; 42:319.
  35. Awouters F, Megens A, Verlinden M, et al. Loperamide. Survey of studies on mechanism of its antidiarrheal activity. Dig Dis Sci 1993; 38:977.
  36. Shannon HE, Lutz EA. Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats. Neuropharmacology 2002; 42:253.
  37. Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil 2004; 16 Suppl 2:17.
  38. Ooms LA, Degryse AD, Janssen PA. Mechanisms of action of loperamide. Scand J Gastroenterol Suppl 1984; 96:145.
  39. Penfold D, Volans GN. Overdose from Lomotil. Br Med J 1977; 2:1401.
  40. Pelemans W, Vantrappen F. A double blind crossover comparison of loperamide with diphenoxylate in the symptomatic treatment of chronic diarrhea. Gastroenterology 1976; 70:1030.
  41. Amery W, Duyck F, Polak J, van den Bouwhuysen G. A multicentre double-blind study in acute diarrhoea comparing loperamide (R 18553) with two common antidiarrhoeal agents and a placebo. Curr Ther Res Clin Exp 1975; 17:263.
  42. Cornett JWD, Aspeling RL and Mallegol D. A double-blind comparative evaluation of loperamide versus diphenoxylate with atropine for acute diarrhea. Curr Therapeutic Res 1977; 21:629.
  43. Dom J, Leyman R, Schuermans V, Brugmans J. Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 8: Clinical investigation. Use of a flexible dosage schedule in a double-blind comparison of loperamide with diphenoxylate in 614 patients suffering from acute diarrhea. Arzneimittelforschung 1974; 24:1660.
  44. Verhaegen H, De Cree J, Schuermans V. Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 7: Clinical investigation. Efficacy and safety of loperamide in patients with severe chronic diarrhea. Arzneimittelforschung 1974; 24:1657.
  45. Jaffé G. A comparison of lomotil and imodium in acute non-specific diarrhoea. J Int Med Res 1977; 5:195.
  46. Bergman L, Djärv L. A comparative study of loperamide and diphenoxylate in the treatment of chronic diarrhoea caused by intestinal resection. Ann Clin Res 1981; 13:402.
  47. Palmer KR, Corbett CL, Holdsworth CD. Double-blind cross-over study comparing loperamide, codeine and diphenoxylate in the treatment of chronic diarrhea. Gastroenterology 1980; 79:1272.
  48. Shee CD, Pounder RE. Loperamide, diphenoxylate, and codeine phosphate in chronic diarrhoea. Br Med J 1980; 280:524.
  49. Vehreschild MJ, Vehreschild JJ, Hübel K, et al. Diagnosis and management of gastrointestinal complications in adult cancer patients: evidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Oncol 2013; 24:1189.
  50. Maroun JA, Anthony LB, Blais N, et al. Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea. Curr Oncol 2007; 14:13.
  51. Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome--a double-blind placebo controlled study. Scand J Gastroenterol Suppl 1987; 130:77.
  52. Tijtgat GN, Meuwissen SG, Huibregtse K. Loperamide in the symptomatic control of chronic diarrhoea. Double-blind placebo-controlled study. Ann Clin Res 1975; 7:325.
  53. Mainguet P, Fiasse R. Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection. Gut 1977; 18:575.
  54. Galambos JT, Hersh T, Schroder S, Wenger J. Loperamide: a new antidiarrheal agent in the treatment of chronic diarrhea. Gastroenterology 1976; 70:1026.
  55. Petrelli NJ, Rodriguez-Bigas M, Rustum Y, et al. Bowel rest, intravenous hydration, and continuous high-dose infusion of octreotide acetate for the treatment of chemotherapy-induced diarrhea in patients with colorectal carcinoma. Cancer 1993; 72:1543.
  56. Cascinu S, Fedeli A, Fedeli SL, Catalano G. Control of chemotherapy-induced diarrhoea with octreotide in patients receiving 5-fluorouracil. Eur J Cancer 1992; 28:482.
  57. Mercadante S. Diarrhea in terminally ill patients: pathophysiology and treatment. J Pain Symptom Manage 1995; 10:298.
  58. Cascinu S, Bichisao E, Amadori D, et al. High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients. Support Care Cancer 2000; 8:65.
  59. Cascinu S, Fedeli A, Fedeli SL, Catalano G. Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial. J Clin Oncol 1993; 11:148.
  60. Abigerges D, Armand JP, Chabot GG, et al. Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994; 86:446.
  61. Rothenberg ML, Eckardt JR, Kuhn JG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996; 14:1128.
  62. Conti JA, Kemeny NE, Saltz LB, et al. Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1996; 14:709.
  63. Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801.
  64. Rougier P, Bugat R, Douillard JY, et al. 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.
  65. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334:246.
  66. Edwards C, Cann PA, Read NW, Holdsworth CD. Effect of two new antisecretory drugs on fluid and electrolyte transport in a patient with secretory diarrhoea. Gut 1986; 27:581.
  67. Dueno MI, Bai JC, Santangelo WC, Krejs GJ. Effect of somatostatin analog on water and electrolyte transport and transit time in human small bowel. Dig Dis Sci 1987; 32:1092.
  68. Maton PN, O'Dorisio TM, Howe BA, et al. Effect of a long-acting somatostatin analogue (SMS 201-995) in a patient with pancreatic cholera. N Engl J Med 1985; 312:17.
