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Published in:

01-02-2007

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

Authors: Simone Mocellin, MD, Pierluigi Pilati, MD, Pierpaolo Da Pian, MD, Marco Forlin, MD, Susanna Corazzina, MD, Carlo Riccardo Rossi, MD, Federico Innocente, MD, Carlo Ori, MD, Dario Casara, MD, Francesca Ujka, MD, Donato Nitti, MD, Mario Lise, MD

Published in: Annals of Surgical Oncology | Issue 2/2007

Abstract

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.

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Title: Correlation Between Melphalan Pharmacokinetics and Hepatic Toxicity Following Hyperthermic Isolated Liver Perfusion for Unresectable Metastatic Disease
Authors: Simone Mocellin, MD
Pierluigi Pilati, MD
Pierpaolo Da Pian, MD
Marco Forlin, MD
Susanna Corazzina, MD
Carlo Riccardo Rossi, MD
Federico Innocente, MD
Carlo Ori, MD
Dario Casara, MD
Francesca Ujka, MD
Donato Nitti, MD
Mario Lise, MD
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 2/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-006-9108-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Patients and methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Patients and methods

Results

Conclusions

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