Skip to main content
SpringerLink
Log in

Gastrointestinal Cancer: Selection of Clinically Relevant Drug-Induced Toxicities Encountered in Gastrointestinal Cancer Treatment

  • Chapter
  • First Online:
Side Effects of Medical Cancer Therapy

  • 1624 Accesses

Abstract

The chemotherapeutic options have increased dramatically in patients with gastrointestinal cancer and have led to an improved outcome. With this, an in-depth understanding of the side effects of chemotherapy is becoming increasingly important in order to minimize the negative impact of the use of these agents. Chemotherapeutic agents have a long list of potential side effects. In this chapter, we focus specifically on some of the more common and/or more relevant and challenging side effects related to frequently used agents in gastrointestinal cancer. The fluoropyrimidines may cause cardiac toxicity, most frequently angina-like chest pain. The knowledge of the catabolism of fluorouracil has led to the possibility of testing for dihydropyrimidine dehydrogenase (DPD) in order to avoid serious fluorouracil-related toxicity in patients with DPD deficiency. Oxaliplatin-induced neurotoxicity is probably the most important clinical problem associated with the administration of oxaliplatin. With the increasing use of oxaliplatin, hypersensitivity reactions are more frequently reported and become challenging in clinical practice. The introduction of the targeted agents in colorectal cancer led also to specific problems: the anti-VEGF-related side effects, of which gastrointestinal perforation, although relatively rare, is very relevant for the patient, and the anti-EGFR-related side effects, including skin rash, hypomagnesemia, and allergic reactions, are common. Understanding the underlying causes, mechanisms, risk factors, and developing treatment guidelines has made these side effects often more acceptable for many patients. However, the side-effect profile always has to be balanced against the activity and benefit of the anticancer agents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23–44.

    Article  PubMed  CAS  Google Scholar 

  2. Cassidy J, Saltz L, Twelves C, Van Cutsem E, Hoff P, Kang Y, et al. Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol. 2011;22(12):2604–9. Epub 2011 Mar 17.

    Article  PubMed  CAS  Google Scholar 

  3. Becker K, Erckenbrecht JF, Häussinger D, Frieling T. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs. 1999;57(4):475–84.

    Article  PubMed  CAS  Google Scholar 

  4. Ang C, Kornbluth M, Thirlwell MP, Rajan RD. Capecitabine-induced cardiotoxicity: case report and review of the literature. Curr Oncol. 2010;17(1):59–63.

    Article  PubMed  CAS  Google Scholar 

  5. Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol. 2008;134(1):75–82. Epub 2007 Jul 17.

    Article  PubMed  CAS  Google Scholar 

  6. Burger AJ, Mannino S. 5-Fluorouracil-induced coronary vasospasm. Am Heart J. 1987;114(2):433–6.

    Article  PubMed  CAS  Google Scholar 

  7. Van Cutsem E, Hoff PM, Blum JL, Abt M, Osterwalder B. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol. 2002;13(3):484–5.

    Article  PubMed  Google Scholar 

  8. Van Cutsem E. Raltitrexed (Tomudex). Expert Opin Investig Drugs. 1998;7(5):823–34.

    Article  PubMed  Google Scholar 

  9. Ciccolini J, Gross E, Dahan L, Lacarelle B, Mercier C. Routine ­dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil-related severe toxicities: hype or hope? Clin Colorectal Cancer. 2010;9(4):224–8.

    Article  PubMed  CAS  Google Scholar 

  10. Yen JL, McLeod HL. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur J Cancer. 2007;43(6):1011–6. Epub 2007 Mar 12.

    Article  PubMed  Google Scholar 

  11. Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Renée N, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol. 1994;12(11):2248–53.

    PubMed  CAS  Google Scholar 

  12. Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine ­dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011;12(9):1321–36.

    Article  PubMed  CAS  Google Scholar 

  13. Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH. High prevalence of the IVS14  +  1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics. 2002;12(7):555–8.

    Article  PubMed  Google Scholar 

  14. Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008;26(13):2131–8. Epub 2008 Feb 25.

    Article  PubMed  CAS  Google Scholar 

  15. Giorgio E, Caroti C, Mattioli F, Uliana V, Parodi MI, D’Amico M, et al. Severe fluoropyrimidine-related toxicity: clinical implications of DPYD analysis and UH2/U ratio evaluation. Cancer Chemother Pharmacol. 2011;68(5):1355–61. Epub 2011 Aug 11.

