Recommendation for Caution with Irinotecan, Fluorouracil, and Leucovorin for Colorectal Cancer

Sargent, Daniel J.; Niedzwiecki, Donna; Mj, O'Connell; Rl, Schilsky

doi:10.1056/nejm200107123450213

Cited by 144 publications

(8 citation statements)

References 5 publications

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“…Diarrhea is one of the lethal major side effects in the cancer patients receiving CPT-11 [7,31]. We and others have previously demonstrated that intestinal alkalization by 3 …”

Section: Discussionmentioning

confidence: 99%

“…This chemotherapeutic agent has been approved by the FDA for treatment of colorectal cancer in the United States, but has shown clinical responses for many other malignancies such as lung, gastric, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma [2][3][4][5][6]. However, this agent has major limitation in the therapeutic use for the patients with cancer due to severe side effect as the lethal delayed diarrhea [7,8] including the marked intestinal injury and the presence of pseudomembranous jejunoileitis [9].…”

Section: Introductionmentioning

confidence: 99%

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Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line

Miyazaki¹,

Ikegami²,

Nagai³

et al. 2013

JCT

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The anti-cancer therapy of irinotecan (CPT-11) is often limited due to severe late-onset diarrhea. Because the higher toxic form of CPT-11/its active metabolite (SN-38) is produced at acidification, the usefulness of oral sodium bicarbonate treatment against the CPT-11/SN-38-induced intestinal injuries and diarrhea has been confirmed. However, the roles of bicarbonate have been suggested to affect not only intestinal pH environment but also intracellular pH and CPT-11/SN-38 dynamics. The present study proposed to clarify the hypothesis in CPT-11/SN-38-exposed colon cell line in various pH conditions adjusted by bicarbonate. HT29 cell pre-exposed to ~1.0 µM SN-38 lactone or carboxylate forms was incubated at different pH adjusted by either bicarbonate or HCl/NaOH. The degrees of SN-38-induced cell injury depended on the higher proportion of the toxic form (lactone) of SN-38 rather than mere pH condition of medium. Apoptosis and cell injury induced by SN-38 were significantly inhibited by bicarbonate in a dose-dependent manner. Intercellular pH acidification induced by SN-38 was significantly prevented by 30 mM bicarbonate. Cell cytotoxicity of SN-38 depended on not only extracellular but also intracellular pH that converts the SN-38 form, while the intracellular acidification was prevented by bicarbonate. The multiple regulations of bicarbonate on both exracellular and intracellular pH would be essential mechanism against intestinal cell injury by CPT-11/SN-38.

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“…Diarrhea is one of the lethal major side effects in the cancer patients receiving CPT-11 [7,31]. We and others have previously demonstrated that intestinal alkalization by 3 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line

Miyazaki¹,

Ikegami²,

Nagai³

et al. 2013

JCT

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“…Once diarrhea has occurred, a high-dose loperamide regimen may render this side effect manageable [7], however frequently limiting its use. Moreover, 5-FU during combined treatment with irinotecan has been reported to be implicated in the early death of treated patients [8], thus demanding an effective prevention of side effects of irinotecan, especially diarrhea. Irinotecan-induced delayed-type diarrhea has been reported to be severe (NCI-CTC grade 3–4) in up to 40% of the patients [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Phase II Clinical Trial for Prevention of Delayed Diarrhea with Cholestyramine/Levofloxacin in the Second-Line Treatment with Irinotecan Biweekly in Patients with Metastatic Colorectal Carcinoma

Flieger¹,

Klassert

Hainke

et al. 2007

Oncology

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Background: Irinotecan is an established therapeutic option in colorectal cancer. An essential side effect of irinotecan treatment is the induction of severe WHO grade 3–4 delayed diarrhea in up to 25% of treated patients. The aim of the study is the prevention of delayed diarrhea with cholestyramine/levofloxacin. Patients and Methods: Fifty-one patients with a mean age of 64 years (range: 41–81 years) with metastatic colorectal cancer in second-line treatment were included. A cycle corresponds to 4 applications of irinotecan 250 mg/m², every 2 weeks, then a break of 2 weeks. Results: After 1 treatment cycle 12% of patients achieved a partial response, 59% had stable disease and 29% progressive disease. Twenty-two patients received a second or more cycles to a total of 379 applications. Forty patients did not develop diarrhea whereas 11 patients had WHO 1–2 diarrhea after at least 1 application of chemotherapy. Diarrhea WHO 3 occurred in only 1 patient (2%) whereas severe diarrhea WHO 4 did not occur. Conclusion: The combination of cholestyramine/levofloxacin is a promising option for the prevention of delayed diarrhea caused by irinotecan. This prophylactic regime may help in future to escalate the dose of irinotecan as a monotherapy or in combination protocols.

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“…Moreover, diarrhea has been reported to be implicated in early death during combined treatment with irinotecan and 5-fluorouracil, which has been suggested as a standard regimen for colorectal cancer [10]. …”

Section: Introductionmentioning

confidence: 99%

Prevention of Irinotecan-Induced Diarrhea by Oral Sodium Bicarbonate and Influence on Pharmacokinetics

et al. 2004

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Alkalization of the intestinal tract by oral administration of sodium bicarbonate has been reported to be a promising method for preventing delayed diarrhea, a dose-limiting toxicity in patients receiving chemotherapy with irinotecan hydrochloride. However, it is feared that this method may adversely affect the pharmacokinetics of irinotecan by inhibiting its intestinal absorption and that of its active metabolites. We compared the pharmacokinetics and toxicity of irinotecan with and without oral alkalization in a cross-over study that enrolled 10 colorectal cancer patients. We found that alkalization did not decrease the blood levels of irinotecan and its active metabolite. In fact, the area under concentration versus time curves (AUCs) of irinotecan and 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) were statistically equivalent both with and without oral alkalization. Also, the AUC of SN-38 with alkalization was statistically equivalent or larger than that without alkalization. Oral alkalization reduced the incidence of diarrhea and gastrointestinal symptoms, and these adverse effects were not worsened by long-term administration. These results suggest that oral alkalization can control diarrhea and gastrointestinal toxicity without decreasing the blood levels of irinotecan and its active metabolites, thus improving the tolerability of long-term chemotherapy without reducing efficacy.

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Recommendation for Caution with Irinotecan, Fluorouracil, and Leucovorin for Colorectal Cancer

Cited by 144 publications

References 5 publications

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line

Phase II Clinical Trial for Prevention of Delayed Diarrhea with Cholestyramine/Levofloxacin in the Second-Line Treatment with Irinotecan Biweekly in Patients with Metastatic Colorectal Carcinoma

Prevention of Irinotecan-Induced Diarrhea by Oral Sodium Bicarbonate and Influence on Pharmacokinetics

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Recommendation for Caution with Irinotecan, Fluorouracil, and Leucovorin for Colorectal Cancer

Cited by 144 publications

References 5 publications

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular &lt;i&gt;pHs&lt;/i&gt; in Intestine Cell Line

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular &lt;i&gt;pHs&lt;/i&gt; in Intestine Cell Line

Phase II Clinical Trial for Prevention of Delayed Diarrhea with Cholestyramine/Levofloxacin in the Second-Line Treatment with Irinotecan Biweekly in Patients with Metastatic Colorectal Carcinoma

Prevention of Irinotecan-Induced Diarrhea by Oral Sodium Bicarbonate and Influence on Pharmacokinetics

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Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line