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© 2000 American Society for Clinical Oncology
Glutamine for Irinotecan DiarrheaUMass Memorial Health Care Worcester, MA To the Editor:Irinotecan is an important drug for the management of metastatic colorectal cancer. Frequently, diarrhea is dose-limiting. Intensive loperamide treatment reduces the incidence of severe diarrhea.1,2 If loperamide fails to control the diarrhea, the dose must be reduced; results of the use of octreotide in this setting have not been published. We describe here the administration of oral glutamine supplementation to successfully prevent late-onset irinotecan-related diarrhea in five patients, which allowed higher doses to be administered in subsequent courses in four of the five patients. The first patient, a 65-year-old man with fluorouracil-refractory metastatic colon cancer, developed grade 4 diarrhea (by National Cancer Institute common toxicity criteria) requiring hospital admission for hydration and bowel rest 4 days after receiving cycle 1 week 2 of irinotecan administered at 125 mg/m2/wk, despite intensive loperamide treatment. Treatment was reinstituted at 100 mg/m2/wk after a 2-week break; no worse than grade 1 diarrhea resulted for the 4 weeks of therapy. For the next and all subsequent cycles, the dose was re-escalated to 125 mg/m2/wk with Glutamine-Enriched Antioxidant Formula (10-g packet; Cambridge Nutraceuticals, Boston MA), starting the morning of irinotecan treatment and administered every 8 hours thereafter for 48 hours after each dose. He has now received 30 weeks of irinotecan therapy at full dose without recurrence of higher than grade 1 diarrhea; his tumor is responding after two full cycles of therapy; he has not required additional loperamide after each treatment. The second patient, a 56-year-old woman with metastatic and locally recurrent rectal cancer, had an ileostomy with baseline daily firm stool output of less than 500 mL/d. She received weekly irinotecan 125 mg/m2 after failing fluorouracil-based treatment. After the second week of therapy, she was admitted to the hospital with grade 3 vomiting, grade 4 diarrhea, and more than 1,500 mL/d of watery stool per ileostomy, despite taking up to 20 loperamide tablets every 24 hours. She was intravenously rehydrated, and a new cycle of therapy was instituted 2 weeks later at 100 mg/m2/wk, which still resulted in grade 3 diarrhea, with more than 1,500 mL/d of watery stool output via ileostomy. Glutamine-Enriched Antioxidant Formula (10 g orally tid) was begun the night before she received her next weekly dose of irinotecan at 100 mg/m2, and she continued glutamine every 8 hours for six additional doses after receiving each week’s therapy. She tolerated this dose well and continues to receive therapy at a dose of 100 mg/m2/wk with no watery ileostomy output. Further dose escalation has not been attempted. She currently takes two to three loperamide tablets per week in addition to the glutamine. We have treated three additional patients, all of whom were receiving irinotecan therapy for metastatic colorectal cancer and all of whom were dose-limited by severe diarrhea at 125 mg/m2/wk, despite the use of intensive loperamide. All three were able to re-escalate the irinotecan dose back to 125 mg/m2/wk during subsequent courses of therapy with continued use of glutamine supplementation. Late diarrhea after irinotecan has been shown to be multifactorial, with contributions from dysmotility and secretory factors as well as a direct toxic effect of the drug on the intestinal mucosa.3,4 The onset and duration of late diarrhea varies with the dosing schedule.5 Age greater than 65 years seems to be a risk factor for severe diarrhea.5,6 Glutamine is a neutral gluconeogenic amino acid that plays a pivotal role in whole-body nitrogen metabolism. Glutamine is the primary oxidative fuel for the enterocyte and is necessary for the maintenance of intestinal structure in both normal and stressed states, having trophic effects on the bowel mucosa. Over time, marked glutamine depletion develops in the host with cancer. This depletion may have a negative impact on the function of host tissues that require glutamine (eg, intestinal epithelial cells, lymphocytes). Supplemental glutamine enhances nutrient transport and facilitates the enteral absorption of electrolytes in animals with experimental diarrhea, an effect that may be germane to the management of postirinotecan diarrhea.7,8 Providing dietary glutamine has also been shown to enhance chemotherapeutic effectiveness while reducing gut-related morbidity and mortality in animals treated with methotrexate.9 Our preliminary work suggests that oral glutamine supplementation may play a role in alleviating the late diarrhea in patients receiving irinotecan. A larger trial of this inexpensive dietary supplement is warranted and a prospective study is underway to confirm these initial findings. REFERENCES
1.
Abigerges D, Armand J: Irinotecan (CPT) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446-449, 1994 2. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. Clin Oncol 14:709-715, 1996 3. Saliba F, Hagipantelli R, Misset JL: Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer. J Clin Oncol 16:2745-2751, 1998[Abstract] 4. Hecht JR: Gastrointestinal toxicity of irinotecan. Oncology 12:72-78, 1998 (suppl 6)[Medline] 5. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. Oncol 15:2910-2919, 1997
6.
Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naïve patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997
7.
Rhoads JM. Keku EO, Bennett LE, et al: Development of L-glutamine-stimulated electroneural sodium absorption in piglet jeunum. Am J Physiol 259:G99-107, 1990 8. Rhoads JM, Keku EO, Quinn J, et al: L-Glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis. Gastroenterology 100:683-691, 1991[Medline] 9. Fox AD, Kripke SA, DePaula J, et al: Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. JPEN J Parenter Enteral Nutr 12:325-331, 1988[Abstract] This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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