The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable of killing tumor cells, in vitro as well as in vivo. This unique capacity has focused the attention on a possible role for this cytokine in the treatment of human cancer.  ...

Zie: Samenvatting.

Zwaveling, Jan Harm,

English

Zwaveling, Jan Harm

University of Groningen

Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable of killing tumor cells, in vitro as well as in vivo. This unique capacity has focused the attention on a possible role for this cytokine in the treatment of human cancer. ... Zie: Samenvatting

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Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha
Zwaveling, Jan Harm
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Zwaveling, J. H. (1997). Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha
s.n.
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SYSTEMIC SIDE EFFECTS
OF
 ISOLATED LIMB PERFUSION
WITH
TUMOR NECROSIS FACTOR ALPHA
J. H. Zwaveling
RIJKSUNIVERSITEIT GRONINGEN
Systemic side effects of isolated limb perfusion
with
 tumor necrosis factor alpha
PROEFSCHRIFT
ter verkrijging van het doctoraat in de
Medische Wetenschappen
aan de Rijksuniversiteit Groningen
op gezag van de
 Rector Magnificus, dr. F. van der Woude,
 in het openbaar te verdedigen op
woensdag 19 februari 1997
des namiddags te 2.45 uur
door
Jan Harm Zwaveling
geboren op 7 juni 1955
te Utrecht
Promotores: Prof. Dr. H. Schraffordt Koops
Prof. Dr. R. van Schilfgaarde
Referenten: Dr. A.R.J. Girbes
Dr. H.J. Hoekstra
Dr. J. van der Meer
Promotiecommissie: Prof. Dr. H.J. ten Duis
Prof. Dr. N. H. Mulder
Prof. Dr. L.G. Thijs (V.U. Amsterdam)
Paranimfen: Drs. H. Delwig
Drs. J.C. Paling
Omslag: Dr. William B. Coley
Financial support of this thesis by Boehringer Ingelheim, Knoll, Glaxo/Wellcome and U-gene is
gratefully acknowledged.
De reis, niet de bestemming
Aan mijn ouders
Voor Mieke
Contents
page
Introduction 7
Chapter I Side effects of cancer treatment with recombinant human tumor
necrosis factor alpha: A new challenge for the intensive care
9
Submitted
Chapter II High plasma tumor necrosis factor alpha concentrations and a sepsis-
like syndrome in patients undergoing hyperthermic isolated limb
perfusion with recombinant tumor necrosis factor alpha, interferon
gamma and melphalan
25
Crit Care Med 1996; 24: 765-770
Chapter III Augmented procoagulant activity in cancer patients, treated with
recombinant interferon gamma in addition to recombinant tumor
necrosis factor alpha and melphalan
37
Thromb Haemost 1996; 76: 897-901
Chapter IV Effects of hyperthermic isolated limb perfusion with recombinant
tumor necrosis factor alpha and melphalan on the human fibrinolytic
system
49
Cancer Res 1996; 56: 3948-3953
Chapter V Renal function in cancer patients treated with hyperthermic isolated
limb perfusion with recombinant tumor necrosis factor alpha and
melphalan
65
Nephron, in press
Chapter VI Role of nitric oxide in recombinant tumor necrosis factor alpha -
induced circulatory shock: A study in patients treated for cancer with
isolated limb perfusion
77
Crit Care Med, in press
Chapter VII Summary and concluding remarks 87
Chapter VIII Samenvatting en conclusies 91
Dankwoord 95
Introduction
7
Introduction
Tumor necrosis factor alpha (TNF-a) is a naturally occurring glycoprotein which displays an
intriguing variety of biological functions. On the one hand it is cytotoxic for tumor cells, and as such
has been used in the treatment of cancer since, with molecular cloning, it became available in sufficient
quantities. On the other hand TNF-a is a central mediator in the metabolic changes observed during the
systemic response to infection, be it bacterial, viral or protozoal. It is identical to ‘cachectin’, the
lipoprotein lipase inhibitor that was isolated by Cerami and coworkers from the serum of severely
wasted rabbits, infected with Trypanosoma brucei [1]. Administration of recombinant TNF-a (r-TNF-
a) to experimental animals induces a clinical picture that is virtually identical to the septic shock
syndrome [2].
In view of these potent pro-inflammatory actions of TNF-a, it is hardly surprising that systemic
toxicity has been a notorious drawback of cancer treatment with r-TNF-a. Early clinical trials have
been disappointing due to both a lack of objective tumor response and serious systemic side effects.
Treatment related fatalities have been described. It was generally felt that higher concentrations of r-
TNF-a were needed to achieve significant anti-tumor effect, but that toxicity would preclude the use of
such high dosages. A breakthrough in the clinical use of r-TNF-a occurred in 1992 when the first
report on isolated limb perfusion with high dose r-TNF-a was published [3]. With this technique, very
high concentrations of r-TNF-a were achieved locally, while systemic toxicity seemed to be
manageable. An impressive clinical response rate was obtained in patients with unresectable sarcomas
and melanomas of a limb [4,5].
When isolated limb perfusion with r-TNF-a was introduced at the University Hospital in
Groningen, it became readily apparent that toxicity, though indeed manageable in a modern Intensive
Care Unit, was still considerable. During perfusion and in the immediate post-operative phase, most
patients developed a sepsis syndrome characterized by high fever, systemic vasodilation and low
bloodpressure. The studies presented in this thesis were conducted to explore the exact nature of this
toxic response and, if possible, to clarify its mechanism.
Chapter I summarizes what is known of the side effects of treatment with r-TNF-a in gene al. It
also offers some guidelines for the treatment of patients undergoing isolated limb perfusion with r-
TNF-a, and it suggests a number of experimental strategies that may prove useful in the future.
Chapter II defines the clinical response as it is seen in post-perfusion patients and relates the severity of
symptoms to the amount of leakage of r-TNF-a f om the perfusion circuit to the systemic circulation.
In chapter III the effects of leakage of r-TNF-a on systemic coagulation variables are studied, in
particular the added influence of pretreatment with interferon gamma (IFN-g). Chapter V is about the
impact of isolated limb perfusion with r-TNF-a on the human fibrinolytic system. In chapter V renal
effects of this type of treatment are studied in some detail. Finally, in chapter VI, the role of nitric
oxide as a possible mediator of TNF-a-induced systemic vasodilation is investigated.
Introduction
8
References
1. Kawakami M, Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp
Med 1981; 154: 631-639.
2. Beutler B, Cerami A. Tumor necrosis, cachexia, shock, and inflammation: A common mediator. Annu
Rev Biochem 1988; 57: 505-518.
3. Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune F. High-dose recombinant tumor necrosis
factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs
for melanoma and sarcoma. J Clin Oncol 1992; 10: 52-60.
4. Eggermont AMM, Schraffordt Koops H, Lienard D, Kroon BBR, van Geel AN, Hoekstra HJ, Lejeune
FJ. Isolated limb perfusion with high dose tumor necrosis factor a in combination with interferon g and
melphalan for irresectable extremity soft tissue sarcomas: a multicenter trial. J Cl n Oncol 1996; 14:
2653-2665.
5. Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with melanoma of the
extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and
interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 1996; 14: 479-
489.


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Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

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