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Journal of Surgical Oncology 2011;104:397–404

Treatment of Melanoma Metastases in a Limb by Isolated Limb Perfusion and

Isolated Limb Infusion

ALESSANDRO TESTORI, MD,1* CORNELIS VERHOEF, MD, PhD,2 HIDDE M. KROON, MD,3

E. PENNACCHIOLI, MD,1 MARK B. FARIES, MD,4 ALEXANDER M.M. EGGERMONT, MD,5 AND

JOHN F. THOMPSON, MD6,7

1Melanoma and Sarcoma Division, European Institute of Oncology, Milan, Italy2Erasmus University MC, Rotterdam, the Netherlands

3Rijnland Hospital, Leiderdorp, the Netherlands4Department of Surgery, Yale School of Medicine, New Haven, Connecticut

5Cancer Institute Gustave Roussy, Villejuif/Paris-Sud, France6Melanoma Institute Australia, North Sydney, Australia

7University of Sydney, Sydney, Australia

In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb

infusion can be a remarkably effective regional treatment option.

J. Surg. Oncol. 2011;104:397–404. � 2011 Wiley-Liss, Inc.

KEY WORDS: melanoma in-transit metastases; isolated limb perfusion; isolated limb infusion

INTRODUCTION

Management of in-transit melanoma metastases remains challeng-

ing because relapse rates and survival are dictated mainly by the

biological behavior of the tumor. Treatment options include surgery,

intralesional injection, electrochemotherapy (ECT), radiotherapy, iso-

lated limb perfusion (ILP), and isolated limb infusion (ILI). When

lesions are few and of limited size, and when the skin of the patient

is in good condition, simple surgical excision is likely to be the most

appropriate treatment option. When lesions are multiple or associated

with lymphedema and local inflammation, ECT may be a good alter-

native. However, if the lesions are localized to a limb but present in

large numbers, ILP or ILI should be considered to target the com-

plete surface of the limb. This review discusses these regional perfu-

sion and infusion treatments for in-transit melanoma.

ISOLATED LIMB PERFUSION

Isolated limb perfusion (ILP) was introduced in 1958 by Creech

et al. [1]. This regional treatment for in-transit metastases allows

tumors in extremities to be exposed to concentrations of chemothera-

py up to 25 times higher than can be achieved with systemic admin-

istration, but avoiding systemic toxicity.

The Technique

The surgical procedure entails dissecting and isolating the vessels;

regional node dissection can be performed if clinically indicated at

the time of vascular isolation.

After heparinization, the targeted blood circuit is isolated by

clamping and cannulating the major artery and vein, then connecting

the limb to a heated, oxygenated extracorporeal circuit. By means of

ligation of the collateral vessels and application of a tourniquet prox-

imally to the perfusion level, vascular isolation is achieved and leak-

age is prevented (Fig. 1). A precordial scintillation probe that detects

technetium-labeled albumin is used to monitor leakage throughout

the procedure [2].

Once isolation is secured and the absence of leakage is demon-

strated, drugs can be introduced to the system. Melphalan is the

most commonly used chemotherapeutic agent, at a dose of 10 mg/L

for a leg and 13 mg/L for an arm, because of its favorable local

toxicity and its efficacy [3,4]. Depending on the site of the tumors,

ILP is executed via the axillary, brachial, iliac, or femoral artery.

After 60–90 min of perfusions, a washout procedure using 1 L (arm)

to 4 L (iliac) of a balanced electrolyte solution is performed.

Clinical response is usually slow; it may take 3–6 months

before a complete response (CR) is reached. Locoregional toxicity

after ILP is usually classified using the grading system proposed by

Wieberdink et al. [5]: I, no reaction; II, slight erythema or edema;

III, considerable erythema or edema with some blistering, slightly

disturbed motility permissible; IV, extensive epidermolysis or

obvious damage to the deep tissues causing definite functional distur-

bance and threatening or manifesting a compartment syndrome;

V, severe reaction that may necessitate amputation.

Hyperthermia

Isolation of the limb also allows regional hyperthermia to be

achieved, which has been shown to augment the effects of the deliv-

ered chemotherapy. Moreover, an adequate temperature of perfused

tissue prevents vasoconstriction in the skin and the subcutis, which is

especially important when superficial lesions are treated [6]. Hyper-

thermia has been shown to improve the cytotoxicity of chemothera-

peutics in vitro especially at temperatures >418C [7,8]. A significant

drawback is the increased damage to normal tissues with hyperther-

mia, which is reason for it to be used less often these days [9,10]. As

*Correspondence to: Alessandro Testori, MD, Istituto Europeo diOncologia, via Ripamonti 435, 20141 Milano, Italy. Fax: þ39-0294379230. E-mail: [email protected]

Received 20 June 2011; Accepted 21 June 2011

DOI 10.1002/jso.22028

Published online in Wiley Online Library(wileyonlinelibrary.com).

