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GRÜNHAGEN, KROON, AND VERHOEF
Perfusion and Infusion for Melanoma In-Transit Metastases in
the Era of Effective Systemic Therapy
Dirk J. Grünhagen, MD, PhD, Hidde M. Kroon, MD, PhD, and Cornelis Verhoef, MD, PhD
OVERVIEW
The management of melanoma in-transit metastases (IT-mets) is challenging. For many years, the absence of effective systemic therapy
has prompted physicians to focus on regional therapies for melanoma confined to the limb. The introduction of isolated limb perfusion
(ILP) and isolated limb infusion (ILI) has enabled effective delivery of cytotoxic drugs in an isolated circuit, so as to overcome systemic
toxicity and maximize local response. Both techniques have evolved over years and both tumor necrosis factor (TNF)-alpha–based ILP
and ILI have distinct indications. The development of new systemic treatment options for patients with melanoma in the past decade
has shed a new light on melanoma therapy. The present manuscript focuses on the modern role of ILI and ILP in the treatment of
patients with melanoma with in-transit metastases in the era of effective systemic therapy. The response and control rates of ILI/ILP
are still superior to rates achieved with systemic agents. The extent of disease in patients with stage III disease, however, warrants
effective systemic treatment to prolong survival. There is great potential in combining rapid response therapy such as ILI/ILP with
systemic agents for sustainable response. Trial results are eagerly awaited.
Melanoma incidence in the United States has increased
during recent decades to an estimated number of
76,100 new cases in 2014, 1 comprising 4.6% of all new cancer
cases. In approximately 5% to 8% of these patients, IT-mets
will develop during the course of the disease. These IT-mets
are a result of tumor emboli trapped within the dermal and
subdermal lymphatics and can occur anywhere between the
site of the primary tumor and the draining regional lymph
node basin. The management of these IT-mets is challenging,
as they are often numerous and can be bulky. The median
time between diagnosis of the primary tumor and the development
of IT-mets is between 13 months and 16 months. If a
patient develops IT-mets, this is often a prelude to the appearance
of systemic disease. In the current American Joint
Committee on Cancer Melanoma Staging and Classifıcation,
patients with IT-mets are staged N2 or N3, depending on associated
lymph node metastases. The corresponding 5-year
survival rates are 69% and 52%, respectively. 2
Various treatment options exist for melanoma IT-mets, as
the presentation can range from very few and tiny lesions
easily amenable to local excision, to more than 100 and extremely
bulky lesions in previously extensively treated extremities.
This wide range of clinical presentation demands a
tailored approach for each patient. Whereas, in some patients,
resection of limited disease is part of a curative approach,
other patients may need treatment of their IT-mets
even in the presence of stage IV disease for palliative reasons.
The treatment of these IT-mets can therefore be challenging,
especially when the interval between new lesions is short,
when numerous and bulky metastases are present, or when
multiple treatment modalities have already been applied and
failed. It is in this context that Creech and Krementz developed
the concept of ILP in 1958. 3
ILP TECHNIQUE
Until recently, melanoma was infamously refractory to any
kind of systemic treatment. This resistance stimulated the
search for techniques that could deliver high concentrations
of chemotherapy or other agents to the affected limb, without
the risk for systemic toxicity. In this way, drug concentrations
would potentially suffıce to achieve antitumor effect. As
IT-mets of extremity melanomas are, per defınition, confıned
to a limb, isolation of the affected limb from the systemic circulation
would offer such an opportunity. This isolation can
be achieved by surgical access to the artery and vein on either
iliac, femoral, popliteal, axillary, or brachial level. The artery
and vein are clamped and cannulated after which the catheters
can be connected to a heart-lung machine to get an oxygenated
circuit. To further isolate the limb, a tourniquet is
placed proximal to the site of the perfusion. Melphalan (Lphenylalanine
mustard) has been the standard drug used in
ILP because of its effıcacy and toxicity profıle. 4 Drug concentrations
in the limb are 20-times higher than can be achieved
From the Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Dirk J. Grünhagen, MD, PhD, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, Netherlands; email: d.grunhagen@erasmusmc.nl.
© 2015 by American Society of Clinical Oncology.
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