Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies

Abstract

Background

Diarrhoea and constipation are common toxicities of chemotherapy, and both are poorly understood. They are manifestations of alimentary mucositis, a condition which affects the entire gastrointestinal tract.

Discussion

The absolute percentage of patients that have diarrhoea or constipation as a result of their treatment has yet to be fully defined, although general estimates place 10% of patients with advanced cancer as being afflicted. Although there has been some major progress in recent years with understanding the mechanisms of oral and small intestinal mucositis, diarrhoea and constipation have received very little attention. Although diarrhoea is a well-recognised side-effect of both chemotherapy and radiotherapy, very little research has been conducted on the mechanisms behind diarrhoea or its treatment. Much of the information in the published literature is based on clinical observations with very little basic science existing. Constipation is not as well recognised and very little is known about its mechanisms.

Objectives

This review will examine in detail the potentially complex pathogenesis of post-chemotherapy diarrhoea in both animal models and the clinical setting. Furthermore, it will explore what is known about chemotherapy-induced constipation. It will then outline an evidence-based pathway for the investigation and treatment of post-chemotherapy diarrhoea and constipation.

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References

  1. 1.

    Abigerges D, Armand JP, Chabot GG, DaCosta L, Fadel E, Cote C, Heraot P, Gandia D (1994) Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhoea. J Natl Cancer Inst 86:446–449

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Alimonti A, Satta F, Pavese I, Burattini E, Zoffoli V, Vecchione A (2003) Prevention of irinotecan plus 5-fluorouracil/leucovorin-induced diarrhoea by oral administration of neomycin plus bacitracin in first-line treatment of advanced colorectal cancer. Ann Oncol 14:805–806

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Alimonti A, Gelibter A, Pavese I, Satta F, Cognetti F, Ferretti G, Rasio D, Vecchione A, Di Palma M (2004) New approaches to prevent intestinal toxicity of irinotecan-based regimens. Cancer Treat Rev 30:555–562

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Araki E, Ishikawa M, Iigo M, Koide T, Itabashi M, Hoshi A (1993) Relationship between development of diarrhaea and the concentration of SN-38, and active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res 84:697–702

    PubMed  CAS  Google Scholar 

  5. 5.

    Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, McCallum R, Mitchell EP, O’Dorisio TM, Vokes EE, Wadler S (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22:2918–2926

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Campbell T, Draper S, Reid J, Robinson L (2001) The management of constipation in people with advanced cancer. Int J Palliat Nurs 7:110–119

    PubMed  CAS  Google Scholar 

  7. 7.

    Cao S, Rustum YM (2000) Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 60:3717–3721

    PubMed  CAS  Google Scholar 

  8. 8.

    Cao S, Rustum YM, Spector T (1994) 5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. Cancer Res 54:1507–1510

    PubMed  CAS  Google Scholar 

  9. 9.

    Cao S, Frank C, Rustum YM (1996) Role of fluoropyrimidine schedule and (6R,S)leucovorin dose in a preclinical animal model of colorectal carcinoma. J Natl Cancer Inst 88:430–436

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Cao S, Black JD, Troutt AB, Rustum YM (1998) Interleukin 15 offers selective protection from Irinotecan-induced intestinal toxicity in a preclinical animal model. Cancer Res 58:3270–3274

    PubMed  CAS  Google Scholar 

  11. 11.

    Cao S, Troutt AB, Rustum YM (1998) Interleukin 15 protects against toxicity and potentiates against antitumor activity of 5-flououracil alone and in combination with leucovorin in rats bearing colorectal cancer. Cancer Res 58:1695–1699

    PubMed  CAS  Google Scholar 

  12. 12.

    Carpenter CCJ (1982) The pathophysiology of secretory diarrheas. Med Clin North Am 66:597–610

    PubMed  CAS  Google Scholar 

  13. 13.

    Cascinu S (1995) Drug therapy in diarrheal diseases in oncology/hematology patients. Crit Rev Oncol Hematol 18:37–50

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Cascinu S, Fedeli A, Fedeli SL, Catalano G (1992) Control of chemotherapy-induced diarrhoea with octreotide in patients receiving 5-fluorouracil. Eur J Cancer 28:482–3

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Castro-Rodriguez JA, Salazar-Lindo E, Leon-Barua R (1997) Differentiation of osmotic and secretory diarrhoea by stool carbohydrate and osmolar gap measurements. Arch Dis Child 77:201–205

    PubMed  CAS  Google Scholar 

  16. 16.

    de Roy van Zuidewijn DB, Schillings PH, Wobbes T, Hendriks T, de Boer HH (1992) Morphometric analysis of the effects of antineoplastic drugs on mucosa of normal ileum and ileal anastomoses in rats. Exp Mol Pathol 56:96–107

    Article  PubMed  Google Scholar 

  17. 17.

