Phase I dose-escalation trial of irinotecan with continuous infusion 5-FU first line, in metastatic colorectal cancer

Abstract

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m À2 ) in combination with 250 mg m À2 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m À2 . However, three out of five patients at the 100 mg m À2 irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m À2 . The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m À2 ) combined with a continuous infusion of 5-FU (250 mg m À2 ) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study. Colorectal cancer (CRC) is second in the league of cancer deaths in developed countries. Approximately 25% of patients have liver metastases at presentation and eventually 50% of newly diagnosed patients will succumb to metastatic disease. The liver is the most common site of disease spread, and approximately 60% of patients with liver metastases have no evidence of extrahepatic disease (Faivre et al, 1995). However, only 10 -20% of these patients are candidates for surgical resection (Adam, 2003), and although there are new treatment techniques evolving, such as radiofrequency ablation (Nordlinger and Rougier, 2002) and the regional delivery of chemotherapy by hepatic arterial infusion (Kemeny and Ron, 1999;Kemeny, 2000), systemic chemotherapy still plays the major role in the treatment of metastatic CRC.The fluoropyrimidine 5-fluorouracil (5-FU) has been the cornerstone of therapy for CRC for over 30 years and during this time has been the subject of extensive investigation with regard to the optimisation of its use. In combination with the biochemical modulator leucovorin (folinic acid (FA)), it remains the reference drug for the treatment of CRC in adjuvant, first-line and secondline settings, with response rates of 22 and 14% for continuous infusion a...

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

“…FU as first-line treatment of metastatic colorectal cancer. Interestingly, the combination was well tolerated and demonstrated a significant clinical activity, obtaining an overall response rate of 55%, a clinical response benefit of 82% and a time to progression of 8 months (Saunders et al, 2004). Thus, the results of our study clearly suggest that the schedule of administration of the two drugs is critical to achieve the maximal supra-additive cytotoxic activity and that the lack of full synergism in some traditional schedules of IRI and FU may depend on the use of bolus FU (i.e.…”

Novel Strategies to Improve the Efficacy of Anticancer Agents in Human Colorectal Carcinoma

“…Interestingly, the combination demonstrated significant clinical activity, obtaining an overall response rate of 55%, a clinical response benefit of 82% and a time to progression of eight months. 20 These results clearly suggest that the schedule of administration of FU and IRI is critical in achieving the maximal supra-additive cytotoxic activity and that the lack of a full synergism in some traditional schedules of IRI and FU may depend on the use of bolus FU and/or the need to optimise the sequence of administration of the two agents. It seems possible to improve the clinical activity of the FU/IRI combination by avoiding simultaneous administration of the two drugs and/or by prolonging the infusion of FU.…”

A modified grading system for post‐hepatectomy metastatic liver cancer originating from colorectal carcinoma

“…The followup included measurement of serum carcinoembryonic antigen (CEA) every 3 months and abdominal CT or MRI and chest X-ray every 3-6 months. When recurrence was detected, patients received reoperation or chemotherapy (intravenous or intraarterial infusion of anti-cancer drugs such as 5-fluorouracil [Kyowa Hakko Chemical Co., Tokyo, Japan] and irinotecan [CPT-11; Yakult Pharmaceutical Inc. Co., Tokyo, Japan]) [30]. In this regard, no defined protocols of adjuvant chemotherapy were applied before or after hepatectomy for prevention of tumor recurrence.…”