Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)802-809
Number of pages8
JournalAnnals of Surgical Oncology
Volume14
Issue number2
DOIs
Publication statusPublished - Feb 2007

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Melphalan
Pharmacokinetics
Perfusion
Liver
Pharmaceutical Preparations
Neoplasm Metastasis
Mortality
Liver Failure
Therapeutics

Keywords

  • Isolated hepatic perfusion
  • Liver metastasis
  • Locoregional treatment
  • Pharmacokinetics
  • Treatment personalization

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease. / Mocellin, Simone; Pilati, Pierluigi; Pian, Pierpaolo Da; Forlin, Marco; Corazzina, Susanna; Rossi, Carlo Riccardo; Innocente, Federico; Ori, Carlo; Casara, Dario; Ujka, Francesca; Nitti, Donato; Lise, Mario.

In: Annals of Surgical Oncology, Vol. 14, No. 2, 02.2007, p. 802-809.

Research output: Contribution to journalArticle

Mocellin, S, Pilati, P, Pian, PD, Forlin, M, Corazzina, S, Rossi, CR, Innocente, F, Ori, C, Casara, D, Ujka, F, Nitti, D & Lise, M 2007, 'Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease', Annals of Surgical Oncology, vol. 14, no. 2, pp. 802-809. https://doi.org/10.1245/s10434-006-9108-7
Mocellin, Simone ; Pilati, Pierluigi ; Pian, Pierpaolo Da ; Forlin, Marco ; Corazzina, Susanna ; Rossi, Carlo Riccardo ; Innocente, Federico ; Ori, Carlo ; Casara, Dario ; Ujka, Francesca ; Nitti, Donato ; Lise, Mario. / Correlation between melphalan pharmacokinetics and hepatic toxicity following hyperthermic isolated liver perfusion for unresectable metastatic disease. In: Annals of Surgical Oncology. 2007 ; Vol. 14, No. 2. pp. 802-809.
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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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AU - Mocellin, Simone

AU - Pilati, Pierluigi

AU - Pian, Pierpaolo Da

AU - Forlin, Marco

AU - Corazzina, Susanna

AU - Rossi, Carlo Riccardo

AU - Innocente, Federico

AU - Ori, Carlo

AU - Casara, Dario

AU - Ujka, Francesca

AU - Nitti, Donato

AU - Lise, Mario

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AB - 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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KW - Locoregional treatment

KW - Pharmacokinetics

KW - Treatment personalization

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