Irinotecan in the Treatment of Colorectal Cancer:  Clinical Overview

Vanhoefer, U.; Harstrick, A.; Achterrath, W.; Cao, Shousong; Seeber, S.; Rustum, Youcef M.

doi:10.1200/jco.2001.19.5.1501

Cited by 283 publications

(181 citation statements)

References 110 publications

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“…This rate of grade 3 diarrhoea was consistent with rates reported in prior studies combining irinotecan and cisplatin (Saltz et al, 1998;de Jonge et al, 2000a). The lower frequency of grade 3/4 late diarrhoea in these three studies contrasts with the frequency of 420% grade 3/4 late diarrhoea observed in single-agent studies of CPT-11 administered on a weekly or every-3-week regimen and is presumably related to the lower CPT-11 doses when given in combination (Vanhoefer et al, 2001).…”

Section: Discussionsupporting

confidence: 87%

“…Irinotecan hydrochloride (CPT-11; CAMPTOSAR s ), a semisynthetic camptothecin, is a potent inhibitor of topoisomerase I (Iyer and Ratain, 1998). It has demonstrated a broad spectrum of antitumour activity and has become a standard treatment of metastatic colorectal cancer recently (Saltz et al, 2000;Vanhoefer et al, 2001). Inhibitors of topoisomerase II include epipodophyllotoxins (e.g.…”

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Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

et al. 2003

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This phase I study was conducted to determine the recommended phase II doses, safety profile, and antitumour activity of a combination regimen of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours. Cisplatin and epirubicin were given at fixed doses of 50 and 60 mg m À2 , respectively. The irinotecan dose was escalated at 10 mg m À2 increments from a starting dose level of 70 mg m À2 . Epirubicin, irinotecan, and their metabolites were measured with HPLC methods. In all, 35 patients received 141 courses of treatment. Irinotecan dose was escalated in seven cohorts up to 130 mg m À2 , and then finally de-escalated to 110 mg m À2 . The dose-limiting toxicity was neutropenic fever. Nonhaematologic toxicities included mild to moderate nausea/vomiting, diarrhoea and fatigue. Of 34 patients with evaluable disease, one patient had a complete response and nine patients had partial response, yielding an overall response rate of 29.4%. Pharmacokinetic parameters of epirubicin were not affected by the sequence of drug administration. However, the AUCs of irinotecan and its metabolites were increased significantly when irinotecan and epirubicin were administered concurrently. This combination regimen has promising broad antitumour activity, and will be further evaluated in phase II studies in multiple tumour types.

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

et al. 2003

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“…On the basis of large randomised clinical trials, irinotecan either alone or in combination with fluorouracil has been accepted as first-or second-line chemotherapy for the treatment of patients with colorectal cancer (Cunningham et al, 1998;Rougier et al, 1998;Douillard et al, 2000;Saltz et al, 2000). The most common side effects are bone marrow toxicity, leading to abnormally low blood counts, and ileocolitis, which often results in severe diarrhoea (Vanhoefer et al, 2001). These adverse effects impair the therapeutic efficacy, and could result in the discontinuation of an otherwise effective anticancer treatment.…”

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confidence: 99%

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

et al. 2004

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SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/ 45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P ¼ 0.005). These results maintained the statistical significance in logistic regression analysis (P ¼ 0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1*28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1*28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1*28 polymorphism showed a trend to a poorer OS (P ¼ 0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1*28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.

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“…1 CPT-11 induces remissions in about 11-23% of 5FU-resistant tumors, 2,3 and the combination of CPT-11 and 5FU-leucovorin (5FU/LV) has been approved as first-line chemotherapy for patients with metastatic colorectal cancer. 1,4 The molecular mechanisms behind the therapeutic effects of CPT- 11 have not yet been fully elucidated.…”

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confidence: 99%

Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status

Magrini¹,

Bhonde²,

Hanski³

et al. 2002

Intl Journal of Cancer

110

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Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis. Since sporadic colon carcinomas exhibit in 50 -60% mutations in the p53 gene and in 10 -15% an MSI phenotype due in the great majority of the cases to hMLH1 inactivation, we investigated how these lesions influence the cellular effects of CPT-11 by using colorectal carcinoma cell line HCT116 (which has the genotype p53 ؉/؉ ,hMLH1 -) and 2 derivative cell lines with the genotypes p53 ؉/؉ ,hMLH1 ؉ and p53 -/-,hMLH1 -. CPT-11 treatment induced G2/M arrest in all 3 cell lines within 48 hr. In the p53 ؉/؉ ,hMLH1 ؉ cell line, G2/M arrest was maintained for at least 12 days. There was little concomitant apoptosis, but this was enhanced when the hMLH1 protein was absent. This enhanced apoptosis was accompanied by a shorter duration of the G2/M arrest than in the hMLH1 ؉ cell line. Partial abrogation of G2/M arrest by caffeine enhanced apoptosis in both hMLH1 ؉ and hMLH1 -cells. By contrast, in the p53 -/-cell line, the G2/M arrest was terminated within 4 days. Termination of the G2/M arrest was accompanied by a high level of apoptosis detectable through poly(ADP-ribose)polymerase (PARP) cleavage, DNA fragmentation and by the appearance of cells with a DNA content <2N. The triggering of G2/M arrest was accompanied in the 3 cell lines by a transient phosphorylation of cdc-2, while the maintenance of the arrest in the p53 ؉/؉ cell lines was accompanied by the overexpression of p53 and p21 proteins and, consequently, by the inhibition of cdc-2 kinase activity. These data indicate that: (i) CPT-11 induces long-term arrest in p53 ؉/؉ cells and a short-term arrest followed by apoptosis in p53 -/-cells; (ii) triggering of the arrest is p53 independent and is associated with a brief increase of phosphorylation of cdc-2, while the p53-dependent maintenance of G2/M arrest is associated with the inhibition of cdc-2 kinase activity by p21; and (iii) lack of hMLH1 protein enhances CPT-11-induced apoptosis. These results may be useful for designing rational therapies dependent on the p53 and mismatch-repair status in the tumor.

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Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview

Abstract: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

Cited by 283 publications

References 110 publications

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status

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