High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

Merrouche, Yacine; Extra, Jean Marc; Abigerges, D; Bugat, R.; Catimel, G.; Suc, Etienne; Marty, M.; Hérait, Patrice; Mahjoubi, M.; Armand, J.P.

doi:10.1200/jco.1997.15.3.1080

Cited by 49 publications

(32 citation statements)

References 9 publications

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“…With the exception of one responder treated at 260 mg m À2 , all objective responses were observed at dose levels above 350 mg m À2 . Merrouche et al (1997) provided further support for this from a phase I trial in which an increased tumour response was seen at an irinotecan dose level of 500 mg m À2 . …”

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confidence: 74%

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

et al. 2005

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Although irinotecan 350 mg m À2 is a standard option for relapsed/refractory advanced colorectal cancer, there is some evidence that suggests that a higher dose may be more effective, with acceptable tolerability, following 5-fluorouracil (5-FU). This study assessed the optimal dosing strategy for irinotecan, along with treatment efficacy and safety. A total of 164 patients with metastatic colorectal cancer progressing after failure on 5-FU or raltitrexed received either 350 mg m À2 irinotecan (Group A; n ¼ 36) or 250, 350 or 500 mg m À2 , according to individual patient tolerance (Group B; n ¼ 62) or based on risk factor optimisation (Group C; n ¼ 66). There were no complete responses. There was a trend towards a higher overall response rate in Group B (13%) than in Groups A (8%) and C (9%). Tumour control growth rate was high in all three groups: 58% in group A, 60% in Group B and 50% in Group C. A total of 34% of patients in Group B and 9% in Group C were able to receive a dose of 500 mg m À2 . Median duration of response and time to progression were significantly longer in Groups A and B compared with Group C. No significant between-group differences for any adverse events were seen, although there was a small trend towards better tolerability in Group B. Individual dose escalation based on patient tolerance may allow more patients to receive a higher irinotecan dose without causing additional toxicity and can be an appropriate patient management strategy. 1999). Median overall survival rates of up to 10 months are achievable when irinotecan is used in relapsed/refractory colorectal cancer (Shimada et al, 1993; Rothenberg et al, 1996 Rothenberg et al, , 1999Pitot et al, 1997;Rougier et al, 1997;Van Cutsem et al, 1999). Two European phase III trials investigating the efficacy and safety of irinotecan, following 5-FU failure in advanced colorectal cancer, have demonstrated significant improvements in survival compared with best supportive care and 5-FU (Cunningham et al, 1998;Rougier et al, 1998). The main adverse events accompanying treatment with irinotecan in these trials were diarrhoea, neutropenia, fatigue, nausea and vomiting.Although 350 mg m À2 as an intravenous infusion every 3 weeks is the standard recommended dosage of irinotecan, pharmacokinetic parameters of irinotecan-lactone and the active metabolite SN-38-lactone vary between individuals (Xie et al, 2002). This may be attributed to differences in the levels of the enzymes that metabolise irinotecan, notably carboxylesterase for SN-38. Furthermore, the variable interindividual patient exposure to SN-38 has been identified as an important determinant of toxicity .At the same time, there is convincing evidence of a doseresponse relationship, and therefore a rationale for increasing doses when possible. In a phase I trial by Abigerges et al (1995), there were two recommended doses: 350 mg m À2 without highdose loperamide and 600 mg m À2 with high-dose loperamide. With the exception of one responder treated at 260 mg m À2 , all objective responses...

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confidence: 74%

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

et al. 2005

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“…Irinotecan is effectively used for the treatment of a variety of cancers, including refractory colon adenocarcinomas in adults (Ewesuedo and Ratain, 1997;Saltz, 1997;Stucky-Marshall, 1999). However, side effects include granulocytopenia, gastrointestinal toxicity, and renal failure (Merrouche et al, 1997;Persons et al, 1998). Irinotecan is rapidly converted by HCE-2 546 XIE ET AL.…”

Section: Human and Rodent Carboxylesterasesmentioning

confidence: 99%

Human and Rodent Carboxylesterases: Immunorelatedness, Overlapping Substrate Specificity, Differential Sensitivity to Serine Enzyme Inhibitors, and Tumor-Related Expression

