Irinotecan (CPT11) at 180mg/m² with LV5FU2 for metastatic colorectal cancer (MCRC) has response rates (RRs) of 56 and 4% as first- and second-line treatments, respectively [1Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study J clin Oncol 2004;22(2):229–37.

Cliquez ici pour aller à la section Références, 2Colucci G, Gebbia V, Paoletti G et al. Phase III randomised trial of FOLFIRI versus FOLFOX4 in treatment of Advanced Colorectal Cancer: A multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale. J clin Oncol 23:4866–75.

Cliquez ici pour aller à la section Références], and higher doses of CPT11 result in higher RRs. The present cohort analysis aimed to evaluate the effect of increasing doses of this combination treatment in clinical practice.

Chemo-naive and pretreated patients with MCRC received CPT11 and LV5FU2 (5FU 48-h CI 2400mg/m², D1 bolus leucovorin 200mg/m²), followed by 5FU 400mg/m² (cycles d1–d15). CPT11 dose was increased by 20mg/m² at each cycle, from 180mg/m² up to 260mg/m², unless grade 3 toxicities other than alopecia arose.

Between March 2002 and September 2005, 46 patients were recruited (median age: 62.3 years). A total of 512 cycles of chemotherapy were administered (median: 9 cycles/patient; range: 3–41). Median follow-up was 16.2 months. Altogether, 27 patients had received prior chemotherapy: 24 with an oxaliplatin-based regimen; seven with CPT11; and five with LV5FU2 or oral 5FU. Doses of 260mg/m² were used in 17 patients, 240mg/m² in seven, 220mg/m² in six and 200mg/m² in five, while 11 remained at 180mg/m²; 121 cycles used 260mg/m² (24%), with 76 cycles at 240mg/m² (14%), 78 cycles at 220mg/m² and 58 cycles at 200mg/m². The objective response (OR) was 40%, with stable disease (SD) in 45% and disease progression (DP) in 11%. In the first-line therapy group, partial/complete responses were 55%, with SD in 30% and DP in 15%. In pretreated patients, OR was 30.5%, SD was 58.5% and DP was 11%. Nine patients (20%) had a therapeutic break (median: 5.1 months; range: 3–10). Overall median survival was 17 months, with 16.5 months in pretreated patients and 19.6 months in the first-line group. Toxicity grades 3–4 and overall incidence per cycle were: neutropenia, 3–22%; diarrhea, 4–22%; vomiting, 2–20%; alopecia, 20–26%; anemia, 0.2–2%; thrombocytopenia, 0–0%; and mucositis, 0.4–2.2%.

The toxicity of high-dose CPT11+LV5FU2 chemotherapy was well tolerated when the dose was progressively increased according to individual tolerability, with 37% of patients receiving CPT11 at 260mg/m². Progression-free survival (PFS) increased with higher doses of CPT11. In the chemo-naive and pretreated subgroups, the median PFS was 10.9 and 8.8 months, respectively (P=0.698, NS). Optimization of CPT11 doses in pretreated patients appears to pave the way for new treatment options.