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From the Sydney Melanoma Unit, Sydney Cancer Centre, Royal Prince Alfred Hospital; and Department of Surgery, University of Sydney; Sydney, NSW, Australia.
Correspondence: Address correspondence and reprint requests to: Professor John F. Thompson, The Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia; Fax: 61-2-9550-6316; E-mail: john{at}mel.rpa.cs.nsw.gov.au
Isolated limb perfusion (ILP) was introduced into clinical practice in the mid-1950s, based on the same principles that had been applied to develop extracorporeal cardiopulmonary bypass a few years earlier. The concept was simple. By temporarily isolating the vasculature of a limb, high cytotoxic drug concentrations could be achieved without producing serious systemic side effects. Early studies using hyperthermic ILP with melphalan for limb melanoma produced impressive results, with overall response (OR) rates of around 80% and complete response (CR) rates for measurable limb disease of 30%–50%.1 More recent reports indicate that CR rates exceeding 50% are now obtained in most melanoma treatment centers where ILP is undertaken.2 Even higher CR rates have been reported when tumor necrosis factor (TNF) has been used with melphalan.3 Apart from the generally unacceptable option of amputation, no other form of treatment (systemic, regional, or local) achieves response rates that are consistently as high as those able to be obtained by ILP. It provides results far superior to those able to be achieved by any form of systemic chemotherapy, for example, where OR rates exceeding 20% are uncommon and CR rates rarely exceed 1%–2%.
However, despite the clearly demonstrated effectiveness of ILP for limb melanoma, it is a technique still used in only a small number of centers worldwide. The principal reason for this paradoxical situation is that, although the procedure is elegantly simple in concept, in practice it is a surgical tour-de-force – technically complex and demanding, labor intensive, time consuming, and costly. It has become clear that if ILP is to be effective and safe, meticulous attention to every aspect of the procedure is essential, with comprehensive monitoring of all parameters that might influence efficacy and outcome. These considerations have meant that the use of ILP, both for melanoma and soft tissue sarcoma, has been largely restricted to a few tertiary referral centers with appropriate academic staff and sufficient resources to undertake ILP as a clinical research endeavor. The control and monitoring of systemic drug leakage, as described in the paper by Daryanani et al.4 in this issue of Annals of Surgical Oncology, represents just one of the many technical challenges which must be overcome if ILP is to be performed with safety.
Because of its complexity, cost, and potential morbidity, the objectives of ILP and the indications for its use must be very clearly understood. It was shown to have no effect whatsoever on survival in the large prospective EORTC-WHO-NAPG trial5 comparing standard surgery plus adjuvant ILP with surgery alone for patients with melanomas 
1.5 mm thickness. Nor has it ever been demonstrated to influence survival when used as a therapeutic procedure in the presence of macroscopic limb disease. ILP can nevertheless generate considerable morbidity, depending upon such factors as the type and dose of chemotherapeutic agents used, adequacy of oxygenation, level of hyperthermia, perfusate flow rate, and duration of perfusion. Potential complications, including damage to blood vessels, nerves, and muscles,6 need to be considered before ILP is recommended.
Recurrence or in-transit metastasis confined to a limb is reported to occur in 5%–8% of melanoma patients. Satisfactory but much simpler treatment options than ILP are often available for this small group of patients. In some cases, simple surgical excision of one or two small in-transit metastases will be all that is required. If disease is more extensive but superficial, techniques such as cryotherapy, diathermy curettage, laser treatment, radiofrequency ablation, or direct cytotoxic drug injection into tumor nodules can be effective. For larger and more deeply placed lesions, local radiotherapy can be used. Recent studies have demonstrated that electroporation therapy, in which an electric field is applied across a tumor nodule via a circular array of needle electrodes after injection of a cytotoxic agent into it, is also effective in many cases. Thus, in patients who have limb recurrences of melanoma which are small and few in number, easily removed by surgical excision, or able to be treated by one of the other simple methods outlined above, it is difficult to justify treatment by ILP. In some (but not all) patients, further local or in-transit recurrences will become apparent later, but often these are able to be dealt with by simple means once more. There remains, however, a group of patients with disease that is too advanced or too widespread within the limb to be able to be treated by these methods, and it is in this situation that isolated regional chemotherapy using a technique such as ILP is indicated.
Acknowledging the effectiveness of ILP, but recognizing the limitations and risks imposed by its technical complexity, simpler and safer regional chemotherapy techniques have been sought. Direct intra-arterial infusion of cytotoxic agents was simple, but although an enhanced first-pass effect of the drugs on the tumor was achieved, CR rates were unimpressive and systemic drug toxicity was a major problem. Another alternative technique was described as tourniquet infusion but, again, response rates were low and systemic drug effects were inevitable because only very brief occlusion of venous outflow from the limb was achieved.7
At the Sydney Melanoma Unit, we introduced in 1992 an alternative technique that we called isolated limb infusion (ILI). This has produced results generally comparable to those achieved by ILP, but without requiring complex equipment, many staff, and long periods of operating time. We have found the technique to be well tolerated, even by frail and elderly patients, allowing effective palliative treatment to be given to individuals who would not be considered fit for treatment by conventional ILP. Details of the ILI procedure have been reported elsewhere,8 but it is, in essence, a very low flow ILP performed without oxygenation via standard radiological catheters (6–8 FG). These are inserted percutaneously in the radiology department prior to the actual ILI procedure in the operating room, which involves only 20–30 minutes of drug exposure. Systemic drug leakage is minimized by routine use of a pneumatic tourniquet and a generous washout of the limb vasculature prior to deflation of the tourniquet and removal of the catheters. These maneuvers virtually eliminate the risk of systemic side effects, with systemic melphalan leakage rarely exceeding 1%–2% (calculated from measurements of systemic melphalan concentrations by high performance liquid chromatography). The results of ILI for melanoma in terms of OR and CR rates have been similar to those achieved by conventional ILP, and it has been found easily possible to repeat the procedure if a satisfactory response is not achieved after an initial ILI or if recurrence in the limb occurs later.
Although the effectiveness of isolation techniques used during conventional ILP have improved over the years, as the article by Daryanani et al.4 reports, and a decrease in systemic drug leakage and associated systemic complications has been achieved as a result of this, the procedure remains complex and costly and can produce considerable regional morbidity. Because ILP has no effect on survival, its objective must be to achieve local disease control in a limb. However, it should only be used if it is likely to produce better or more long-lasting results than other forms of locoregional treatment that are simpler, cheaper, less invasive, and safer.
Received for publication February 2, 2001. Accepted for publication March 21, 2001.
REFERENCES
This article has been cited by other articles:
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  K. M. J. Thijssens, R. J. van Ginkel, E. Pras, A. J. H. Suurmeijer, and H. J. Hoekstra Isolated Limb Perfusion With Tumor Necrosis Factor {alpha} and Melphalan for Locally Advanced Soft Tissue Sarcoma: The Value of Adjuvant Radiotherapy Ann. Surg. Oncol., April 1, 2006; 13(4): 518 - 524. [Abstract] [Full Text] [PDF]
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J. H. W. de Wilt and a. J. F. Thompson Is there a Role for Isolated Limb Perfusion With Tumor Necrosis Factor in Patients With Melanoma? Ann. Surg. Oncol., February 1, 2004; 11(2): 119 - 121. [Full Text] [PDF]
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