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Enterotoxicity of chemotherapeutic agents

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


Gastrointestinal (GI) toxicity due to chemotherapeutic drugs is a common problem in cancer patients. The specific chemotherapy-related GI complications that are reviewed here include diarrhea, constipation, colitis (neutropenic, C. difficile-induced, and immune-mediated), and intestinal perforation. Chemotherapy-induced oral toxicity (mucositis), and nausea and vomiting are discussed separately. (See "Oral toxicity associated with chemotherapy" and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".)


Chemotherapy-induced diarrhea (CID) is most commonly described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with or without irinotecan.

Pathogenesis — Both FU and irinotecan cause acute damage to the intestinal mucosa, leading to loss of epithelium [1,2]. FU induces mitotic arrest of crypt cells, leading to an increase in the ratio of immature secretory crypt cells to mature villous enterocytes [1,3]. The increased volume of fluid that leaves the small bowel exceeds the absorptive capacity of the colon, leading to clinically significant diarrhea.

With irinotecan, early onset diarrhea occurs during or within several hours of drug infusion in 45 to 50 percent of patients and is cholinergically mediated [4]. This effect is thought to be due to structural similarity of the drug with acetylcholine. In contrast, late irinotecan-associated diarrhea is not cholinergically mediated. The pathophysiology of late diarrhea appears to be multifactorial with contributions from dysmotility and secretory factors as well as a direct toxic effect on the intestinal mucosa [5,6].

Irinotecan produces mucosal changes associated with apoptosis, such as epithelial vacuolization, and goblet cell hyperplasia, suggestive of mucin hypersecretion [2]. These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa [7].


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  1. Milles SS, Muggia AL, Spiro HM. Colonic histological changes induced by 5-fluorouracil. Gastroenterology 1962; 43:391.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Hecht JR. Gastrointestinal toxicity or irinotecan. Oncology (Williston Park) 1998; 12:72.
  7. Kawato Y, Aonuma M, Hirota Y, et al. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51:4187.
  8. Gupta E, Lestingi TM, Mick R, et al. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 1994; 54:3723.
  9. Wasserman E, Myara A, Lokiec F, et al. Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. Ann Oncol 1997; 8:1049.
  10. Takasuna K, Hagiwara T, Hirohashi M, et al. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 1996; 56:3752.
  11. National Cancer Institute Common Toxicity Criteria http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (Accessed on March 08, 2011).
  12. Mertz HR, Beck CK, Dixon W, et al. Validation of a new measure of diarrhea. Dig Dis Sci 1995; 40:1873.
  13. Grem JL, Shoemaker DD, Petrelli NJ, Douglass HO Jr. Severe life-threatening toxicities observed in study using leucovorin with 5-fluorouracil. J Clin Oncol 1987; 5:1704.
  14. Petrelli N, Herrera L, Rustum Y, et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987; 5:1559.
  15. Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 1995; 13:1303.
  16. Poon MA, O'Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7:1407.
  17. Petrelli N, Douglass HO Jr, Herrera L, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group. J Clin Oncol 1989; 7:1419.
  18. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005; 352:476.
  19. Cascinu S, Barni S, Labianca R, et al. Evaluation of factors influencing 5-fluorouracil-induced diarrhea in colorectal cancer patients. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) study. Support Care Cancer 1997; 5:314.
  20. Kuebler JP, Colangelo L, O'Connell MJ, et al. Severe enteropathy among patients with stage II/III colon cancer treated on a randomized trial of bolus 5-fluorouracil/leucovorin plus or minus oxaliplatin: a prospective analysis. Cancer 2007; 110:1945.
  21. Sloan JA, Goldberg RM, Sargent DJ, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 2002; 20:1491.
  22. Chansky K, Benedetti J, Macdonald JS. Differences in toxicity between men and women treated with 5-fluorouracil therapy for colorectal carcinoma. Cancer 2005; 103:1165.
  23. Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest 1988; 81:47.
