OncologyA phase I study of continuous hepatic arterial infusion of Irinotecan in patients with locally advanced hepatocellular carcinoma
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.
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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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2012, European Journal of Pharmaceutical SciencesCitation Excerpt :In recent years, several camptothecin analogs have been developed but only two drugs, topotecan and irinotecan, have reached clinical approval (Venditto and Simanek, 2010). These compounds, although showing a better pharmacological profile and a greater efficacy compared to camptothecin, either require continuous infusion or frequent administrations to reach effective concentrations (Brandi et al., 2011; Burris et al., 1994; Kummar et al., 2011; Pitot et al., 2000). To overcome these pharmacological disadvantages, we have tested the possibility of using β-Cyclodextrin nanosponge technology to improve CPT delivery to prostate cancer cells, using both androgen-refractory (DU145 and PC-3) and sensitive (LNCaP) cell lines.
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These authors contributed in equal measure to the work and share first coauthorships.