    Elson CO, Sartor RB, Tennyson GS, Riddell RH (1995) Experimental models of inflammatory bowel disease. Gastroenterology 109:1344–1367

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Engelking C, Rutledge DN, Ippoliti C, Neumann J, Hogan CM (1998) Cancer-related diarrhea: a neglected cause of cancer-related symptom distress. Oncol Nurs Forum 25:859–860

    PubMed  CAS  Google Scholar 

  19. 19.

    Fittkau M, Voigt W, Holzhausen HJ, Schmoll HJ (2004) Saccharic acid 1.4-lactone protects against CPT-11-induced mucosa damage in rats. J Cancer Res Clin Oncol 130:388–394

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Gall LS (1970) Normal fecal flora of man. Am J Clin Nutr 23:1457–1465

    PubMed  CAS  Google Scholar 

  21. 21.

    Gelfand MD, Tepper M, Katz LA, Binder HJ, Yesner R, Floch MH (1968) Acute irradiation proctitis in man: development of eosinophilic crypt abscesses. Gastroenterology 54:401–11

    PubMed  CAS  Google Scholar 

  22. 22.

    Gibson RJ, Keefe DMK, Clarke JM, Regester GO, Thompson FM, Goland GJ, Edwards BE, Cummins AG (2002) The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer. Cancer Chemother Pharmacol 50:53–58

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Gibson RJ, Keefe DMK, Thompson FM, Clarke JM, Goland GJ, Cummins AG (2002) Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Dig Dis Sci 47:2751–2757

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Gibson RJ, Bowen JM, Inglis MR, Cummins AG, Keefe DMK (2003) Irinotecan causes severe small intestinal damage as well as colonic damage in the rat with implanted breast cancer. J Gastroenterol Hepatol 18:1095–1100

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Ginopoulos P, Papagiannis T, Safridi C, Karvelas F, Spyropoulos K, Papadas T, Gogos C (1996) Octreotide treatment of chemotherapy-induced diarrhoea. Eur J Cancer 32A:182–183

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Gorbach SL, Banwell JG, Chatterjee BD, Jacobs B, Sack RB (1971) Acute undifferentiated human diarrhea in the tropics: I: Alterations in intestinal microflora. J Clin Invest 50:881–889

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Gosselink MP, Schouten WR, van Lieshout LMC, Hop WCJ, Laman JD, Ruseler-van Embden JGH (2004) Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciproffloxacin in the treatment of pouchitis. Dis Colon Rectum 47:1519–1525

    Article  PubMed  Google Scholar 

  28. 28.

    Gutheil JC, Kearns CM (1997) Antimetabolites. In: Perry MC (ed) The chemotherapy source book. Williams & Wilkins, Baltimore, MD, pp 317–344

    Google Scholar 

  29. 29.

    Gwede CK (2003) Overview of radiation- and chemoradiation-induced diarrhea. Semin Oncol Nurs 19:6–10

    Article  PubMed  Google Scholar 

  30. 30.

    Haenel H (1970) Human normal and abnormal gastrointestinal flora. Am J Clin Nutr 23:1433–1439

    PubMed  CAS  Google Scholar 

  31. 31.

    Hogan CM (1998) The nurse’s role in diarrhea management. Oncol Nurs Forum 25:879–886

    PubMed  CAS  Google Scholar 

  32. 32.

    Ikuno N, Soda H, Watanabe M, Oka M (1995) Irinotecan (CPT-11) and characteristic changes in the mouse ileum and cecum. J Natl Cancer Inst 87:1876–1883

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Ippoliti C, Neumann J (1998) Octreotide in the management of diarrhea induced by graft versus host disease. Oncol Nurs Forum 25:873–878

    PubMed  CAS  Google Scholar 

  34. 34.

    Jansman FG, Sleijfer DT, de Graaf JC, Coenen JL, Brouwers JR (2001) Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. Drug Saf 24:353–367

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Jenkins D, Balsitis M, Gallivan S, Dixon MF, Gilmour HM, Shepherd NA, Theodossi A, Williams GT (1997) Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease. Br Soc Gastroenterol Int J Clin Pathol 50:93–105

    CAS  Google Scholar 

  36. 36.

