Isolated Limb Perfusion and Isolated Limb Infusion
First described by Creech in 1958, isolated limb perfusion (ILP) involves exclusion of the extremity from the systemic circulation, thereby allowing regional delivery of chemotherapy at doses 10 to 25 times higher than can safely be tolerated with systemic administration. This requires cannulation of a major blood vessel of the limb; typically, an iliac or femoral approach is used for the lower limb and an axillary approach for the arm (Figure 2). Perfusion of the extremity proceeds with high flow (500 to 1000 mL/min), with a membrane oxygenator used to maintain oxygenation and an appropriate acid-base balance. The limb is perfused for 60 to 90 minutes with chemotherapy. Systemic leak is minimized and circulating chemotherapy is washed out prior to recirculation, resulting in few to no systemic side effects. The perfused extremity inevitably experiences some local toxicity, ranging from mild erythema to epidermolysis; approximately one third of patients develop a Common Terminology Criteria for Adverse Events (CTAE) grade 3 or higher toxicity, although fascial compartment syndrome or deep tissue damage necessitating amputation results only rarely (in < 3% of cases).[17,18] Retrospective studies have shown that approximately 85% of patients experience an objective response after ILP, and 50% have a complete response.[19,20] It may take 3 to 6 months to see the maximal benefit; however, in patients who experience a complete response, the response is often long-lived, with a 32-month median duration.[17] The overall 5-year survival rate after ILP in a large series was 32%, and improved overall survival was closely associated with achievement of complete response.[21]
Procedure for Isolated Limb Perfusion With Adjunctive Hyperthermia
Melphalan (L-phenylalanine mustard) is the standard chemotherapy for perfusion. Melphalan(Drug information on melphalan) is an alkylating agent with melanoma tumor selectivity, since phenylalanine is an essential component of melanin synthesis. Other agents, including interleukin (IL)-2, interferon (INF)-α, cisplatin(Drug information on cisplatin), temozolomide(Drug information on temozolomide) (Temodar), and ADH-1 (Exherin), have been used alone or in combination with melphalan without significant improvements in response compared with melphalan alone.[22-24] Hyperthermia is typically used as an adjunct to improve response rates.[25] Hyperthermia induces cutaneous vasodilatation and improves drug uptake and cytotoxicity when temperatures exceed 38.5°C (101.3°F).[26] Temperatures over 42°C (107.6°F) are directly cytotoxic to malignant cells but may exacerbate locoregional toxicity.[27] The addition of tumor necrosis factor (TNF)-α to the perfusate results in tumor vasculature destruction, increased cytotoxicity, and modulation of the immune response. TNF-α also augments melphalan uptake into melanoma cells, and promising 4- to 6-fold improved response rates have been reported, especially for bulky or treatment-resistant disease.[28,29] However, TNF-α is associated with significantly increased toxicity and was shown to be no better than melphalan alone in a randomized prospective trial; as a result, it is no longer available off protocol in the United States.[30]
Isolated limb infusion (ILI) is a simpler and less invasive technique with less regional toxicity; it was first described in 1994 by Thompson et al of the Sydney Melanoma Unit.[31] Melphalan is infused at lower concentrations, with lower flow (55 to 75 mL/min), and for a shorter duration (30 minutes) through a percutaneous approach. A membrane oxygenator is not used in the circuit, resulting in a hypoxic and acidotic environment, which may increase cytotoxic activity. However, the same degree of hyperthermia is not obtained, which may contribute to the reduced complete response rate of 30% and the shorter median duration of response (24 months) compared with ILP.[17,18,32] CTAE grade 3 toxicities are only reported in 20% of patients undergoing ILI, and no treatment-related amputations have been reported.[17] The shorter duration of treatment and the significantly less invasive nature of the approach make this technique ideal for the elderly and those with significant comorbidities.[32,33] Another advantage of ILI is the avoidance of long-term morbidity associated with a lymph node dissection. However, occult nodal micrometastasis may be left behind in nearly half of patients[13,14]; this is demonstrated in patterns of relapse, with 75% (21 of 28) of in-field progressions occurring in the undissected regional nodal basin after an ILI.[34]
Both procedures can be repeated and still retain reasonable response rates.[35,36] Therefore, repeat perfusion should be considered in patients who had a prior response but later experienced progression in the extremity. ILI clearly has a distinct advantage in ease of repeating the procedure and decreased morbidity. However, the difference in response rates between the two types of regional therapy when repeated are even more pronounced than the difference between them when used as initial treatment—favoring ILP over ILI.[17,37] Regional chemotherapy in the form of ILP or ILI has the theoretical advantage of sterilizing the entire lymphatic system that is perfused, resulting in treatment of both clinical and subclinical disease. However, the techniques are limited to patients with disease isolated to an extremity. Patients with disease of the head, neck, or trunk are not candidates. Also, because the perfusion catheters are advanced distally from the point of entry into the vessel, the most proximal portion of the extremity will remain outside the treatment field. Therefore we recommend hyperthermic ILP (HILP) for healthy patients with unresectable in-transit melanoma of the extremities. We currently do not offer ILI but consider referring patients with significant comorbidities or advanced age for this less toxic but less effective alternative.
Intralesional Therapy
Intralesional therapy has the distinct advantage of delivering therapy directly into the malignant lesion. Intradermal and subcutaneous lesions lend themselves to this approach since they are easily accessible. The number of agents that can be injected into a lesion and result in cellular death is considerable. However, patients with intralymphatic disease often have multiple lesions, and in-field recurrence following treatment of an individual focus whether by resection or injection of a toxin is the rule. Therefore, the real goal of intralesional therapy is not only to destroy the target lesion but also to stimulate regression of other, untreated lesions. This can be accomplished when the injectant induces a regional and systemic immunization to melanoma antigens.
Bacille Calmette-Guérin (BCG) was the first intralesional treatment described, and it demonstrated local control in 90% of injected intradermal metastases as well as evidence of inducing systemic immune response to melanoma antigens. As early as 1974, Morton et al described a 17% response rate in distant lesions for patients undergoing intralesional injection with BCG.[38]
Intralesional IL-2 allows intratumoral concentrations that are much higher than can be delivered systemically, without significant toxicity. A clinical trial using this approach has demonstrated a complete response in 97% of injected lesions. Unfortunately, despite a significant increase in INF-γ–positive, tumor-specific CD8-positive T cells, there were no objective responses in distant untreated metastasis.[39]
Intralesional injection of granulocyte macrophage colony–stimulating factor (GM-CSF) has demonstrated a high response rate, as well as offering hope of regional immune stimulation and regression of noninjected lesions. A novel extension of this approach was the development of an oncolytic herpes simplex virus type 1 (HSV-1) encoded with the genetic sequence to produce GM-CSF (OncoVEXGM-CSF). A phase I clinical trial demonstrated a 26% objective response rate in both injected and noninjected lesions, highlighting the dual mechanism of action that includes both a direct oncolytic effect in injected tumors and a secondary immune-mediated antitumor effect in noninjected tumors.[40] Despite 80% of the treated patients in this study having stage IV disease, a 58% 1-year survival was observed, which is significantly better than the historical 1-year survival rates of 25% for stage IV disease.[41] Based on these preliminary results, an international prospective, randomized phase III clinical trial in patients with unresectable stage IIIB or IIIC or stage IV melanoma (OPTIM) is currently underway.[42]
