Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion

T. E. Lans, D. L. Bartlett, S. K. Libutti, M. F X Gnant, D. J. Liewehr, D. J. Venzon, E. M. Turner, H. R. Alexander

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Purpose: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF. Experimental Design: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the 1-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured. Results: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P ≤ 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P ≤ 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP. Conclusions: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

Original languageEnglish (US)
Pages (from-to)784-790
Number of pages7
JournalClinical Cancer Research
Volume7
Issue number4
StatePublished - 2001
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Perfusion
Cytokines
Liver
Melphalan
Interleukin-8
Interleukin-6
Blood Pressure
Bilirubin
Arterial Pressure
Necrosis
Serum
Inferior Vena Cava
Aspartate Aminotransferases
Alanine Transaminase
Pulmonary Artery
Alkaline Phosphatase
Blood Vessels
Albumins
Colorectal Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lans, T. E., Bartlett, D. L., Libutti, S. K., Gnant, M. F. X., Liewehr, D. J., Venzon, D. J., ... Alexander, H. R. (2001). Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. Clinical Cancer Research, 7(4), 784-790.

Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. / Lans, T. E.; Bartlett, D. L.; Libutti, S. K.; Gnant, M. F X; Liewehr, D. J.; Venzon, D. J.; Turner, E. M.; Alexander, H. R.

In: Clinical Cancer Research, Vol. 7, No. 4, 2001, p. 784-790.

Research output: Contribution to journalArticle

Lans, TE, Bartlett, DL, Libutti, SK, Gnant, MFX, Liewehr, DJ, Venzon, DJ, Turner, EM & Alexander, HR 2001, 'Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion', Clinical Cancer Research, vol. 7, no. 4, pp. 784-790.
Lans TE, Bartlett DL, Libutti SK, Gnant MFX, Liewehr DJ, Venzon DJ et al. Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. Clinical Cancer Research. 2001;7(4):784-790.
Lans, T. E. ; Bartlett, D. L. ; Libutti, S. K. ; Gnant, M. F X ; Liewehr, D. J. ; Venzon, D. J. ; Turner, E. M. ; Alexander, H. R. / Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. In: Clinical Cancer Research. 2001 ; Vol. 7, No. 4. pp. 784-790.
@article{2b8b9a388079469dada75bac6115e0c7,
title = "Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion",
abstract = "Purpose: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF. Experimental Design: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the 1-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured. Results: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P ≤ 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P ≤ 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP. Conclusions: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.",
author = "Lans, {T. E.} and Bartlett, {D. L.} and Libutti, {S. K.} and Gnant, {M. F X} and Liewehr, {D. J.} and Venzon, {D. J.} and Turner, {E. M.} and Alexander, {H. R.}",
year = "2001",
language = "English (US)",
volume = "7",
pages = "784--790",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion

AU - Lans, T. E.

AU - Bartlett, D. L.

AU - Libutti, S. K.

AU - Gnant, M. F X

AU - Liewehr, D. J.

AU - Venzon, D. J.

AU - Turner, E. M.

AU - Alexander, H. R.

PY - 2001

Y1 - 2001

N2 - Purpose: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF. Experimental Design: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the 1-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured. Results: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P ≤ 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P ≤ 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP. Conclusions: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

AB - Purpose: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF. Experimental Design: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the 1-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured. Results: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P ≤ 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P ≤ 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP. Conclusions: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

UR - http://www.scopus.com/inward/record.url?scp=0034896632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034896632&partnerID=8YFLogxK

M3 - Article

C2 - 11309322

AN - SCOPUS:0034896632

VL - 7

SP - 784

EP - 790

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 4

ER -