Melanoma: Critical Debates Edited by Julia A. Newton Bishop, Martin Gore
Copyright © 2002 Blackwell Science Ltd
17: Who should we consider for isolated limb perfusion?
Ferdy J. Lejeune and Danielle Liénard
A limb heavily affected by a cancer condition—in-transit melanoma metas-tases, locally spreading skin carcinoma—is an appalling clinical situation, sometimes leading to palliative amputation. The idea came to Creech et al. from New Orleans , to isolate the affected limb and to connect it to a heart–lung machine, in order to deliver a high concentration of cytostatics within a closed circuit, while avoiding systemic toxicity (Fig. 17.1). Besides ni-trogen mustard which was the ﬁrst drug, melphalan or phenylalanine mustard (PAM) was quickly established as an effective agent in that setting, although it was poorly effective when given systemically. Regional efﬁciency will depend upon the chosen drug and its concentration: a concentration-dependent anti-tumour effect is a prerequisite. The lack of systemic toxicity will depend on: the quality of surgical isolation; the dissection of the vessels; the ligation of the collateral vessels; and efﬁcacy and location of the tourniquet.
In malignant melanoma, the only indication for isolated limb perfusion (ILP) is in-transit metastasis conﬁned to a limb, in such an anatomical condi-tion that surgical vascular isolation can be performed.
In-transit melanoma metastasis
High-risk primary melanoma (>1.5mm) of the limbs is prone to develop in-transit metastasis within 5 years in 6–10% of cases . These metastases are lymph-borne. They are the consequence of the penetration of the tumour cells into the dermal lymph channels, followed by lymph ﬂotation, adhesion to en-dothelial cells, extravasation and invasion of the adjacent tissues. The term ‘in-transit’ is classically reserved for metastasis developing in the subcutis or in the skin between the primary and the regional lymph basin. The term ‘satelli-tosis’ is assigned to dermo-epidermal metastases all around the primary site within a diameter of 5cm. They originate from tiny dermal lymphatics, where the lymph ﬂow is not necessarily stable, so that they can occur at any point
ISOLATED LIMB PERFUSION 231
High limb drug concentration
Low or no systemic drug concentration
Isolated Limb Perfusion (ILP) with anticancer agent(s)
for malignant melanoma
Fig. 17.1 Isolated limb
High regional efficacy
Limb toxicity (limitation)
Low systemic toxicity
‘around the clock’. Larger lymph channels, especially collectors, have a cen-tripedal ﬂow directing the cell transit, carrying the metastases towards the draining lymph nodes. However, the distinction between satellitosis and in-transit metastasis has little biological signiﬁcance, as the two patterns result from essentially the same stepwise events. Furthermore, it is not clear if some in-transit metastases are not preregional lymph node deposits as demonstrat-ed by the evidence that some sentinel nodes have been found in the transit region .
Table 17.1 summarizes the routine management of in-transit metastasis. It shows that ILP is indicated when other less aggressive modalities have failed. In addition, when the clinical situation permits it, some patients may beneﬁt from an active speciﬁc immunotherapy with peptides (see Prospects section p. 236).
Isolated limb perfusion is a sophisticated procedure which should be per-formed by expert surgeons in adequately equipped operating theatres. The surgeons should be trained in oncological and vascular surgery and have access to heart–lung technology.
For lower limb perfusion—the most common indication—the recom-mended way is to perform an extensive iliac lymph node dissection and to ligate the collateral vessels. The cannulae will be inserted through veno- and arteriotomies above the inguinal ligament. The tip of the cannula should be in the common femoral artery, to allow optimal drug delivery. A tourniquet is ap-plied around the root of the limb and twisted around a pin inserted into the iliac crest, in order to expose the whole root of the limb [2–4]. It is possible to use femoral or popliteal access for more distant disease; however, iliac ILP is
232 CHAPTER 17
Table 17.1 Available treatment for in-transit melanoma metastases
First appearence of several in-transit metastases
Recurrence of in-transit metastases in conﬁned area
Recurrence of in-transit metastases
widespread and/or bulky
Surgical resection and histological conﬁrmation
Surgical resection if not numerous
CO2 laser evaporation if numerous or cryotherapy if superﬁcial
Speciﬁc immunotherapy with peptides (only available in clinical trials)
Isolated limb perfusion
preferred because of the staging provided by the iliac lymph node dissection, and because access is via the vascular area excluded from that to be treated.
Upper limb ILP is performed through axillary dissection and the vessels are best cannulated through a division of the pectoralis major muscle.
The extracorporeal circulation set-up consists of tubing, oxygenator (in-cluding heat exchanger and reservoir) and modular pump for the arterial line. Venous blood is recovered by gravity. The extracorporeal circulation should be monitored by a certiﬁed pump technician.