  24. Maring JG, van Kuilenburg AB, Haasjes J, et al. Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene. Br J Cancer 2002; 86:1028.
  25. Ezzeldin H, Johnson MR, Okamoto Y, Diasio R. Denaturing high performance liquid chromatography analysis of the DPYD gene in patients with lethal 5-fluorouracil toxicity. Clin Cancer Res 2003; 9:3021.
  26. Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer 1991; 68:499.
  27. Takimoto CH, Lu ZH, Zhang R, et al. Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer Res 1996; 2:477.
  28. Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 2004; 4:181.
  29. Diasio RB, Johnson MR. Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res 1999; 5:2672.
  30. van Kuilenburg AB, Meinsma R, Zonnenberg BA, et al. Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res 2003; 9:4363.
  31. Yang CG, Ciccolini J, Blesius A, 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; 67:49.
  32. Mattison LK, Fourie J, Desmond RA, et al. Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clin Cancer Res 2006; 12:5491.
  33. Morel A, Boisdron-Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006; 5:2895.
  34. van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem 2003; 40:41.
  35. Offer SM, Fossum CC, Wegner NJ, et al. Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 2014; 74:2545.
  36. Johnson MR, Diasio RB. Importance of dihydropyrimidine dehydrogenase (DPD) deficiency in patients exhibiting toxicity following treatment with 5-fluorouracil. Adv Enzyme Regul 2001; 41:151.
  37. Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res 2002; 8:768.
  38. Schwab M, Zanger UM, Marx C, 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; 26:2131.
  39. Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH. Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer 2002; 101:253.
  40. Raida M, Schwabe W, Häusler P, et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 2001; 7:2832.
  41. 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; 12:555.
  42. Deenen MJ, Tol J, Burylo AM, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17:3455.
  43. Loganayagam A, Arenas Hernandez M, Corrigan A, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 2013; 108:2505.
  44. Deenen MJ, Meulendijks D, Cats A, et al. Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol 2016; 34:227.
  45. Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16:1639.
  46. Caudle KE, Thorn CF, Klein TE, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013; 94:640.
  47. Ezzeldin HH, Lee AM, Mattison LK, Diasio RB. Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res 2005; 11:8699.
  48. Lee AM, Shi Q, Pavey E, et al. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst 2014; 106.
  49. Ciccolini J. DPD deficiency in patients treated with fluorouracil. Lancet Oncol 2015; 16:1574.
  50. Mandola MV, Stoehlmacher J, Muller-Weeks S, et al. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63:2898.
  51. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1:65.
  52. Ichikawa W, Takahashi T, Suto K, et al. Orotate phosphoribosyltransferase gene polymorphism predicts toxicity in patients treated with bolus 5-fluorouracil regimen. Clin Cancer Res 2006; 12:3928.
  53. Lecomte T, Ferraz JM, Zinzindohoué F, et al. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res 2004; 10:5880.
  54. Thomas HR, Ezzeldin HH, Guarcello V, et al. Genetic regulation of beta-ureidopropionase and its possible implication in altered uracil catabolism. Pharmacogenet Genomics 2008; 18:25.
  55. Thomas HR, Ezzeldin HH, Guarcello V, et al. Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Pharmacogenet Genomics 2007; 17:973.
  56. Ezzeldin HH, Diasio RB. Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 2008; 26:2080.
  57. Braun MS, Richman SD, Thompson L, et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009; 27:5519.
  58. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 2008; 26:2118.
  59. Lewis CJ, Crane NT, Wilson DB, Yetley EA. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 1999; 70:198.
  60. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004; 22:3766.
  61. Sharma R, Rivory L, Beale P, et al. A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer. Br J Cancer 2006; 94:964.
  62. Johnson MR, Yan J, Shao L, et al. Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity. Screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil toxicity. J Chromatogr B Biomed Sci Appl 1997; 696:183.
  63. TheraGuide 5-FU, Myriad Genetics Laboratories http://www.myriadtests.com/hcp/theraguide_testing_process.htm (Accessed on March 08, 2011).