  69. Wadler S, Haynes H, Wiernik PH. Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea. J Clin Oncol 1995; 13:222.
  70. Topkan E, Karaoglu A. Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology 2006; 71:354.
  71. Barbounis V, Koumakis G, Vassilomanolakis M, et al. Control of irinotecan-induced diarrhea by octreotide after loperamide failure. Support Care Cancer 2001; 9:258.
  72. Zidan J, Haim N, Beny A, et al. Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 2001; 12:227.
  73. Bhattacharya S, Vijayasekar C, Worlding J, Mathew G. Octreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article. Acta Gastroenterol Belg 2009; 72:289.
  74. Harris AG, O'Dorisio TM, Woltering EA, et al. Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel. Dig Dis Sci 1995; 40:1464.
  75. Goumas P, Naxakis S, Christopoulou A, et al. Octreotide Acetate in the Treatment of Fluorouracil-Induced Diarrhea. Oncologist 1998; 3:50.
  76. Gebbia V, Carreca I, Testa A, et al. Subcutaneous octreotide versus oral loperamide in the treatment of diarrhea following chemotherapy. Anticancer Drugs 1993; 4:443.
  77. Rosenoff S. Resolution of refractory chemotherapy-induced diarrhea (CID) with octreotide long-acting formulation in cancer patients: 11 case studies. Support Care Cancer 2004; 12:561.
  78. Rosenoff SH, Gabrail NY, Conklin R, et al. A multicenter, randomized trial of long-acting octreotide for the optimum prevention of chemotherapy-induced diarrhea: results of the STOP trial. J Support Oncol 2006; 4:289.
  79. VAN DEN Heuvel B, Peeters M, Hendlisz A, et al. Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea: proof of concept. Minerva Chir 2016.
  80. Saliba F, Hagipantelli R, Misset JL, et al. Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment. J Clin Oncol 1998; 16:2745.
  81. Lenfers BH, Loeffler TM, Droege CM, Hausamen TU. Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment. Ann Oncol 1999; 10:1251.
  82. Ma WW, Saif MW, El-Rayes BF, et al. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Cancer 2017; 123:345.
  83. Ison G, Beaver JA, McGuinn WD Jr, et al. FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs. Clin Cancer Res 2016; 22:4545.
  84. Ma WW, Saif WM, El-Rayes BF, et al. Clinical trial experience with uridine triacetate for 5-fluorouracil toxicity (abstract). J Clin Oncol 34, 2016 (suppl 4S; abstr 655). http://meetinglibrary.asco.org/content/159120-173 (Accessed on February 04, 2016).
  85. von Borstel R, O'Neil JD, Saydoff JA, et al. Uridine triacetate for lethal 5-FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency (abstract ). J Clin Oncol 2010 (suppl abstract e13505).
  86. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm476930.htm (Accessed on December 14, 2015).
  87. Michael M, Brittain M, Nagai J, et al. Phase II study of activated charcoal to prevent irinotecan-induced diarrhea. J Clin Oncol 2004; 22:4410.
  88. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients. Int J Cancer 2001; 92:269.
  89. Osterlund P, Ruotsalainen T, Korpela R, et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer 2007; 97:1028.
  90. Mego M, Chovanec J, Vochyanova-Andrezalova I, et al. Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study. Complement Ther Med 2015; 23:356.
  91. Ychou M, Douillard JY, Rougier P, et al. Randomized comparison of prophylactic antidiarrheal treatment versus no prophylactic antidiarrheal treatment in patients receiving CPT-11 (irinotecan) for advanced 5-FU-resistant colorectal cancer: an open-label multicenter phase II study. Am J Clin Oncol 2000; 23:143.
  92. Meropol NJ, Blumenson LE, Creaven PJ. Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin. Am J Clin Oncol 1998; 21:135.
  93. Hoff PM, Saragiotto DF, Barrios CH, et al. Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol 2014; 32:1006.
  94. Saegusa Y, Ichikawa T, Iwai T, et al. Effects of acid antisecretory drugs on mucus barrier of the rat against 5-fluorouracil-induced gastrointestinal mucositis. Scand J Gastroenterol 2008; 43:531.
  95. Namikawa T, Munekage E, Maeda H, et al. Feasibility study of supportive care using lafutidine, a histamine H2 receptor antagonist, to prevent gastrointestinal toxicity during chemotherapy for gastric cancer. Anticancer Res 2014; 34:7297.
  96. Kee BK, Morris JS, Slack RS, et al. A phase II, randomized, double blind trial of calcium aluminosilicate clay versus placebo for the prevention of diarrhea in patients with metastatic colorectal cancer treated with irinotecan. Support Care Cancer 2015; 23:661.
  97. Bradstock KF, Link E, Collins M, et al. A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia. Br J Haematol 2014; 167:618.
  98. Rotovnik Kozjek N, Kompan L, Soeters P, et al. Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study. Clin Nutr 2011; 30:567.
  99. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 2001; 48:28.
  100. Bozzetti F, Biganzoli L, Gavazzi C, et al. Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study. Nutrition 1997; 13:748.
  101. Jolfaie NR, Mirzaie S, Ghiasvand R, et al. The effect of glutamine intake on complications of colorectal and colon cancer treatment: A systematic review. J Res Med Sci 2015; 20:910.
  102. Decker-Baumann C, Buhl K, Frohmüller S, et al. Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Eur J Cancer 1999; 35:202.