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

Abstract

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...

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

“…The RD of capecitabine coincides with that recently reported by other authors with this same combination (Vasile et al, 2009). Neutropenia was frequently observed, although it was usually short-lived and rarely complicated.…”

Efficacy of Triplet Combination Chemotherapy with Oxaliplatin, Irinotecan and Capecitabine (OCX) in Metastatic Colorectal Cancer in Relation to RAS/RAF Mutation Status: Results of a Retrospective Analysis

“…However, while myelotoxicity was reduced, our patients still experienced a high degree of severe diarrhoea. Since increased rates of diarrhoea were also found in a phase II trial using triplet combination with capecitabine, it might be that 5-FU is the better combination partner with regard to this side effect [15]. Our analysis confirms that OCX is an effective and safe triplet combination with an acceptable and manageable toxicity profile making it a valuable and well-tolerated treatment option for many patients with metastatic colorectal carcinoma.…”

Chemotherapy in the Management of Localized and Metastatic Colon Cancer: New and Yet Unforgotten Approaches

“…Ряд работ посвящен изучению трехкомпонентных режимов химиотерапии при метастатическом колорек-тальном раке [25][26][27][28]. В упоминавшемся ранее исследо-вании GONO применение режима FOLFOXIRI приводило не только к большей частоте объективных эффектов по сравнению с FOLFIRI (60% против 34% соответственно), но и позволило достоверно увеличить число радикаль-ных резекций печени с 12% при лечении FOLFIRI до 36% при FOLFOXIRI (р = 0,017).…”

“…Однако у трети больных данный режим сопровождался нейтро-пенией и диареей 3-4-й степени. Учитывая высокую частоту развития тяжелой диареи, авторы сделали вывод, что изучаемый режим не может быть альтернативой FOLFOXIRI, хотя прямого сравнения не проводилось [28]. В таблице суммированы основные трехкомпонентные режимы химиотерапии при изолированных метастазах КРР в печени.…”