� 2011 Wiley-Liss, Inc.

a compromise between response rates and local toxicity, perfusion is

currently performed under mild hyperthermic conditions (39–408C)with reported overall response (OR) rates of 85–99% [11,12]

(Table I).

Double Perfusion Schedules

Similar to schedules for systemic administration, one could

assume that more frequent application of chemotherapeutic drugs

raises efficiency. The proposal of double perfusion schemes is based

on the idea that residual tumor cells after the first perfusion may be

eliminated by a second perfusion since they might be more exposed

to the drugs in a partially damaged tumor. In normothermic condi-

tions, patients were offered a reduced second dose of melphalan after

a time interval of 3–4 weeks, which led to higher response rates but

had no influence on local, regional lymph node, or distant recurrence

rates [13]. More recently, a double perfusion schedule consisting of a

first perfusion with true hyperthermia (42–438C) without chemother-

apeutic drugs, followed by a second normothermic perfusion of

melphalan (M-ILP) 1 week later showed a CR rate of 65%.

Adjuvant Perfusion

In 1998, Koops et al. [14] reported results of a large multicenter

trial with 832 patients. There was a small benefit with respect to

locoregional recurrence (reduced development of in-transit and

regional lymph node metastases) but no improvement in overall

survival. In another randomized trial, surgical excision followed by

adjuvant M-ILP was compared to excision alone in 69 patients with

resectable in-transit metastases [15]. Despite significantly better

locoregional control there was no improvement in overall survival

and the authors concluded that there is no indication for M-ILP in

patients with resectable in-transit metastases.

We conclude that adjuvant ILP should not be proposed in melano-

ma patients.

Fig. 1. Isolated limb perfusion technique. a: After heparinization, the major artery and vein of the limb are cannulated. The temperature ofthe limb is monitored by thermocouples. b: A tourniquet is inflated proximal to the area to be perfused. c: The extracorporeal circuit isconnected to a perfusion machine.

TABLE I. Overview of Literature in Isolated Limb Perfusion

Refs. Temp. n

CR

(%)

PR

(%)

OR

(%)

Melphalan

Klaase et al. [11] 39–40 120 64 25 89

Lingam et al. [67] 39–40 103 76 23 99

Aloia et al. [12] 39–40 58 57 31 88

Bryant [68] 40–41 85 40 42 85

Thompson et al. [43] 40–41 111 73 13 86

Di Filippo et al. [9] 41.5–43 119 46 40 86

Melphalan � TNF

Noorda et al. [20] 39–40 90 (TM-ILP) 59

40 (M-ILP) 45

Cornett et al. [33] 39–40 58 (TM-ILP) 26 43 69

58 (M-ILP) 25 39 64

Alexander et al. [21] 39–40 44 (TM-ILP) 69� 26� 95�47 (M-ILP)

Rossi et al. [35] 39–40 58 (TM-ILP) 61 29 90

53 (M-ILP) 42 49 91

Melphalan þ TNF

Lienard et al. [16] 39–40 19 89 11 100

Lejeune et al. [22] 39–40 44 90 10 100

Lienard et al. [23] 39–40 64 73 22 95

Rossi et al. [24] 39–40 20 70 25 95

Grunhagen et al. [48] 39–40 100 69 26 95

Hayes et al. [26] 39–40 25 44 40 88

Di Filippo et al. [27] 39–40 113 63 25 88

Lasithiotakis et al. [28] 39–40 14 62 38 100

*Only combined results for ILPs performed with melphalan alone and mel-

phalan þ TNF are reported. Some of the patients treated with TNF also

received interferon gamma during ILP.

398 Testori et al.

Journal of Surgical Oncology

Tumor Necrosis Factor

Probably the most successful modification to melphalan-based

ILP was the introduction of tumor necrosis factor-alpha (TNF) [16].

TNF has a dual role. First, high-dose TNF has a tumor-selective

vasculotoxic effect that plays a role in antitumor activity. Second,

TNF changes tumor pathophysiology and increases the uptake of

concomitantly administered chemotherapeutics [17]. In rats with

advanced large limb tumors, TNF reportedly improved a tumor’s

uptake of drug by a factor of 3–6, as compared to ILP with melpha-

lan or doxorubicin alone [18,19].

