Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

Saliba, Faouzi; Hagipantelli, R.; Misset, Jean-Louis; Bastian, Gerard; Vassal, Gilles; Bonnay, M; Hérait, Patrice; Côté, Claudia; Mahjoubi, M; Mignard, D.; Cvitkovic, Esteban

doi:10.1200/jco.1998.16.8.2745

Cited by 133 publications

(77 citation statements)

References 25 publications

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“…Deconjugation of SN-38G to SN-38 by β-glucuronidase in the intestinal microflora is considered to be a major contributory factor in the intestinal toxicity of CPT-11, which is believed to result from contact of this deconjugated SN-38 with the intestinal mucosa (11,(19)(20)(21)(22)(23)(24). Unlike other camptothecin drugs, the SN-38 lactone form preferentially binds to blood proteins as compared with the corresponding carboxylate form, resulting in significant stability in the presence of human plasma (30).…”

Section: Discussionmentioning

confidence: 99%

“…SN-38G is an inactive metabolite and is secreted in the duodenum (16)(17)(18). Deconjugated SN-38 exerts a toxic effect when it comes into contact with the intestinal mucosa, and deconjugation of SN-38G to SN-38 by β-glucuronidase in the intestinal microflora is considered to be a major contributory factor in the development of CPT-11-induced late-onset diarrhea (11,(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat

et al. 2011

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Abstract.One of the dose-limiting toxicities of irinotecan hydrochloride (CPT-11) is delayed-onset diarrhea. CPT-11 is converted to its active metabolite, SN-38, which is conjugated to SN-38 glucuronide (SN-38G). SN-38G excreted in the intestinal lumen is extensively deconjugated by bacterial β-glucuronidase, resulting in the regeneration of SN-38, which causes diarrhea. However, the deconjugation of SN-38G by the intestinal microflora remains to be clarified. This study aimed to investigate the microbial transformation of SN-38G by an anaerobic mixed culture of rat cecal microorganisms. Concentrations of SN-38G and SN-38 were then determined using high-performance liquid chromatography. Complete deconjugation of SN-38G to SN-38 in the mixed cultures was observed within 1 h of incubation, with 62.7% of the added SN-38G being found in the supernatant. Approximately 80.4% of the SN-38 in the supernatant was bound to protein, and the remaining 19.6% was detected as active free SN-38. In total, only 12.3% (19.6 x 62.7%) of the SN-38G added to the test tube was found in the supernatant in the ultrafiltrable free form, indicating that approximately 90% of the SN-38G added to the growth medium either remained adsorbed onto the pelleted fraction or occurred in a protein-bound form in the supernatant. The remaining 10% of the SN-38G added to the growth medium existed in the unbound form, the form capable of causing damage to the intestinal membrane. In conclusion, these results indicated that the greater part of the SN-38 produced from SN-38G by the action of bacterial β-glucuronidase is rapidly adsorbed onto intestinal bacterial cell walls or dietary fibers in pelleted fraction, and only 10% remains in the ultrafiltrable unbound form in the intestinal luminal fluid.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat

et al. 2011

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“…The pattern of delayed diarrhea is similar to that associated with i.v. administration of irinotecan and could be relieved with loperamide (31). It has been suggested that the (31).…”

Section: Discussionmentioning

confidence: 99%

“…administration of irinotecan and could be relieved with loperamide (31). It has been suggested that the (31). At a daily dose of 80 mg/m 2 /day, two of five patients experienced grade 3 diarrhea and grade 3 fever, which, according to the predefined criteria for the MTD, precluded further doseescalation.…”

Section: Discussionmentioning

confidence: 99%

Phase I Pharmacokinetic, Food Effect, and Pharmacogenetic Study of Oral Irinotecan Given as Semisolid Matrix Capsules in Patients with Solid Tumors

Soepenberg

Dumez²,

Verweij

et al. 2005

Clinical Cancer Research

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Purpose: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules.Experimental Design: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m 2 /day. Results: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m 2 /day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity.Conclusions: For oral irinotecan, a dose of 70 mg/m 2

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“…Therefore, although our primary analysis showed global QOL after 1 year to be unaffected by cediranib, the data also suggest that cediranib could provide improved QOL if better diarrhea control could be achieved. This would, however, depend on the quality of diarrhea control at a population level outside clinical trials, such as was achieved, for example, with detailed studies of the physiology of this adverse effect after irinotecan 23. Our data indicate the incomplete association between patient reports of diarrhea and clinical severity grading and emphasize the importance of evaluating both aspects of adverse effects.…”

Section: Discussionmentioning

confidence: 83%

Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial

Stark

Cook

Brown

et al. 2017

Cancer

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BACKGROUNDThe ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum‐sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health‐related quality of life (QOL) during the first year of treatment.METHODSFour hundred fifty‐six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent‐maintenance cediranib group.RESULTSThe rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent‐maintenance group (+4.5; 95% confidence interval, –2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self‐reported diarrhea.CONCLUSIONSThe 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression‐free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752‐61. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

Abstract: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.

Cited by 133 publications

References 25 publications

Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat

Rapid deconjugation of SN-38 glucuronide and adsorption of released free SN-38 by intestinal microorganisms in rat

Phase I Pharmacokinetic, Food Effect, and Pharmacogenetic Study of Oral Irinotecan Given as Semisolid Matrix Capsules in Patients with Solid Tumors

Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial

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