A critical issue is the leakage to the systemic circulation. A prerequisite for good isolation perfusion is the continuous monitoring of the leakage by using radiolabelled albumin and g probe recording over the heart . The main cause of leakage is too high a pump ﬂow. Continuous leakage monitoring al-lows for the ﬁnding, at any moment, of the best equilibrium between the two compartments (perfusate and systemic circulation) by ﬁne tuning of the pump.
Therapeutic isolated limb perfusion
The rationale for ILP is the view that in-transit metastases are not just ‘satel-lites’ or conﬁned to a restricted area, but represent a contamination of a large portion of the lymph channel network. In the ﬁrst instance, and especially in the primary onset of in-transit metastasis, surgical excision of the metastasis is recommended. It can be therapeutic in some cases and will allow a histological diagnosis. If a recurrence and/or new in-transit metastasis appears shortly after the ﬁrst event (a few weeks) it can be expected that a large area of the lym-phatic network is affected by the micrometastasis; this is a typical situation for therapeutic ILP. The metastases should not be excised prior to ILP because they will allow the evaluation of the efﬁcacy of the treatment. Moreover, a ran-domized trial addressing the issue of prophylactic ILP with melphalan after re-moval of all in-transit metastases, showed no difference in survival rates .
ISOLATED LIMB PERFUSION 233
Gold standard of therapeutic isolated limb perfusion
What drug regimen to use?
The gold standard is melphalan given at a dosage producing a perfusate con-centration 10–30-fold the area under the curve (AUC) of systemic administra-tion. There is a 50% chance of complete remission and 25% chance of partial remission . It does not appear that the addition of actinomycin D increases efﬁcacy although it does increase local toxicity . Other drugs used alone, such as platinum or dacarbazine, do not reach the 50% response rate obtained by melphalan . As shown in Table 17.2, response rates are not given for some regimens because excision of the in-transit metastasis was performed at the time of ILP.
New approaches to isolated limb perfusion
Recently, two new combinations based on synergism have been proposed (Table 17.2):
1 tumour necrosis factor (TNF) combined with melphalan (TM-ILP) or with melphalan and g-interferon (IFN-g), (TIM-ILP); and
2 systemic dacarbazine followed by a nitrosourea in the perfusate.
Table 17.2 Drugs used in isolated limb perfusion for melanoma in-transit metastasis
Single agents Melphalan (PAM)
Combinations Actinomycin D +
melphalan Dacarbazine‡ +
TNF +melphalan +IFN-g
Bifunctional alkylating agents
Percentage of CR†
Skin and soft tissues
Skin and soft
Skin and soft tissues
Late inﬂammation, necrosis
Skin and soft
*Overal response rate (ORR).
†Complete reponse (CR) of unresected metastases. ‡Dacarbazine given 4h before fotemustine.
234 CHAPTER 17
The ﬁrst approach is based on dual targeting: TNF speciﬁcally destroys tu-mour-associated microvasculature by inducing apoptosis in angiogenic en-dothelial cells, while melphalan produces apoptosis of tumour cells . Combined (or not) with IFN-g, this regimen obtained the highest response rates ever seen: overall response of 90–100% and complete response of 70–80% . While this regimen has been registered by the European pharma-ceutical authorities (CPMP) for inextirpable soft tissue sarcoma, it has not been registered for melanoma because of the lack of randomized trial data comparing combined treatments with melphalan alone. However, compari-son of TIM or TM-ILP with historical matched series treated by melphalan alone, show that the latter provided only 52% complete response as compared to 68–78% in combination with TNF .
Resistance to nitrosourea is a result of the enzyme alkyl transferase (AT) which demethylates alkylated DNA. Dacarbazine and temozolomide inacti-vate AT, thereby sensitizing melanomas to the nitrosourea fotemustine. It was reported  that the administration of dacarbazine systemically 4h before ILP with fotemustine gave a response rate of 50%, equal to melphalan. A Phase I–II study on this schedule is currently being conducted by the European Organization for Research on Treatment of Cancer Melanoma Cooperative Group (EORTC-MCG).
Follow-up after therapeutic isolated limb perfusion
Most sensitive in-transit melanoma metastases are the superﬁcial ‘epider-motropic’ metastases which are often seen to dry off after a few weeks. Subcu-taneous metastases are usually less responsive and slower to regress. It can sometimes take a few months before necrosis is seen. If a good but partial response is seen for multiple tumours, ILP should be repeated. Otherwise, destruction of the remaining tumours, 6–8 weeks after ILP, with laser or cryotherapy, or even scalpel, is a good option.
There is one area of the lower limb where drug penetration is almost al-ways lower, the proximal and external aspect of the thigh, because it is vascu-larized by the vessels from the ischiatic artery and they are closed by the tourniquet. Irradiation of this region is a useful option, especially when in-transit metastases are already developed in this area.
ILP could be considered as an induction therapy and would ideally be fol-lowed by maintenance therapy. However, there is no established efﬁcient ad-juvant therapy after ILP although, in some selected cases, the administration of dacarbazine and/or temozolomide and/or fotemustine can induce useful response, even in the long term.
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