  64. Mattison LK, Ezzeldin H, Carpenter M, et al. Rapid identification of dihydropyrimidine dehydrogenase deficiency by using a novel 2-13C-uracil breath test. Clin Cancer Res 2004; 10:2652.
  65. Yen JL, McLeod HL. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur J Cancer 2007; 43:1011.
  66. van Kuilenburg AB. Screening for dihydropyrimidine dehydrogenase deficiency: to do or not to do, that's the question. Cancer Invest 2006; 24:215.
  67. Wilson KS, Fitzgerald CA, Barnett JB, et al. Adjuvant therapy with raltitrexed in patients with colorectal cancer intolerant of 5-fluorouracil: British Columbia Cancer Agency experience. Cancer Invest 2007; 25:711.
  68. Deenen MJ, Terpstra WE, Cats A, et al. Standard-dose tegafur combined with uracil is not safe treatment after severe toxicity from 5-fluorouracil or capecitabine. Ann Intern Med 2010; 153:767.
  69. 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).
  70. Bamat MK, Tremmel R, O'Neil JD, et al. Uridine triacetate: An orally administered, life-saving antidote for 5-FU overdose (abstract #9084). J Clin Oncol 2010; 28:656s.
  71. 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).
  72. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm476930.htm (Accessed on December 14, 2015).
  73. Rosmarin D, Palles C, Church D, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 2014; 32:1031.
  74. O'Donnell PH, Stark AL, Gamazon ER, et al. Identification of novel germline polymorphisms governing capecitabine sensitivity. Cancer 2012; 118:4063.
  75. Sulkes A, Benner SE, Canetta RM. Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer. J Clin Oncol 1998; 16:3461.
  76. Takiuchi H, Ajani JA. Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol 1998; 16:2877.
  77. Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 1993; 53:4004.
  78. Takechi T, Nakano K, Uchida J, et al. Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 1997; 39:205.
  79. Rino Y, Takanashi Y, Yukawa N, et al. A phase I study of bi-weekly combination therapy with S-1 and docetaxel for advanced or recurrent gastric cancer. Anticancer Res 2006; 26:1455.
  80. Kobayashi M, Tsuburaya A, Nagata N, et al. A feasibility study of sequential paclitaxel and S-1 (PTX/S-1) chemotherapy as postoperative adjuvant chemotherapy for advanced gastric cancer. Gastric Cancer 2006; 9:114.
  81. Goto A, Yamada Y, Yasui H, et al. Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer. Ann Oncol 2006; 17:968.
  82. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357:1810.
  83. Pazdur R. Irinotecan: toward clinical end points in drug development. Oncology (Williston Park) 1998; 12:13.
  84. Rothenberg ML. CPT-11: an original spectrum of clinical activity. Semin Oncol 1996; 23:21.
  85. 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.
  86. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 2003; 21:807.
  87. Sanoff HK, Sargent DJ, Green EM, et al. Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol 2009; 27:4109.
  88. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343:905.
  89. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355:1041.
  90. Sargent DJ, Niedzwiecki D, O'Connell MJ, Schilsky RL. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001; 345:144.
  91. 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.
  92. Delaunoit T, Goldberg RM, Sargent DJ, et al. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer 2004; 101:2170.
  93. Miller L, Emanuel D, Elfring G, et al. 60-day, all-cause mortality with first-line irinotecan/fluorouracil/leucovorin (IFL) or fluorouracil/leucovorin for metastatic colorectal cancer (abstract). Proc Am Soc Clin Oncol 2002; 20:129a.
  94. Elfring G, Emanuel D, Rostagi R, et al. Patterns of use and mortality in the community oncology practice setting among patients receiving first-line weekly bolus irinotecan/5-fluorouracil/leucovorin (IFL) for metastatic colorectal cancer (abstract). Proc Am Soc Clin Oncol 2002; 20:133a.
  95. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25:4779.
  96. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229.
  97. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005; 23:4866.
