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Correlation Between Melphalan Pharmacokinetics and Hepatic Toxicity Following Hyperthermic Isolated Liver Perfusion for Unresectable Metastatic Disease

¹ Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, via Giustiniani 2, 35128, Padova, Italy
² Department of Anesthesiology and Pharmacology, University of Padova, via Giustiniani 2, 35128, Padova, Italy
³ Department of Radiotherapy, Section of Nuclear Medicine, University of Padova, via Giustiniani 2, 35128, Padova, Italy
⁴ Laboratory and Clinical Medicine, University of Padova, via Giustiniani 2, 35128, Padova, Italy

Correspondence: Address correspondence and reprint requests to: Pierluigi Pilati, MD, Clinica Chirurgica 2, Dipartimento di Scienze Oncologiche e Chirurgiche, Università di Padova, Via Giustiniani 2, 35128, Padova, Italy; E-mail: pl.pilati{at}unipd.it

Background: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity.

Patients and methods: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement 50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC).

Results: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3–4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1–6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028).

Conclusions: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

Key Words: Isolated hepatic perfusion • Liver metastasis • Locoregional treatment • Pharmacokinetics • Treatment personalization