    Keefe DMK (1998) The effect of cytotoxic chemotherapy on the mucosa of the small intestine. Department of Medicine, University of Adelaide, Adelaide

    Google Scholar 

  37. 37.

    Keefe DM (2004) Gastrointestinal mucositis: a new biological model. Support Care Cancer 12:6–9

    Article  PubMed  Google Scholar 

  38. 38.

    Keefe DM, Cummins AG, Dale BM, Kotasek D, Robb TA, Sage RE (1997) Effect of high-dose chemotherapy on intestinal permeability in humans. Clin Sci 92:385–389

    PubMed  CAS  Google Scholar 

  39. 39.

    Keefe DM, Brealey J, Goland GJ, Cummins AG (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Keefe DM, Gibson RJ, Hauer-Jenson M (2004) Gastrointestinal mucositis. Semin Oncol Nurs 20:38–47

    Article  PubMed  Google Scholar 

  41. 41.

    Klainer AS, Gorbach SL, Weinstein L (1967) Studies of intestinal microflora. VI: Effect of X irradiation on the fecal microflora of the rat. J Bacteriol 92:378–382

    Google Scholar 

  42. 42.

    Klainer AS, Gorbach SL, Weinstein L (1967) Studies of intestinal microflora: VII: Effect of diet and fecal microbial flora on survival of animals exposed to X irradiation. J Bacteriol 94:383–387

    PubMed  CAS  Google Scholar 

  43. 43.

    Kofteridis DP, Maraki S, Mixaki I, Mantadakis E, Samonis G (2004) Impact of prolonged treatment with trimethoprim-sulfamethoxazole on the human gut flora. Scand J Infect Dis 36:771–772

    PubMed  CAS  Google Scholar 

  44. 44.

    Leiper K, Campbell BJ, Jenkinson MD, Milton J, Yu LG, Democratis J, Rhodes JM (2001) Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis. Clin Sci (Lond) 101:395–402

    CAS  Article  Google Scholar 

  45. 45.

    Li L-J, Wu Z-W, Xiao D-S, Sheng J-F (2004) Changes of gut flora and endotoxin in rats with d-galactosamine-induced acute liver failure. World J Gastroenterol 10:2087–2090

    PubMed  CAS  Google Scholar 

  46. 46.

    Ma MK, McLeod HL (2003) Lessons learned from the irinotecan metabolic pathway. Curr Med Chem 10:41–49

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Macdonald DR (1997) Neurotoxicity of chemotherapeutic agents. In: Perry MC (ed) The chemotherapy source book. Williams & Wilkins, Baltimore, MD, pp 745–766

    Google Scholar 

  48. 48.

    Mancini I, Bruera E (1998) Constipation in advanced cancer patients. Support Care Cancer 6:356–364

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    McCormick DA, Horton LW, Mee AS (1990) Mucin depletion in inflammatory bowel disease. J Clin Pathol 43:143–6

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Mercadante S (1995) Diarrhea in terminally ill patients: pathophysiology and treatment. J Pain Symptom Manage 10:298–308

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Milles SS, Muggia AL, Spiro HM (1962) Colonic histologic changes induced by 5-fluououracil. Gastroenterology 43:391–399

    Google Scholar 

  52. 52.

    Nostrant TT, Kumar NB, Appelman HD (1987) Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 92:318–328

    PubMed  CAS  Google Scholar 

  53. 53.

    Pico J-L, Avila-Garavito A, Naccache P (1998) Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3:446–451

    PubMed  Google Scholar 

  54. 54.

    Portenoy R (1987) Constipation in the cancer patient: causes and management. Med Clin North Am 71:303–310

    PubMed  CAS  Google Scholar 

  55. 55.

    Read NW, Timms JM (1986) Defecation and the pathophysiology of constipation. Clin Gastroenterol 15:937–965

    PubMed  CAS  Google Scholar 

  56. 56.

    Reinecker HC, MacDermott RP, Mirau S, Dignass A, Podolsky DK (1996) Intestinal epithelial cells both express and respond to interleukin 15. Gastroenterology 111:1706–1713

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Rubenstein EB, Peterson DE, Schubert MM, Keefe DM, McGuire DB, Epstein JB, Elting LS, Fox PC, Loprinzi CL, Sonis ST (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100:2026–2046

    Article  PubMed  Google Scholar 

  58. 58.