  98. Chang TC, Shiah HS, Yang CH, et al. Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients. Cancer Chemother Pharmacol 2015; 75:579.
  99. Chen L-T, Von Hoff DD, Li C-P, et al. Expanded analysis of NAPOLI-1: Phase 3 study of MM-398 (nal-IRI_ with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy (abstr). J Clin Oncol 33, 2015 (suppl 3; abstr 234). Liposomal irinotecan (Accessed on October 22, 2015).
  100. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938.
  101. Scheithauer W, Kornek GV, Raderer M, et al. Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. J Clin Oncol 1999; 17:902.
  102. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23.
  103. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343.
  104. Díaz-Rubio E, Tabernero J, Gómez-España A, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 2007; 25:4224.
  105. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; 358:36.
  106. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589.
  107. Rusthoven JJ, Eisenhauer E, Butts C, et al. Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1999; 17:1194.
  108. Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program. J Thorac Oncol 2008; 3:764.
  109. Pivot X, Koralewski P, Hidalgo JL, et al. A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol 2008; 19:1547.
  110. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 2009; 15:723.
  111. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376:1147.
  112. Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003; 8:508.
  113. Harvey RD. Incidence and management of adverse events in patients with relapsed and/or refractory multiple myeloma receiving single-agent carfilzomib. Clin Pharmacol 2014; 6:87.
  114. Offidani M, Corvatta L, Caraffa P, et al. An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther 2014; 7:1793.
  115. Mann BS, Johnson JR, Cohen MH, et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12:1247.
  116. Prescribing information for belinostat available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206256lbl.pdf?et_cid=34049616&et_rid=789337055&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2014%2f206256lbl.pdf (Accessed on July 11, 2014).
  117. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; 15:1195.
  118. Pawlyn C, Khan MS, Muls A, et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood 2014; 124:2467.
  119. Shah NT, Kris MG, Pao W, et al. Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol 2005; 23:165.
  120. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327.
  121. Messersmith WA, Laheru DA, Senzer NN, et al. Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res 2004; 10:6522.
  122. Czito BG, Willett CG, Bendell JC, et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol 2006; 24:656.
  123. Deininger MW, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003; 21:1637.
  124. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf?et_cid=29953027&et_rid=463638624&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2012%2f203341lbl.pdf (Accessed on September 05, 2012).
  125. Azim HA Jr, Agbor-Tarh D, Bradbury I, et al. Pattern of rash, diarrhea, and hepatic toxicities secondary to lapatinib and their association with age and response to neoadjuvant therapy: analysis from the NeoALTTO trial. J Clin Oncol 2013; 31:4504.
  126. Cortés J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012; 30:1594.
  127. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449.
  128. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271.
  129. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24:4914.
  130. Hanna N, Lilenbaum R, Ansari R, et al. Phase II trial of cetuximab in patients with previously treated non-small-cell lung cancer. J Clin Oncol 2006; 24:5253.
  131. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22:1201.
  132. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337.
  133. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25:1658.
  134. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110:980.
  135. Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013; 31:482.
  136. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367:107.
  137. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf (Accessed on November 20, 2015).
  138. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369:507.
  139. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205858lbl.pdf (Accessed on July 30, 2014).
  140. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014; 123:3406.
  141. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370:1008.
  142. 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.
  143. 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.
  144. 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.
  145. 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.
  146. 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.
  147. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334:246.
  148. 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.
  149. 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.
  150. 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.
  151. Topkan E, Karaoglu A. Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology 2006; 71:354.
  152. 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.
  153. Barbounis V, Koumakis G, Vassilomanolakis M, et al. Control of irinotecan-induced diarrhea by octreotide after loperamide failure. Support Care Cancer 2001; 9:258.
  154. Goumas P, Naxakis S, Christopoulou A, et al. Octreotide Acetate in the Treatment of Fluorouracil-Induced Diarrhea. Oncologist 1998; 3:50.
  155. 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.
  156. Gupta E, Wang X, Ramirez J, Ratain MJ. Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 1997; 39:440.
  157. Takasuna K, Kasai Y, Kitano Y, et al. Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn J Cancer Res 1995; 86:978.