Clinical Experience

The first study on the addition of TNF to M-ILP (TM-ILP) was

by Lienard et al. [16]. This study reported an OR of 100% in

19 patients (Table I). Subsequently more studies reported very high

response rates [20–29]. These results seem better than those with M-

ILP. Whereas a large meta-analysis on M-ILP showed a CR rate of

54% [30], TM-ILP studies in Table I show higher CR rates (Figs. 2

and 3).

Certainly in bulky disease, TNF is of additional value. Melphalan

uptake is very low in large tumors; TNF improves drug uptake

significantly so that tumors respond like large soft tissue sarcomas

(STS). ILP was largely abandoned for STS until the introduction of

TNF allowed very large tumors to respond well to ILP [31]. This has

led to a successful multicenter trial and the approval of TNF for

unresectable extremity STS in Europe [32].

In melanoma, however, the results of a randomized controlled

trial reported in 2006 by Cornett et al. [33] were disappointing. TNF

was associated with increased local and systemic toxicity but no

beneficial effect (CR rate 26% for TM-ILP vs. 25% for M-ILP). The

methods and conclusions of this publication were criticized [34]

because clinical response was assessed after 3 months, which is un-

common since most CRs are reached between 3 and 6 months after

ILP. Thus a low CR rate was reported. Also, the true indication,

bulky disease, could not be assessed. Therefore the conclusions of

this trial should be interpreted with caution.

In a nonrandomized mixed retrospective series, Rossi et al. [35]

demonstrated a significant difference between TM-ILP and M-ILP: a

CR rate of 61% was achieved after TM-ILP, whereas patients treated

with M-ILP showed a CR rate of 42% (P ¼ 0.05). Overall TM-ILP

has been demonstrated to be a safe treatment modality with limited

local and systemic toxicity, which can be repeated with retained

activity [36–39].

Prognosis After ILP

Main prognostic factors for survival after a relapse of melanoma

are characteristics of the primary (thickness, ulceration), stage of dis-

ease and type of recurrence (local, in transit, regional lymph node,

and distant) [40]. Several studies report a very strong correlation be-

tween a CR after TM-ILP and prolonged survival [25,35]. Apparent-

ly patients with a CR have a more favorable tumor biology.

ISOLATED LIMB INFUSION

In the early 1990s, isolated limb infusion (ILI) was developed by

Thompson et al. [41] at the Sydney Melanoma Unit (now Melanoma

Institute Australia; MIA) as a simplified and minimally invasive

alternative to ILP.

The Technique

During ILI, no open surgical procedure is needed because arterial

and venous catheters are inserted percutaneously. The catheters are

placed by a radiologist via the contralateral femoral artery and vein

using a standard Seldinger technique. The tips of the catheters are

positioned at the level of the knee or elbow joint of the disease-

bearing limb. Following this, the patient is brought to the operating

room and a general anesthetic is administered. The catheters are con-

nected to an extracorporeal circuit primed with saline solution and

incorporating a heat exchanger but no mechanical pump or oxygena-

tor. In order to achieve reliable isolation, a pneumatic tourniquet is

inflated proximally around the affected limb. In this isolated circuit a

low blood flow can be achieved by repeated aspiration from the

venous catheter and reinjection into the arterial catheter, using a

syringe. The lack of oxygenation results in a hypoxic and acidotic

environment, in contrast to the ILP technique (Table II) [42]. Great

care is given to heating the limb since cooling of the extremity has a

negative influence on the efficacy of the cytotoxic drugs. Heating of

the limb is achieved by a heat exchanger in the external circuit, a

warm air blanket placed around the limb, and a radiant heater placed

above it [30].

The cytotoxic drug of choice for ILI is melphalan. At the MIA,

actinomyocin-D is used additionally because of the satisfactory

results of ILP with the melphalan/actinomycin-D combination, with-

out a negative effect on toxicity [43]. After infusion of the drugs, the

blood in the isolated circuit is circulated manually for 30 min using

a syringe and three-way stopcock. Since the half-life of melphalan is

15–20 min and both melphalan and actinomycin-D are quickly

absorbed by the tissues of the isolated limb, a relatively short circu-

lation time of 30 min is sufficient [44,45]. Real-time leakage control

of the cytotoxic drugs to the systemic circulation during ILI is not

Fig. 2. Melanoma in-transit metastases of the leg, in a 59-year-oldwoman. a: Clinical presentation at baseline: multiple reddishnodules, nearly ulcerated, of different size and age. b: Clinical result3 months after ILP with melphalan and TNF.

