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GRÜNHAGEN, KROON, AND VERHOEF
systemic toxicity because of leakage of the perfusate to the
systemic circulation, and local toxicity of the treated extremity.
In the situation in which ILPs are performed in specialized
and experienced teams, clinically relevant leakage
percentages of greater than 10% are extremely rare and median
leakage should be 0%. 38 In ILI, systemic leakage is not an
issue because of the low pressure of the perfusion system. 48
Local toxicity of perfusions is scored according to the
Wieberdink classifıcation. 49 A few modifıcations of the ILP
have reduced the local toxicity signifıcantly. Firstly, TNF
dose is reduced. In the original series it was 3 mg to 4 mg TNF
for leg perfusions and 2 mg for the arm; at present dosages of
2 mg and 1 mg are used, respectively. This modifıcation has
widely been accepted after a randomized trial in patients with
sarcoma showed equal effectiveness of the low-dose perfusions
but with decreased local toxicity. 50 The effect of lowdose
ILPs on local toxicity could be affırmed in further case
series of patients with sarcoma but proved to be of no influence
in patients with melanoma. 38 Reasons for this difference
are unknown. Another adjustment in ILP leading to less local
toxicity is the tendency to perform more distal perfusions to
reduce the perfused limb volume. This has a profound effect
on local toxicity in both ILP and ILI procedures. 40,51 Major
local toxicity (Wieberdink grade greater than 3) is seldom
seen in ILI/ILP and is in recent reports 3% for both procedures.
It can be concluded that ILP, and ILI to even a higher
extent, are safe procedures with little and manageable toxicity.
Perfusions have been performed safely in the older population
and repeat procedures can be performed without
increased toxicity.
ILI/ILP AND SYSTEMIC THERAPY
The poor survival after perfusion, despite the excellent regional
response rates, raise the question of whether a local
therapy such as ILI/ILP should still be used on a stand-alone
basis in patients with extensive disease. In this light, a parallel
can be seen in patients with positive deep pelvic lymph nodes.
Both IT-mets and deep pelvic nodes reflect extensive disease
and, recently, it has been shown that the extent of surgery to
the deep pelvic and obturator nodes does not improve the
outcome of these patients. In other words, the prognosis of
these patients is dictated by the biology of the disease rather
than by the extent of surgery. 52,53 The same mechanism is
likely to be applicable to the IT-met situation. Until recently,
response rates on systemic therapies were poor, and complete
focus lied on treating the local situation. Fortunately,
this situation has changed dramatically by the introduction
of BRAF/MEK/KIT inhibitors, anticytotoxic T-lymphocyteassociated
(CTLA) protein-4 antibodies and programmed
death (PD)-1 pathway inhibitors. 54 Patients with stage IV
melanoma experience response rates of approximately 50%
and, in a subset of patients, long-term benefıt can be obtained.
54 Although the majority of patients who entered the
trials of these new drugs indeed had stage IV disease, most
protocols allowed patients with unresectable stage III disease
to enroll as well. The patient with IT-mets eligible for perfusion
has by defınition unresectable stage III disease and,
therefore, trial results can be extrapolated to this subset of
patients, albeit with caution and in the awareness that response
to ILP is dependent on stage of disease. 55
It is, however, unlikely that systemic therapy will replace
ILI/ILP in patients with extensive IT-mets. The response
rates of the new agents are impressive compared with standard
chemotherapy but are far below those that can be
achieved with a perfusion. BRAF inhibitors have impressive
and rapid response rates of approximately 60% (overall response)
in patients with BRAF mutation. Drawbacks are numerous,
however; the median duration of response is only
about 7 months, after which resistance seems almost inevitable,
there is a wide interpatient variability in response to
treatment, and toxicity associated with BRAF inhibition cannot
be neglected. 54 A more durable response can be obtained
with anti-CTLA4 antibodies, but only a minority of patients
will respond. Patients with multiple unresectable IT-mets
will remain unresectable after a PR, so that the aim of therapy
should ideally be CR. The CR rates of ILI and especially ILP of
around 60% are still unmet by any systemic agent. The superior
local control rate of a perfusion combined with the mild
toxicity compared with systemic treatment mean that perfusion
remains the optimal treatment option in these patients.
Although replacement of a perfusion by systemic therapy is
unlikely in the near future, the development of new potent
agents in the systemic treatment of patients with melanoma
offers new possibilities in combining drugs. The fırst data on
combining new systemic agents are encouraging with OR
rates of 64%, a duration of response of 11 months, and a
1-year overall survival rate of 72% with the combination of a
BRAF and MEK inhibitor. 56 BRAF inhibition followed by
anti-CTLA4 therapy is also appealing, but this regimen has
produced disappointing results in retrospective series. 54 The
combination of two different ways of drug delivery (systemic
and in the isolated circuit) is a logical next step. When systemic
targeted therapies are administered in combination
with chemotherapy administered by ILI, chemotherapy resistance
can potentially be overcome by increasing the cytotoxic
effıcacy and, thereby, the responses. 57 In a multicenter
phase II study combining melphalan ILI and systemic
ADH-1, a cyclic pentapeptide that disrupts N-cadherin adhesion
complexes, an overall response rate of 60% was
achieved without increasing toxicity, compared with an overall
response rate of 40% achieved previously with melphalan
alone at the same institutions. 58 Improved responses were
also seen when melphalan ILI was performed after systemic
bevacizumab, a monoclonal antibody against VEGF causing
increased delivery of melphalan to the tumor cells, in a preclinical
melanoma model. 59 A clinical trial administering bevacizumab
in combination with melphalan ILI is eagerly awaited.
Currently, the use of the systemic anti-CTLA-4 antibody ipilimumab,
before or after melphalan ILI, is being investigated in
phase I and II trials (NCT01323517, NCT02115243).
Potentially more attractive is the combination of ILI/ILP for
rapid response, followed by systemic therapy for survival bene-
e532
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