    Article  PubMed  CAS  Google Scholar 

  16. Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C, et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemother Pharmacol. 2011;67(1):49–56. Epub 2010 Mar 5.

    Article  PubMed  CAS  Google Scholar 

  17. Weickhardt A, Wells K, Messersmith W. Oxaliplatin-induced neuropathy in colorectal cancer. J Oncol. 2011;2011:201593. Epub 2011 Dec 12.

    Article  PubMed  Google Scholar 

  18. Hoff PM, Saad ED, Costa F, Coutinho AK, Caponero R, Prolla G, et al. Literature review and practical aspects on the management of oxaliplatin-associated toxicity. Clin Colorectal Cancer. 2012;11(2):93–100. Epub 2011 Dec 6.

    Article  PubMed  CAS  Google Scholar 

  19. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.

    Article  PubMed  Google Scholar 

  20. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938–47.

    PubMed  Google Scholar 

  21. Gamelin L, Capitain O, Morel A, Dumont A, Traore S, le Anne B, et al. Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway. Clin Cancer Res. 2007;13(21):6359–68.

    Article  PubMed  CAS  Google Scholar 

  22. Grolleau F, Gamelin L, Boisdron-Celle M, Lapied B, Pelhate M, Gamelin E, et al. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol. 2001;85(5):2293–7.

    PubMed  CAS  Google Scholar 

  23. Won HH, Lee J, Park JO, Park YS, Lim HY, Kang WK, et al. Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer. 2012;118(11):2828–36. doi:10.1002/cncr.26614. Epub 2011 Oct 21.

    Article  PubMed  CAS  Google Scholar 

  24. Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011;12(12):1151–61. Epub 2011 Jun 28.

    Article  PubMed  CAS  Google Scholar 

  25. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study. J Clin Oncol. 2006;24(3):394–400.

    Article  PubMed  CAS  Google Scholar 

  26. Díaz-Rubio E, Gómez-España A, Massutí B, Sastre J, Abad A, Valladares M, et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: The Phase III MACRO TTD Study. Oncologist. 2012;17(1):15–25. Epub 2012 Jan 10.

    Article  PubMed  Google Scholar 

  27. Grothey A, Nikcevich DA, Sloan JA, Kugler JW, Silberstein PT, Dentchev T, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29(4):421–7. Epub 2010 Dec 28.

    Article  PubMed  CAS  Google Scholar 

  28. Park SB, Goldstein D, Lin CS, Krishnan AV, Friedlander ML, Kiernan MC, et al. Neuroprotection for oxaliplatin-induced neurotoxicity: what happened to objective assessment? J Clin Oncol. 2011;29(18):e553–4; author reply e555-6. Epub 2011 May 23.

    Article  PubMed  Google Scholar 

  29. Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2012;23(1):200–5. Epub 2011 Mar 22.

    Article  PubMed  CAS  Google Scholar 

  30. Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Met Based Drugs. 2010;2010. pii: 207084. Epub 2010 Sep 20.

    Google Scholar 

  31. Kim BH, Bradley T, Tai J, Budman DR. Hypersensitivity to oxaliplatin: an investigation of incidence and risk factors, and literature review. Oncology. 2009;76(4):231–8. Epub 2009 Feb 25.

    Article  PubMed  CAS  Google Scholar 

  32. Siu SW, Chan WL, Liu KY, Choy TS, Leung TW, Au KH. Re-challenging patients with oxaliplatin allergy: the successful use of a standardised ­pre-medication protocol in a single institute. Clin Oncol (R Coll Radiol). 2011;23(8):558–9. doi:10.1016/j.clon.2011.04.005. Epub 2011 Apr 23.

    Article  CAS  Google Scholar 

  33. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27.

    Article  PubMed  CAS  Google Scholar 

  34. Jenab-Wolcott J, Giantonio BJ. Antiangiogenic therapy in colorectal cancer: where are we 5 years later? Clin Colorectal Cancer. 2010;9 Suppl 1:S7–15.

    Article  PubMed  CAS  Google Scholar 

  35. de Gramont A, de Gramont A, Chibaudel B, Larsen AK, Tournigand C, André T, GERCOR French Oncology Research Group. The evolution of adjuvant therapy in the treatment of early-stage colon cancer. Clin Colorectal Cancer. 2011;10(4):218–26.

    Article  PubMed  Google Scholar 

  36. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol. 2009;10(6):559–68.

    Article  PubMed  CAS  Google Scholar 

  37. Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol. 2007;14(6):1860–9. Epub 2007 Mar 14.