Locoregional Treatment of Melanoma 399


needed due to the low flow and low pressure in the isolated limb

circuit and the effective isolation reliably achieved by the pneumatic

tourniquet. After 30 min the limb vasculature is flushed, after which

normal circulation to the limb is restored by removing the tourniquet

and the catheters. Figure 4 provides a schematic overview of the

procedure [46,47].

Results of Isolated Limb Infusion

Since 1992 more than 400 ILI procedures have been performed at

MIA, mostly for melanoma but also for patients with locally

advanced squamous cell carcinoma and sarcoma. Following ILI, a

CR rate of 38% and a partial response (PR) rate of 46% were

achieved in patients suffering from melanoma [41]. The median limb

relapse-free interval (LRFI) in these patients was 13 months; it was

22 months (range 5 to >72) for those experiencing a CR and

9 months (range 4 to 47; P ¼ .012) following a PR. The median

survival following a CR was 53 months (range 28 to >120); it was

26 months (range 14 to >120) following a PR and only 6 months for

the small group of patients who had stable or progressive disease

following the procedure (P ¼ 0.004). These results are similar to

those reported after ILP [20,48].

To date only one multicenter retrospective analysis of ILI results

has been published [49]. In this analysis 31% of the patients

experienced a CR, 33% a PR, and 36% had no response to the treat-

ment. As well as the institutions that contributed data to the multi-

center study, a number of other institutions around the world have

reported their experiences. Their results are listed in Table III [50–

56]. The fairly wide range of results obtained in these studies is

likely to be related to the low patient numbers in some of them and

to the process of learning a new technique. Furthermore, different

institutions use protocols that are different in small but potentially

important ways. The impact of these differences in protocol and the

influence of increased experience have recently been investigated by

Huismans et al. [57]. They showed that increased experience and

small modifications that were made to the ILI protocol at the MIA

over the years had a positive effect on the results. Another explana-

tion for the reported range in results could be the point in time when

the response of the procedure was investigated. Beasley et al. [53],

for example, assessed the response after exactly 3 months, whereas

others took the best response at any time after ILI. Despite the differ-

ences in protocols and results, most investigators have reported that

patients who obtain a CR have significantly improved survival com-

pared with nonresponders. Based on the same principle as in ILP,

double ILI schedules were evaluated and reported to be without

benefit on clinical response, local or systemic progression and

survival [58].

After ILI, regional toxicity due to the cytotoxic drug is generally

low [42,53]. Slight erythema and edema are seen in 41–57% of

patients, 39–53% of whom also may have some blistering. In most

cases conservative treatment involving bed rest, elevation and

sometimes the administration of corticosteroids is sufficient. In 3%

of the patients there is concern that a compartment syndrome might

be developing due to muscle damage, and occasionally a fasciotomy

is performed. In the experience to date at MIA, it has not been

necessary to amputate a limb due to severe tissue damage following

an ILI with melphalan and actinomycin-D.

Fig. 3. Locally advanced relapse of melanoma of the thigh, in a 60-year-old man. a: Clinical presentation at baseline: extensive nodularlesion, ulcerated, expression of multiple nodular lesions clustered together. b: Initial response after ILP with melphalan and TNF, at 20 days.The lesion appears extensively necrotic. c: Clinical result after 3 months, diagnosed as a pathologic CR. d: Clinical result 3 years after ILP.In addition to the evident local CR, no distant metastases had occurred.

TABLE II. Mean Blood Gas Values in the Isolated Limb After 30 min in

185 Patients [42]

pO2 8.4 mmHg

pCO2 54.3 mmHg

pH 7.11

Base excess �10.8 mmol/l

SO2 6.9%

400 Testori et al.


A study by Kroon et al. [59] focusing on toxicity showed that

patients with larger limb volumes experienced increased toxicity

grades without receiving higher cytotoxic drug doses. Beasley et al.

[60] corrected the melphalan dose for ideal body weight (IBW) to

test the hypothesis that this would decrease toxicity in such patients.

They reported that this did decrease toxicity significantly (P ¼ .001)

with only a small decrease in response that was not statistically

significant (P ¼ .345). However, these results could not be repro-

duced in a study undertaken at MIA, in which it was found that the

ratio between IBW and actual body weight did not predict toxicity or

outcome (Huismans AM, Kroon HM, Haydu LE, Thompson JF,

July 2011, unpublished work).