Xie¹,

Yang²,

Liu³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Carboxylesterases hydrolyze numerous endogenous and foreign compounds with diverse structures. Humans and rodents express multiple forms of carboxylesterases, which share a high degree of sequence identity (ϳ70%). Alignment analyses locate in carboxylesterases several functional subsites such the catalytic triad as seen in acetylcholinesterase. The aim of this study was to determine among human and rodent carboxylesterases the immunorelatedness, overlapping substrate specificity, differential sensitivity to serine enzyme inhibitors, tissue distribution, and tumor-related expression. Six antibodies against whole carboxylesterases or synthetic peptides were tested for their reactivity toward 11 human or rodent recombinant carboxylesterases. The antibodies against whole proteins generally exhibited a broader cross-reactivity than the anti-peptide antibodies. All carboxylesterases hydrolyzed para-nitrophenylacetate and para-nitrophenylbutyrate. However, the relative activity varied markedly from enzyme to enzyme (>20-fold), and some carboxylesterases showed a clear substrate preference. Carboxylesterases with the same functional subsites had a similar profile on substrate specificity and sensitivity toward phenylmethylsulfonyl fluoride (PMSF) and paraoxon, suggesting that these subsites play determinant roles in the recognition of substrates and inhibitors. Among three human carboxylesterases, HCE-1 hydrolyzed both substrates to a similar extent, whereas HCE-2 and HCE-3 showed an opposite substrate preference. All three enzymes were inhibited by PMSF and paraoxon, but they showed a marked difference in relative sensitivities. Based on immunoblotting analyses, HCE-1 was present in all tissues examined, whereas HCE-2 and HCE-3 were expressed in a tissue-restricted pattern. Colon carcinomas expressed slightly higher levels of HCE-1 and HCE-2 than the adjacent normal tissues, whereas the opposite was true with HCE-3.

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“…One can also hypothesise that TA 6 homozygotes may tolerate a higher IRI dosage, possibly increasing treatment benefit. Indeed, several reports show that IRI dose can be increased in a subset of patients (Merrouche et al, 1997;Ducreux et al, 1999;Ychou et al, 2002), and there is indirect evidence that the efficacy of IRI seems dose-dependent (Abigerges et al, 1995). Recently, the FDA has approved the updated Camptosar s (IRI) product labelling that recommends a reduced starting dose for TA 7 /TA 7 patients to prevent haematological toxicity.…”

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confidence: 99%

UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

et al. 2008

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The aim of the study was to investigate the associations between UGT1A1*28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1*28 genotype was determined in 218 patients receiving irinotecan (either first-line therapy with capecitabine or second-line as monotherapy) for metastatic colorectal cancer. TA 7 homozygotes receiving irinotecan combination therapy had a higher incidence of febrile neutropenia (18.2%) compared to the other genotypes (TA 6 /TA 6 : 1.5%; TA 6 /TA 7 : 6.5%, P ¼ 0.031). TA 7 heterozygotes receiving irinotecan monotherapy also suffered more febrile neutropenia (19.4%) compared to TA 6 /TA 6 genotype (2.2%; P ¼ 0.015). Response rates among genotypes were not different for both regimens: combination regimen, P ¼ 0.537; single-agent, P ¼ 0.595. TA 7 homozygotes did not receive a lower median irinotecan dose, number of cycles (P-values X0.25) or more frequent dose reductions compared to the other genotypes (P-values for trend; combination therapy: 0.62 and single-agent: 0.45). Reductions were mainly (480%) owing to grade X3 diarrhoea, not (febrile) neutropenia. TA 7 /TA 7 patients have a higher incidence of febrile neutropenia upon irinotecan treatment, but were able to receive similar dose and number of cycles compared to other genotypes. Response rates were not significantly different.

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High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

Abstract: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.

Cited by 49 publications

References 9 publications

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

Human and Rodent Carboxylesterases: Immunorelatedness, Overlapping Substrate Specificity, Differential Sensitivity to Serine Enzyme Inhibitors, and Tumor-Related Expression

UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

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