Chapter 48 Isolated Limb Perfusions and Extremity Amputations
INTRODUCTION
In-transit metastatic disease in melanoma is defined as recurrent melanoma within the intradermal or subcutaneous lymphatics that does not enter the nodal basins. In the current American Joint Committee on Cancer (AJCC) staging system, in-transit disease without metastatic lymph nodes is considered stage IIIb and carries with it a 5year survival of 30% to 50%.1 For recurrent melanoma confined to an extremity, simple excision can usually eradicate the disease. Simple excision is sufficient and a wide local excision is not necessary because it does not improve recurrence rates. For larger numbers of lesions, simple excision becomes technically prohibitive. For these patients, isolated limb perfusion (ILP) is the treatment of choice. ILP involves surgical isolation of an extremity’s circulation and placing that circulation into an extracorporeal circulation, which is separated from the systemic circulation. After creating the new circuit, the isolated limb is perfused with high doses of heated chemotherapy. ILP should be contemplated in patients with intradermal or subcutaneous in-transit melanoma metastases confined to an extremity when there is no evidence of systemic metastatic disease.
ILP was first used to treat melanoma in the late 1950s by Creech and coworkers.2 His group introduced the practice of using an extracorporeal oxygenator to treat melanoma confined to an extremity. Stehlin and associates3 modified the technique 20 years later to include hyperthermia to enhance the cytotoxic effects of the chemotherapy. Hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents and can cause selective killing of neoplastic cells.3
Hyperthermic ILP with melphalan leads to an objective response rate in 79% of patients, with a complete response in 54%.4 Patients with a complete response have the best prognosis. In patients with a complete response after perfusion, the 3-year survival is 60%, versus 35% in patients not obtaining a complete response.4 Unfortunately, despite the high objective response rates including a majority of patients with complete remissions after ILP, there is a 22% to 100% recurrence rate.5 Patients can be eligible for repeat ILPs for recurrence.
Melphalan is the chemotherapeutic agent of choice for ILP.6 Melphalan is an alkylating agent that is a derivative of phenylalanine. Phenylalanine is a precursor in melanin synthesis and is taken up preferentially by melanocytes, making it an optimal choice for the treatment of melanoma.7 Other agents, including cisplatin, interferon, and tumor necrosis factor–alpha (TNF-α), have been used in combination with or separately from melphalan, but response rates and durations of response are not significantly higher than with melphalan alone.
Isolated Limb Perfusion in Melanoma
OPERATIVE PROCEDURE
Blood Vessel Dissection and Collateral Ligation
The first step in ILP is to isolate inflow and outflow vessels to the perfused extremity. ILP of the lower extremity is most commonly performed through the external iliacs but can also be performed via the femoral or popliteal vessels. The location of vessel dissection depends on the distribution of the in-transit metastases as well as technical considerations. These technical points include the patient’s body habitus as well as history of previous lymph node dissections or previous surgeries in the area. ILP in the upper extremity is most commonly performed via the axillary vessels; however, brachial vessels can also be used, depending on the circumstances. In the lower extremity, a more proximal perfusion does not improve the rate of inguinal nodal recurrence. Thus, inguinal nodal recurrences are comparable for iliac and femoral vessels.8
Cannulation and Attachment to the Pump Oxygenator
The external iliac vessels are cannulated and connected to the inflow and outflow lines of an extracorporeal bypass circuit. The perfusion circuit contains a heat exchanger, an oxygenator, and a roller pump. The circuit is primed using 700 ml of balanced salt solution, 1 unit of packed red blood cells, and 1500 units of heparin. The typical hematocrit in the circuit is 25%. One unit of blood is used because regional toxicity cannot be further prevented by providing a higher hematocrit.9 Flow rates of 300 to 500 ml/min for the lower extremity and 150 to 300 ml/min in the upper extremity are optimal for the perfusion. Flows are adjusted depending on line pressure and volume of the reservoir or because of systemic leak.10 The circuit is warmed using a heat exchanger, and the extremity is covered in external warming blankets to maintain tissue temperatures of 38.5°C to 40°C. Temperatures are monitored by thermistor probes placed in the lower extremity.
Dosing for melphalan is based either on body weight or on actual limb volume. Older series used dosing regimens based on body weight and ranged from 0.8 to 2.0 mg/kg for the lower extremity and 0.45 to 0.75 mg/kg for the upper extremity. Wieberdink and coworkers11 modified the dosing regimen so that it was based on measuring the actual volume of the limb. They then developed a system to grade regional toxicity related to the perfusion11 (Box 48-1). The volume of the extremity is determined by the volume of water it disperses when submerged in a container of water, with an additional 10% added for the lower extremity to estimate the volume of the lateral thigh that is not submerged. Based on this regimen, an optimal dose of melphalan was found that resulted in reversible grade II or III toxicity in the majority of perfusions. In the lower extremity, this dose is 10 mg/L. The upper extremity can tolerate a slightly higher dose of 13 mg/L. These doses are currently used by most centers.
Box 48-1 Wieberdink Grading System for Regional Tissue Toxicity after ILP11
| Grade I | No subjective or objective evidence of reaction |
| Grade II | Slight erythema and/or edema |
| Grade III | Considerable erythema and/or edema with some blistering; slight disturbed mobility permissible |
| Grade IV | Extensive epidermolysis and/or obvious damage to the deep tissues, causing definite functional disturbances; threatening or manifest compartmental syndromes |
| Grade V | Reaction that may necessitate amputation |
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