DISCUSSION

One of the main advantages of ILI is the simple, minimally inva-

sive character of the procedure. Morbidity as a result of the surgical

approach to the blood vessels, as sometimes occurs after ILP, is not

experienced after ILI, and normally patients can be discharged from

hospital after a few days [55]. ILI can also safely be performed in

elderly and frail patients without risking severe adverse effects. No

excessive toxicity or morbidity was seen in MIA patients, despite the

fact that their average age was considerably higher than that of

patients in most ILP studies [41,61]. Even in patients who suffer

from distant metastatic disease and have concurrent symptomatic

limb disease, ILI can effectively be used as a palliative treatment to

provide local limb tumor control and limb salvage [62]. Also,

because there is hardly any groin scar tissue following ILI, the

procedure can easily be repeated if there is disease recurrence. The

response rates following these repeat procedures are similar to those

occurring after a first ILI [63].

Another major advantage of ILI is the hypoxic and acidotic

environment that develops in the isolated limb during the course of

the procedure. Animal studies have shown that hypoxia and acidosis

enhance the effect of melphalan by a factor of 3 [64]. Clinically, an

enhanced response has been reported when limb isolation has lasted

longer than 40 min [56].

ILI also has a number of practical advantages over ILP. The time

in the operating room is considerably shorter (on average 1 hr

compared to 3–5 hr for ILP), no complex or expensive equipment is

used and fewer personnel are needed. Because of this, ILI is much

less expensive. Another advantage is that ILI can be used in a clini-

cal trial setting to provide insight into developing novel treatment

Fig. 4. Schematic illustration of the circuit used for isolated infusion of a lower limb [46,47].

TABLE III. Isolated Limb Infusion Studies Using Melphalan and Actinomycin-D

Refs.

No. of

patients Response criteria CR (%) PR (%) SD (%) PD (%)

Mian et al. [50] 9a Best response 44 56 0 0

Lindner et al. [54] 128 Best response 41 43 12 4

Brady et al. [56] 22b 3 months 23 27 0 50

Kroon et al. [42] 185 Best response 38 46 10 6

Beasley et al. [65] 50 3 months 30 14 10 46

Marsden [69] 16c Unknown 26 58 — 16

Barbour et al. [55] 74 Best response 24 30 37 7

Beasley et al. [49] 128 3 months 31 33 7 29

CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.aThree patients had >1 ILI’s.bOne patient had advanced sarcoma.



strategies [65]. One of these studies used systemic ADH-1 in combi-

nation with melphalan. It was well-tolerated and a CR of 50% was

reported [66]. Table IV lists the differences between ILI and ILP.

CONCLUSIONS

When simple surgical excision is not possible, ILP and ILI are

excellent treatment modalities for in-transit metastases, as they

achieve high CR and PR rates with limited local and systemic

toxicity. TM-ILP is an option for recurrence after ILP or ILI, and for

bulky tumors when angiogenesis justifies the use of TNF.

An important consideration is the general condition of the patient;

ILI is often possible in patients who would not be considered fit to

undergo conventional ILP. Also to be considered is the availability

of various treatments; for example, in the United States, ECT is not

yet commercialized, and TNF is not approved for ILP. In Europe,

where both treatments are available, the choice of treatment is main-

ly based on the characteristics of the disease, but in part also on the

characteristics and wishes of the patient.

Over the last 15 years ILI has become a reasonable and cost-

effective alternative to the long-established ILP procedure. Multiple

studies, most published recently, have shown that when performed

correctly the response rates following ILI are similar to those seen

after ILP but with less toxicity and morbidity. In the future, random-

ized, controlled trials will be needed to better document the efficacy

of ILI and formally compare it with ILP. It is then likely to become

the preferred treatment option for patients who have extensive mela-

noma or in-transit metastases in a limb.

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TABLE IV. Differences Between Isolated Limb Perfusion and Isolated Limb Infusion

Isolated limb perfusion Isolated limb infusion

Technically complex Technically simple

Open surgical exposure of vessels for catheter insertion Percutaneous vascular catheter insertion in radiology department

3–5 hr duration Approximately 1 hr

Perfusionist and ancillary staff required No perfusionist required and fewer total staff

Complex and expensive equipment needed Equipment requirements modest

Magnitude of procedure excludes many patients Well tolerated by medically compromised, frail and elderly patients

Not possible in patients with occlusive vascular disease Can be performed in patients with occlusive vascular disease

Technically challenging to perform a repeat procedure Not difficult to perform a repeat procedure

Systemic metastases normally a contraindication Systemic metastases not a contraindication

Higher perfusion pressures predispose to systemic leakage Low pressure system, effective vascular isolation with pneumatic tourniquet

Limb tissues oxygenated, with normal blood gases maintained Progressive hypoxia and acidosis

Hyperthermia (>418C) can be achieved Usually not possible to raise limb temperature above 39–408CGeneral anesthesia required Possible with regional anesthesia

402 Testori et al.


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