    Article  PubMed  Google Scholar 

  38. Walraven M, Witteveen PO, Lolkema MP, van Hillegersberg R, Voest EE, Verheul HM. Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review. Angiogenesis. 2011;14(2):135–41. Epub 2010 Dec 29.

    Article  PubMed  Google Scholar 

  39. You B, Chen EX. Anti-EGFR Monoclonal antibodies for treatment of colorectal cancers: development of cetuximab and panitumumab. J Clin Pharmacol. 2012; 52:128–55. [Epub 2011 Mar 22].

    Google Scholar 

  40. Prenen H, Tejpar S, Van Cutsem E. New strategies for treatment of KRAS mutant metastatic colorectal cancer. Clin Cancer Res. 2010;16(11):2921–6. Epub 2010 May 11.

    Article  PubMed  CAS  Google Scholar 

  41. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005;16(9):1425–33. Epub 2005 Jul 12.

    Article  PubMed  CAS  Google Scholar 

  42. Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities of targeted therapies. Eur J Cancer. 2009;45 Suppl 1:295–308.

    Article  PubMed  Google Scholar 

  43. Green MR, Couchman JR. Differences in human skin between the epidermal growth factor receptor distribution detected by EGF binding and monoclonal antibody recognition. J Invest Dermatol. 1985;85(3):239–45.

    Article  PubMed  CAS  Google Scholar 

  44. Giovannini M, Gregorc V, Belli C, Roca E, Lazzari C, Viganò MG, et al. Clinical significance of skin toxicity due to EGFR-targeted therapies. J Oncol. 2009;2009:849051. Epub 2009 Jun 22.

    Article  PubMed  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov [online]. http://clinicaltrials.gov/ct2/show/study/NCT01251536 Accessed on sep 14, 2012.

  46. Costa A, Tejpar S, Prenen H, Van Cutsem E. Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents. Target Oncol. 2011;6(4):227–33. doi:10.1007/s11523-011-0200-y. Epub 2011 Nov 24.

    Article  PubMed  Google Scholar 

  47. Tejpar S, Piessevaux H, Claes K, Piront P, Hoenderop JG, Verslype C, et al. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol. 2007;8(5):387–94.

    Article  PubMed  CAS  Google Scholar 

  48. Groenestege WM, Thébault S, van der Wijst J, van den Berg D, Janssen R, Tejpar S, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117(8):2260–7.

    Article  PubMed  CAS  Google Scholar 

  49. Fakih MG, Wilding G, Lombardo J. Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin Colorectal Cancer. 2006;6(2):152–6.

    Article  PubMed  CAS  Google Scholar 

  50. Fakih M. Management of anti-EGFR-targeting monoclonal antibody-induced hypomagnesemia. Oncology (Williston Park). 2008;22(1):74–6.

    Google Scholar 

  51. Saif MW, Peccerillo J, Potter V. Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature. Cancer Chemother Pharmacol. 2009;63(6):1017–22. Epub 2008 Sep 10.

    Article  PubMed  Google Scholar 

  52. George Jr TJ, Laplant KD, Walden EO, Davis AB, Riggs CE, Close JL, et al. Managing cetuximab hypersensitivity-infusion reactions: incidence, risk factors, prevention, and retreatment. J Support Oncol. 2010;8(2):72–7.

    PubMed  CAS  Google Scholar 

  53. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17.

    Article  PubMed  CAS  Google Scholar 

  54. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12(5):601–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven, Leuven, Belgium

    Julie Bogaert M.D., Pieter-Jan Cuyle M.D. & Eric Van Cutsem M.D., Ph.D.

Authors
  1. Julie Bogaert M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pieter-Jan Cuyle M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Van Cutsem M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. , Department of Hematology-Oncology, Centre Hospitalier de Luxembourg, Rue Barble 4, Luxembourg, 1210, Luxembourg

    Mario A. Dicato

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag London

About this chapter

Cite this chapter

Bogaert, J., Cuyle, PJ., Van Cutsem, E. (2013). Gastrointestinal Cancer: Selection of Clinically Relevant Drug-Induced Toxicities Encountered in Gastrointestinal Cancer Treatment. In: Dicato, M. (eds) Side Effects of Medical Cancer Therapy. Springer, London. https://doi.org/10.1007/978-0-85729-787-7_4

Download citation

  • DOI: https://doi.org/10.1007/978-0-85729-787-7_4

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-0-85729-786-0

  • Online ISBN: 978-0-85729-787-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation