Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer

Bajetta, Emilio; Celio, Luigi; Ferrario, E.; Bartolomeo, Maria Di; Denaro, A.; Dotti, Katia Fiorella; Mancin, Maddalena; Bajetta, Roberto; Colombo, A.; Pusceddu, Sara

doi:10.1093/annonc/mdm347

Cited by 33 publications

(27 citation statements)

References 20 publications

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“…Neutropenia was frequently observed, although it was usually short-lived and rarely complicated. These findings are in contrast to those reported by Bajetta et al (2007) where no grade 3/4 neutropenia was reported. The different capecitabine dose (1000 mg/m 2 /day on days 2 -6) might partly explain these discrepancies.…”

Section: Discussioncontrasting

confidence: 99%

“…The different capecitabine dose (1000 mg/m 2 /day on days 2 -6) might partly explain these discrepancies. Reported incidence of grade 3/4 diarrhoea in previous studies with this same triplet combination is 25 -30%, (Masi et al, 2004;Bajetta et al, 2007) with CPT-11 doses of 165 -180 mg m À2 every two weeks. The lower CPT-11 dose used in our study may be partly responsible of the two-fold decrease in the incidence of severe diarrhoea, without apparently compromising efficacy.…”

Section: Discussionmentioning

confidence: 88%

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Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

Zárate¹,

Rodríguez

Bandrés³

et al. 2010

Br J Cancer

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BACKGROUND: A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naïve mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m -2 ) and CPT-11 (150 mg m -2 ), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m -2 bid on days 1 -7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m À2 bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6 -13.4) and 27 months (95% CI; 17.2 -36.8), respectively. The GSTP1-G genotype, the Kö hne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P ¼ 0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A4G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 88%

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

Zárate¹,

Rodríguez

Bandrés³

et al. 2010

Br J Cancer

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“…The overall response rate of 67% and the median PFS of 10.1 months are comparable to those obtained in phases II and III trials with FOLFOXIRI. Moreover, our results are also comparable to those of a single-centre phase I -II study recently reported by the ITMO with the combination of irinotecan 180 mg m À2 on day 1, oxaliplatin 85 mg m À2 on day 2 and capecitabine 2000 mg m À2 per day from day 2 to day 6 (COI), in 29 mCRC patients (Bajetta et al, 2007). However, the ITMO COI schedule seems more complex with a lengthy outpatient 2-day schedule for irinotecan and oxaliplatin administration.…”

Section: Discussionsupporting

confidence: 88%

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

et al. 2009

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The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m À2 and oxaliplatin 85 mg m À2 on day 1 plus capecitabine 2000 mg m À2 per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3 -4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4 -82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI. In the past decade, the advent of oxaliplatin and irinotecan has led to changes in the first-line treatment of metastatic colorectal cancer (mCRC; Saunders and Iveson, 2006). In fact, the combination of one of these new cytotoxic drugs with 5-fluorouracil (5-FU) and leucovorin (LV) significantly increases tumour response and prolongs survival of patients with unresectable advanced colorectal cancer over 5-FU/LV alone (Punt, 2004). Moreover, a pooled analysis of seven phase III trials comparing 5-FU/LV plus irinotecan or oxaliplatin containing doublets vs 5-FU alone demonstrated that survival of mCRC patients might be improved administrating all the three active drugs in the course of the disease. However, in a sequential strategy, 20 -50% of patients who progress after first-line chemotherapy cannot receive second-line treatment, mainly because of deterioration of their performance status and liver function (Grothey et al, 2004). Furthermore, another pooled analysis indicated that there is a strong correlation between the response rate to first-line chemotherapy and the possibility of a postchemotherapy radical resection of metastases that may be associated with long-term survival (Folprecht et al, 2005).Keeping these concepts in mind, the GONO group developed in phases I and II trials a triple-drug combination of oxaliplatin, irinotecan and 5-FU/LV named FOLFOXIRI (Falcone et al, 2002;Masi et al, 2004) and compared this combination to a standard doublet combination of 5-FU/LV plus irinotecan (FOLFIRI) in a phase III study on 244 mCRC patients (Falcone et...

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“…However, it remains to be explored whether oral capecitabine (mimicking a prolonged infusion of Xuorouracil) could represent a preferable component of this triplet. Some preliminary experiences demonstrated the feasibility of such combination in metastatic colorectal cancer [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group

Comella

Lorusso²,

Maiorino

et al. 2009

Cancer Chemother Pharmacol

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Purpose This phase II trial assessed the tolerability and eYcacy of a triplet of oxaliplatin, irinotecan, and Xuorouracil/folinic acid in advanced gastric cancer. Methods Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m 2 iv and irinotecan 150 mg/m 2 iv on day 1, 6S-folinic acid 250 mg/m 2 iv and Xuorouracil 750 mg/m 2 iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. Results Sixty-three patients were treated, with a median of eight (range 1-12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22-46%]). Median progression-free survival was 7.5 (95% CI, 5.6-9.4) months, and median overall survival was 12.1 (95% CI, 10.8-13.4) months. Most common grade ¸3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity aVected 33% of patients. Conclusions Oxaliplatin, irinotecan, and Xuorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer. Keywords

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Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer

Abstract: Biweekly COI is feasible and active. Tolerability and ease of administration make the regimen well suited for downsizing hepatic colorectal metastases before curative surgery.

Cited by 33 publications

References 20 publications

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

Oxaliplatin, irinotecan and capecitabine as first-line therapy in metastatic colorectal cancer (mCRC): a dose-finding study and pharmacogenomic analysis

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group

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