Elsevier

Digestive and Liver Disease

Volume 43, Issue 12, December 2011, Pages 1015-1021
Digestive and Liver Disease

Oncology
A phase I study of continuous hepatic arterial infusion of Irinotecan in patients with locally advanced hepatocellular carcinoma

https://doi.org/10.1016/j.dld.2011.08.005Get rights and content

Abstract

Purpose

Aim of this phase I study was to identify the maximum tolerated dose and dose limiting toxicity of continuous infusion of Irinotecan through a port-a-cath placed in the hepatic artery in patients with hepatocellular carcinoma and cirrhosis to explore new strategies in advanced hepatocellular carcinoma. Response rate and time-to-progression were analysed.

Methods

Irinotecan was delivered as a five-day continuous infusion every 21 days, with increases of 2.5 mg/m2/day every three patients, starting from 7.5 mg/m2/day. Dose limiting toxicity corresponded to one patient in each triplet developing G4 haematological or G3 non-haematological toxicity, confirmed in two triplets. Twenty-eight patients (17 Child-Pugh A, 11 B) received treatment and tumour response was assessed after three courses completed by 22 patients.

Results

Dose limiting toxicity was G3 diarrhoea in two patients, reached at 27.5 mg/m2/day and the recommended dose was set at 25 mg/m2/day. Nineteen of 30 patients experienced adverse events related to porth-a-cath placement and one died from liver ischemia and sepsis. Median time-to-progression was 11.3 months.

Conclusion

Intrarterial infusion of Irinotecan is feasible in patients with hepatocellular carcinoma on cirrhosis at a recommended dose of 25 mg/m2/day, with no major adverse drug-related events, but with some concerns about the insertion and management of the intra-arterial device.

Introduction

Curative therapies for hepatocellular carcinoma (HCC) can be applied only to patients in the early or very early tumour stage [1]. Amongst non-curative therapies, TACE (trans-arterial chemoembolization) and sorafenib are the only treatments positively influencing survival, in intermediate and advanced stage patients respectively [2], [3], [4] and should be applied only in patients with well-preserved liver function (Child-Pugh class A) [3]. However, a large number of patients (up to 50%) do not have a truly satisfactory response.

Irinotecan is a topoisomerase-I inhibitor registered for the treatment of gastro-intestinal cancer in humans [5], [6], [7], which has been shown to exert more activity on HCC cell lines in vitro than other anticancer agents [8], but failed to provide definitive information in vivo particularly through intravenous infusion in HCC patients [9], [10], [11].

HAI (hepatic artery infusion) allows high drug concentration in the liver [12] and was preliminarily tested with Irinotecan both in patients with healthy liver and liver colo-rectal metastasis [6], [7] and in patients with HCC on cirrhosis [13]. Suto et al. [13] yielded a promising response rate with mild and manageable toxicity, although no dose limiting toxicity (DLT) was investigated in cirrhotic subjects. Moreover, preliminary pharmacokinetic data suggested that hepatic artery administration via continuous infusion of Irinotecan could be an effective and tolerable strategy, despite a certain rate of complications [13].

Based on these premises, we planned and ran a phase I study of continuous HAI of Irinotecan in patients with advanced HCC starting in 2003, when sorafenib had not yet become accepted and reimbursed as a standard treatment for patients with advanced HCC. The aim of the study was to identify the MTD (maximum tolerated dose) and DLT of continuous HAI of Irinotecan for a period of five days every 21 days. Secondary endpoints were the response of the target lesion and a comparison between the pharmacokinetics of Irinotecan delivered by HAI and by i.v. administration.

Section snippets

Materials and methods

Inclusion criteria: We considered for enrolment patients with intermediate HCC (Barcelona Clinic Cancer Classification = BCLC-B) refractory or non suitable to standard therapies or locally advanced HCC (BCLC-C) [14], with at least one measurable lesion; no distant extrahepatic metastasis; no invasion of the proximal tract of the portal trunk. Additional criteria: no major cardiologic or respiratory dysfunction; adequate bone marrow function (neutrophils ≥1500/mm3; platelets ≥50,000/mm3;

Patient disposition

Between December 2003 and November 2006, 33 patients were enrolled, but only 28 received HAI treatment: two could not receive port-a-cath placement due to vascular abnormalities, one withdrew consent, one deteriorated too rapidly due to massive HCC, whilst a 84-year-old woman died from hepatic ischaemia followed by infection and sepsis complicating porth-a-cath placement. Patient and HCC characteristics are summarized in Table 1, Table 2. At the time of Irinotecan HAI infusion 16 patients out

Discussion

At the time of planning the present study no systemic treatment was available for locally advanced HCC and controlled studies were recommended. The present study showed that HAI Irinotecan could be administered at dosages even higher than those utilized in non-cirrhotic cancer patients (colorectal liver metastases) and that the recommended dosage of HAI Irinotecan in patients with HCC on cirrhosis is between 22.5 and 25 mg/m2/day.

Prolonged Irinotecan infusions are expected to produce increased

Conflict of interest

None declared.

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