  158. Gupta E, Safa AR, Wang X, Ratain MJ. Pharmacokinetic modulation of irinotecan and metabolites by cyclosporin A. Cancer Res 1996; 56:1309.
  159. Ratain MJ. Insights into the pharmacokinetics and pharmacodynamics of irinotecan. Clin Cancer Res 2000; 6:3393.
  160. Kehrer DF, Sparreboom A, Verweij J, et al. Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 2001; 7:1136.
  161. Govindarajan R, Heaton KM, Broadwater R, et al. Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 2000; 356:566.
  162. Fiorentini G, Rossi S, Lanzanova G, et al. Potential use of imatinib mesylate in ocular melanoma and liposarcoma expressing immunohistochemical c-KIT (CD117). Ann Oncol 2003; 14:805.
  163. de Jong FA, Kehrer DF, Mathijssen RH, et al. Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening: a double-blind, randomized, placebo-controlled study. Oncologist 2006; 11:944.
  164. Farrell CL, Bready JV, Rex KL, et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res 1998; 58:933.
  165. Cao S, Troutt AB, Rustum YM. Interleukin 15 protects against toxicity and potentiates antitumor activity of 5-fluorouracil alone and in combination with leucovorin in rats bearing colorectal cancer. Cancer Res 1998; 58:1695.
  166. 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.
  167. 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.
  168. 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.
  169. 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.
  170. 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.
  171. Hoff PM, Saragiotto DF, Barrios CH, et al. A 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 (abstract). J Clin oncol 2012; 30(suppl 4): abstract 549. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=88684 (Accessed on March 09, 2012).
  172. 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.
  173. 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.
  174. Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 1990; 35:477.
  175. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008; 358:2332.
  176. Sharma RK. Vincristine and gastrointestinal transit. Gastroenterology 1988; 95:1435.
  177. Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1986; 1:421.
  178. Holland JF, Scharlau C, Gailani S, et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 1973; 33:1258.
  179. Anderson H, Scarffe JH, Lambert M, et al. VAD chemotherapy--toxicity and efficacy--in patients with multiple myeloma and other lymphoid malignancies. Hematol Oncol 1987; 5:213.
  180. Hohneker JA. A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Semin Oncol 1994; 21:42.
  181. Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer 1994; 73:2515.
  182. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565.
  183. Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18:708.
  184. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med 2004; 117:508.
  185. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108:3458.
  186. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357:2133.
  187. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357:2123.
  188. Prescribing information for pomalidomide available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf?et_cid=31038989&et_rid=463638624&linkid=www.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2013%2f204026lbl.pdf (Accessed on February 12, 2013).
  189. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:1059.
  190. Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2010; 95:2664.
  191. Wells, SA, Robinson, BG, Gagel, RRF, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA) (Abstract 5503). J Cliin Oncol 2010; 28:421s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50718 (Accessed on April 25, 2011).
  192. Weed HG. Lactulose vs sorbitol for treatment of obstipation in hospice programs. Mayo Clin Proc 2000; 75:541.
  193. 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.
  194. 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.
  195. Ibrahim NK, Sahin AA, Dubrow RA, et al. Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer. Lancet 2000; 355:281.
  196. Kreis W, Petrylak D, Savarese D, Budman D. Colitis and docetaxel-based chemotherapy. Lancet 2000; 355:2164.
  197. Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993; 17:109.
  198. 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.
  199. Kamthan AG, Bruckner HW, Hirschman SZ, Agus SG. Clostridium difficile diarrhea induced by cancer chemotherapy. Arch Intern Med 1992; 152:1715.
  200. 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.
  201. McClay H, Cervi P. Thalidomide and bowel perforation: four cases in one hospital. Br J Haematol 2008; 140:360.
  202. Link to 2009 FDA MedWatch announcement at www.fda.gov/medwatch/safety/2009/safety09.htm#Tarceva (Accessed on April 01, 2011).
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