NcXHF

PERFUSION AND INFUSION IN THE ERA OF EFFECTIVE SYSTEMIC THERAPY
systemically using this isolated circuit. Melphalan concentrations
of 10 mg/L (leg) or 13 mg/L (arm) are considered standard
dosages. The major concern of ILP is potential leakage
of the effective agents to the systemic circulation. Therefore,
leakage monitoring is mandatory and a precordial scintillation
probe is placed to detect any radioactively labeled albumen
administered to the isolated circuit that has potentially
leaked to the systemic circulation.
Melphalan-based ILPs have been used for decades in the
previous century as complete response (CR) rates of 40% to
50% and overall response rates of 75% to 80% were achieved,
unmet by any other treatment modality.
ILP MODIFICATIONS
Since the introduction of ILP, many modifıcations have
been applied to improve tumor response. These modifıcations
have led to an improved insight in the optimal temperature,
the optimal drugs, and the optimal indications
for the procedure.
Temperature
Temperature of the perfused tissue is important in more than
one way. The temperature of the skin has to be warmed during
perfusion to prevent vasoconstriction in the dermal and
subdermal tissues. Especially in superfıcial IT-mets, application
of a warm water mattress can improve the local drug
delivery as the uptake of the drug by in-transit metastases in
vivo has proven to be twice as high at 39.5°C than at 37°C. 5
The second reason for hyperthermia is the idiosyncratic sensitivity
of tumor cells to heat. Moreover, hyperthermia can
improve the uptake of the drug in tumor cells, especially at
temperatures greater than 41°C. 6,7 However, hyperthermia is
associated with increased local toxicity. Tissue temperatures
of 41.5°C to 43°C during ILP can yield high response rates, 8
but the local toxicity of these procedures can lead to major
complications and even amputation of the perfused limb. 9
KEY POINTS
Therapy for patients with extensive melanoma in-transit
metastases should be effective in providing local control.
Tumor necrosis factor-based isolated limb perfusion (TM-
ILP) is effective in the treatment of bulky melanoma intransit
metastases; isolated limb infusion (ILI) is effective
in the treatment of lower-burden disease.
Modern TM-ILP and ILI treatment is safe.
New systemic agents for melanoma treatment have
changed the treatment of patients with stage IV melanoma
drastically, but response and local control rates do not
reach ILI/ILP standards.
Combination of ILI/ILP to induce rapid local response,
followed by effective systemic therapy to increase overall
survival, has great potential to become standard therapy in
patients with extensive melanoma in-transit metastases.
The use of true hyperthermia should therefore be avoided.
Mild hyperthermia for ILP is used as a compromise between
response and toxicity.
Drugs
Several attempts have been made to improve the response on
ILP by using other cytostatic drugs than melphalan. Commonly
used drugs in the treatment of systemically metastasized
melanoma, either alone or in a combination schedule,
are dacarbazine and cisplatinum. Therefore, among others,
these drugs were tested in the ILP-setting, but no drug or
drug combination used for patients with melanoma has
proven to achieve results superior to melphalan. 4,10 Probably
the only alternative schedule still in use is the combination of
melphalan and actinomycin-D. 11
Probably the most influential adjustment of ILP has been
the introduction of TNF by Lejeune and Liénard in 1988.
TNF was isolated as an endogenous factor, especially active
in inflammation, with necrotizing ability on tumor cells. 12
We now know that TNF has a dual mechanism of action:
the direct cytotoxic effect of high-dose TNF to tumor cells
certainly plays a role in antitumor activity, 13 but more importantly
the TNF effect on the so-called tumor-associated
vasculature induces a rapid change in tumor morphology
characterized by hemorrhagic necrosis. 14 However, the systemic
application in patients with melanoma was very disappointing.
15 TNF turned out to be a potent mediator in septic
shock and, therefore, the systemic side effects (acute drop in
vascular resistance leading to low blood pressure, fever, etc.)
were the major factors hindering systemic application of this
cytokine. 16 The maximum tolerated dose of TNF in humans
turned out to be 10-times to 50-times lower than required for
antitumor effect, 17 so that systemic, but also intralesional administration
of TNF, was not clinically applicable. The concept
of ILP combines the advantages of the TNF antitumor
activity with the avoidance of systemic effects. Moreover, the
cytotoxic effects of TNF are known to be enhanced in hyperthermic
conditions and with the addition of alkylating chemotherapeutics,
18,19 both prerequisites already existing in the
ILP model. The reintroduction of TNF in anticancer therapy
by application in the ILP protocol combined optimal activity
with minimal toxicity. 20
Indications
The success of ILP in the treatment of melanoma IT-mets has
prompted trials to test the effıcacy of ILP in the adjuvant setting
after excision of the primary melanoma. After the fırst
disappointing results, this indication was largely abandoned
by most melanoma centers. 21 Recently, the long-term results
of a Swedish trial were published that affırmed the conclusion
that adjuvant ILP after excision of high-risk primary melanomas
does not improve survival of these patients. 22 Another
plausible thought has been the repetition of perfusion soon
after the fırst ILP, the so-called double perfusion schedule.
The premise that repeated administration of chemotherapeutic
agents is more effective than single use is adopted from
the systemic chemotherapy situation and is based on the idea
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