    Rutledge DN, Engelking C (1998) Cancer-related diarrhea: selected findings of a national survey of oncology nurse experiences. Oncol Nurs Forum 25:861–873

    PubMed  CAS  Google Scholar 

  59. 59.

    Saltz LB (2003) Understanding and managing chemotherapy-induced diarrhea. J Support Oncol 1:35–46; discussion 38–41, 45–6

    PubMed  CAS  Google Scholar 

  60. 60.

    Saltz L, Shimada Y, Khayat D (1996) CPT-11 (irinotecan) and 5-fluorouracil: a promising combination for therapy of colorectal cancer. Eur J Cancer 32A(Suppl 3):S24–S31

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Sharma R, Tobin P, Clarke SJ (2005) Management of chemotherapy-induced nausea, vomiting, oral mucositis, and diarrhoea. Lancet Oncol 6:93–102

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Shinohara H, Killion JJ, Kuniyasu H, Kumar R, Fidler IJ (1998) Prevention of intestinal toxic effects and intensification of Irinotecan’s therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. Clin Cancer Res 4:2053–2063

    PubMed  CAS  Google Scholar 

  63. 63.

    Shinohara H, Killion JJ, Bucana CD, Yano S, Fidler IJ (1999) Oral administration of the immunomodulator JBT-3002 induces endogenous interleukin 15 in intestinal macrophages for protection against irinotecan-mediated destruction of intestinal epithelium. Clin Cancer Res 5:2148–2156

    PubMed  CAS  Google Scholar 

  64. 64.

    Si J-M, Yu Y-C, Fan Y-J, Chen S-J (2004) Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol 10:1802–1805

    PubMed  Google Scholar 

  65. 65.

    Sonis ST (1998) Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34:39–43

    Article  PubMed  CAS  Google Scholar 

  66. 66.

    Sonis ST, Tracey C, Shklar G, Jenson J, Florine D (1990) An animal model for mucositis induced by cancer chemotherapy. Oral Surg Oral Med Oral Pathol 69:437–443

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Sonis ST, Costa JW, Jr, Evitts SM, Lindquist LE, Nicolson M (1992) Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol 74:749–755

    Article  PubMed  CAS  Google Scholar 

  68. 68.

    Sonis ST, Van Vugt AG, Brien JP, Muska AD, Bruskin AM, Rose A, Haley JD (1997) Transforming growth factor-beta 3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis. Oral Oncol 33:47–54

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Sonis S, Edwards L, Lucey C (1999) The biological basis for the attenuation of mucositis: the example of interleukin-11. Leukemia 13:831–834

    Article  PubMed  CAS  Google Scholar 

  70. 70.

    Sonis ST, Elting LS, Keefe DM, Peterson DE, Schubert MM, Hauer-Jenson M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein E (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025

    Article  PubMed  Google Scholar 

  71. 71.

    Stern J, Ippoliti C (2003) Management of acute cancer treatment-induced diarrhea. Semin Oncol Nurs 19:11–16

    Article  PubMed  Google Scholar 

  72. 72.

    Sykes NP (1994) Current approaches to the management of constipation. Cancer Surv 21:137–146

    PubMed  CAS  Google Scholar 

  73. 73.

    Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1996) Involvement of β-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 56:3752–3757

    PubMed  CAS  Google Scholar 

  74. 74.

    Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1998) Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats. Cancer Chemother Pharmacol 42:280–286

    Article  PubMed  CAS  Google Scholar 

  75. 75.

    Talley NJ (2004) Definitions, epidemiology, and impact of chronic constipation. Rev Gastroenterol Dis 4:S3–S10

    Article  CAS  Google Scholar 

  76. 76.

    Viele CS (2003) Overview of chemotherapy-induced diarrhea. Semin Oncol Nurs 19:2–5

    Article  PubMed  Google Scholar 

  77. 77.

    Wadler S, Benson AB, 3rd, Engelking C, Catalano R, Field M, Kornblau SM, Mitchell E, Rubin J, Trotta P, Vokes E (1998) Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 16:3169–3178

    PubMed  CAS  Google Scholar 

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Correspondence to Rachel J. Gibson.

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Gibson, R.J., Keefe, D.M.K. Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies. Support Care Cancer 14, 890 (2006). https://doi.org/10.1007/s00520-006-0040-y

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Keywords

  • Diarrhoea
  • Constipation
  • Mucositis
  • Chemotherapy