Combined Systemic Chronotherapy and Hepatic Artery Infusion for the Treatment of Metastatic Colorectal Cancer Confined to the Liver

Abstract

Background: The optimal treatment of patients with metastatic colorectal cancer is still a clinical challenge. We describe the use of combined hepatic arterial infusion (HAI) of irinotecan (CPT-11) in conjunction with systemic chronotherapy infusion of 5-fluorouracil (5FU), folinic acid and carboplatin in patients with colorectal liver metastases. Methods: Twenty-three patients with colorectal cancer and isolated liver metastases were enrolled in this trial. Intraoperative insertion of an intra-arterial catheter into the hepatic artery was accomplished during the colon operation (in cases of synchronous tumor) or as a separate procedure in colorectal cancer patients with newly diagnosed liver metastases. A systemic double-lumen double-chamber port was inserted via the subclavian vein as a separate procedure. The treatment plan included irinotecan given by intra-arterial infusion at 150 mg/m² for 1 h. After 2 weeks of rest chronomodulated 5FU (700 mg/m²; peak delivery rate at 04:00 h), leucovorin (175 mg/m²; peak delivery rate at 04:00 h) and carboplatin (40 mg/m²; peak delivery rate at 16:00 h) for 4 days was followed by 10 days’ rest and then given again. After 10 days’ rest another HAI was introduced using the same method. Each cycle of therapy included 2 HAI courses and 2 chronotherapy courses in between. After 2 complete cycles, patients were evaluated for their response with weekly accessed toxicity recording. Results: Seven women, 8 men, median age 61 years (range 46–72). Eight patients had synchronous colon and hepatic disease and 7 patients had metachronous disease. Ten patients had previously been treated with 5FU and leucovorin while 5 patients were chemonaive. The mean number of cycles were 11.6 per patient (range 8–19). Partial response was achieved in 6 patients (40%) and was followed by laparoscopic radiofrequency ablation in 5 patients (33%). Disease stabilization was observed in 2 patients (13%) and disease progression in 7 patients (47%) mainly after previous chemotherapy failure. Side effects were infrequent and mild including grade 2 GIT complaints (5 patients), RUQ pain during HAI (9 patients) and grade 2 hematological complaints in 2 patients. Conclusion: A combined chemotherapy protocol (HAI and chronotherapy) with irinotecan (CPT-11) together with chronomodulated infusion of 5FU, folinic acid and carboplatin can be used in metastatic colorectal patients with a high efficacy rate and minor side effects especially in pretreated patients.

Phase II Study of UFT with Leucovorin Plus Hepatic Arterial Infusion with Irinotecan, 5-Fluorouracil and Leucovorin for Non-Resectable Liver Metastases of Colorectal Cancer

“…The efficacy of intravenous irinotecan and oxaliplatin in the treatment of mCRC has led to their evaluation in combination with FUDR HAI [5,6] . Studies of HAI with irinotecan as a single agent [17][18][19] or in combination with a fluoropyrimidine [20,21] have shown that it is an effective and well-tolerated treatment of CRC hepatic metastases, with ORRs of 14-27 and 38-40%, respec tively.…”

“…In order to overcome 5-FU resistance, phase I and II studies have investigated the use of irinotecan HAI as a single agent [17][18][19] or in combination with a fluoropyrimidine [20,21] . These studies showed that irinotecan HAI had good tolerability and significant anti-tumor activity.…”

Nonviral Vectors for Cancer Gene Therapy: Prospects for Integrating Vectors and Combination Therapies

“…In contrast to conventional chemotherapies, which commonly require repeated administration (Kaubisch et al 2004;Pentheroudakis et al 2005;Reck et al 2005), a single administration of a genetic vector can provide long-term anti-tumor activity by converting transduced cells into therapeutic protein factories in situ (Heidenreich et al 2004b;Ma et al 2002a;Ma et al 2002b;Pulkkanen et al 2002). Furthermore, gene transfer directly into the tumor may be able to restrict toxicity to localized areas while also concentrating the therapeutic protein at the tumor site, whereas chemotherapy often has nonspecific, systemic toxicity (Brain et al 2005;Shimonov et al 2005;Winquist et al 2005). Besides targeting the tumor site for injection of vector, additional specificity can be obtained by using tumor-specific promoters (Akbulut et al 2004;Lillehammer et al 2005;Su et al 2005;Zeng et al 2005), vectors that preferentially transduce tumor cells (Kursa et al 2003;Morizono et al 2005;Ogris and Wagner 2002), and therapeutic genes that facilitate preferential killing of tumor cells (Kawakami et al 2003;Lam and Breakefield 2001).…”

Dosing Time-Dependent Effect of Temocapril on the Mortality of Stroke-Prone Spontaneously Hypertensive Rats

“…A chronopharmacological approach seems to be desirable for developing a more effective and safe dosage regimen. There are precedents for this approach in clinical practice (Tsuruoka et al, 2003;Debon et al, 2004;Shimonov et al, 2005).…”

“…A chronopharmacological approach seems to be desirable for developing a more effective and safe dosage regimen. There are precedents for this approach in clinical practice (Tsuruoka et al, 2003;Debon et al, 2004;Shimonov et al, 2005).Previous animal (Oosting et al, 1999) and human (Palatini et al, 1992;Witte et al, 1993;Sunaga et al, 1995) studies have shown dosing time-dependent differences in the blood pressure-lowering effects of ACE inhibitors. In addition, the preventive effect of an ACE inhibitor for cardiac hypertrophy in hypertensive animals was reported to depend on its dosing time (Sugimoto et al, 2001).…”