Irinotecan (CPT-11) High-Dose Escalation Using Intensive High-Dose Loperamide to Control Diarrhea

Abigerges, D; Armand, J.P.; Chabot, Guy G.; Costa, L Da; Fadel, Élie; Côté, Claudia; Hérait, Patrice; Gandía, Daniel

doi:10.1093/jnci/86.6.446

Cited by 218 publications

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“…However, its use is limited by the severity of the diarrhea it causes, making an otherwise effective drug very difficult to use clinically. Oral loperamide works to slow diarrhea in many, 27 but there is still a significant incidence of grade 4 diarrhea and occasional mortality, leading to cessation of treatment. 4,5,28 Previous research has shown that palifermin is an effective antimucotoxic, reducing severity and duration of mucositis in both animal models 12,15,[20][21][22]29,30 and the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Gibson

Bowen

Keefe

2005

Intl Journal of Cancer

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Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent, causing severe gastrointestinal mucositis and diarrhea. Previous research suggests that palifermin is potentially antimucotoxic. The primary aim of this study was to determine whether palifermin was effective in ameliorating irinotecan-induced gastrointestinal mucositis. We also determined the protective effects of single large and multiple small doses of palifermin. Tumor-bearing DA rats were treated with a single large (10 mg/kg) dose of palifermin 3 days prior to, or multiple small (3 mg/kg day for 3 days) doses of palifermin or vehicle control prior to, receiving 2 doses of 150 mg/kg irinotecan. Animals were killed at 6, 24, 48, 72, 96, 120, or 144 hr after treatment. The primary endpoints were diarrhea and mortality. Gastrointestinal morphometry, histopathology and apoptosis were assessed. Tumor weights and mitoses were measured to ensure palifermin did not promote tumor growth. Data were analyzed using Peritz' F-test, Student's t-test and Tukey-Kramer multiple comparison test. Animals pretreated with palifermin tolerated irinotecan treatment better than control animals with less severe diarrhea (5% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 3 3 mg/kg palifermin and 28% in animals receiving irinotecan only) and reduced mortality (2% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 3 3 mg/kg palifermin and 28% in animals receiving irinotecan only). Small and large intestinal weights were maintained. Intestinal morphometry was not maintained in palifermin-pretreated rats despite being increased prior to irinotecan treatment. Palifermin pretreatment did not prevent apoptosis that peaked at 6 hr in the jejunum or colon, but prevented apoptosis at 96 hr in the small intestine. Palifermin pretreatment in both treatment regimens significantly reduces diarrhea and mortality following irinotecan administration without adversely affecting tumor growth. This positive response warrants further investigation, particularly in humans. ' 2005 Wiley-Liss, Inc.Key words: mucositis; irinotecan; palifermin; diarrhea Mucositis is a major oncologic problem caused by the cytotoxic effects of cancer chemotherapy. The condition affects the entire gastrointestinal tract from the mouth to the anus and causes pain and ulceration in both the mouth and small and large intestines. In addition, it causes abdominal bloating, vomiting and diarrhea.

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Section: Discussionmentioning

confidence: 99%

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Gibson

Bowen

Keefe

2005

Intl Journal of Cancer

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“…Diarrhoea was another principal dose-limiting toxicity observed with this combination regimen (Table 4). The recent introduction of the use of high-dose loperamide by Abigerges et al (1994) has substantially reduced the previously marked CPT-11 -induced diarrhoea. However, 19% of patients still suffered from grade 3 or 4 delayed diarrhoea in this trial.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

Masuda

Fukuoka²,

Fujita³

et al. 1998

Br J Cancer

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Summary A phase trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients. This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase 11 study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m-2 intravenously (IV) on days 1, 8 and 15, and cisplatin 80 mg m-2 (IV) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response. Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%). The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively. A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.

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“…Diarrhea occurring >12 hours after irinotecan was treated with loperamide 4 mg orally at the first episode followed by 2 mg every 2 hours (4 mg every 4 hours at night) until there was complete resolution of diarrhea for at least 12 hours. 27 Pretreatment and Follow-Up Studies. Patients had a complete history and physical examination, a determination of ECOG performance status, complete blood counts with differential, electrolytes, and standard liver and renal function tests performed within two weeks of treatment initiation and weekly while enrolled in the trial.…”

Section: Methodsmentioning

confidence: 99%

Phase I Dose Escalation Trial of Weekly Docetaxel Plus Irinotecan in Patients with Advanced Cancer

Bleickardt¹,

Argiris²,

Rich³

et al. 2002

Cancer Biology & Therapy

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Background. Docetaxel and irinotecan have additive or synergistic activity in vitro and in vivo as well as differing toxicities and unique mechanisms of action. We conducted a phase I trial to determine the maximum-tolerated dose of docetaxel and irinotecan given on a weekly schedule.Methods. Eligible patients had advanced, incurable, solid tumors. Docetaxel was administered as a 1-hour infusion and escalated over four dose levels (25,30, 35, and 40 mg/m 2 ) followed by irinotecan administered over 30 minutes at a fixed dose of 50 mg/m 2 . Treatment was administered weekly for four weeks followed by two weeks of rest. To improve tolerability, the schedule was modified to weekly administration for two weeks with one week of rest, and irinotecan was escalated over 3 dose levels (55, 60, and 65 mg/m 2 ) with docetaxel fixed at 35 mg/m 2 .Results. Forty-four patients were treated and the most common dose-limiting toxicity was diarrhea observed in 11% of patients. Severe neutropenia was rare (grade 4: 2%, grade 3: 23%). Other nonhematologic toxicities included nausea/vomiting, dehydration and fatigue. Partial responses occurred in two patients with pancreatic cancer, and one patient each with non-small cell lung and esophageal cancer.Conclusions. Weekly docetaxel and irinotecan is a promising non-cisplatin doublet with preliminary evidence of activity in advanced solid tumors. Diarrhea is the predominant dose-limiting toxicity but unlike the every 3 weeks schedule myelosuppression is modest. The recommended phase II doses are docetaxel 35 mg/m 2 and irinotecan 60 mg/m 2 on days 1 and 8 of a 21-day schedule. Phase II trials of this regimen are ongoing or planned in lung, head and neck, stomach, esophageal, and pancreatic cancers.

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Irinotecan (CPT-11) High-Dose Escalation Using Intensive High-Dose Loperamide to Control Diarrhea

Abstract: The effectiveness of CPT-11 might be increased by higher dose intensities, which can be made tolerable by control of diarrhea with loperamide.

Cited by 218 publications

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Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats

A phase II trial of combination of CPT-11 and cisplatin for advanced non-small-cell lung cancer

Phase I Dose Escalation Trial of Weekly Docetaxel Plus Irinotecan in Patients with Advanced Cancer

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