Isolated limb perfusion (ILP) for malignant melanomaMedical editor Stephan Stoldt MD
Oslo University Hospital
Isolated limb perfusion (ILP) is a treatment in which the blood circulation is isolated in an extremity providing local treatment with chemotherapy using a heart/lung maching. The purpose is to give large doses of tumor-toxic medications which are 15- to 20-fold higher than can be given by systemic treatment. The treatment provides an increased cytostatic effect on the tumor with minimal systemic exposure.
Today, ILP is an established treatment method for regionally advanced malignant melanoma and for advanced soft tissue sarcoma limited to an extremity. In most cases, the treatment leads to complete remission of the tumor. In some cases, ILP leads to partial remission or stabilization of the illness.
In Norway, this treatment is centralized to Oslo University Hospital.
- For locoregional spreading and in-transit metastases which can no longer be treated by local excision
- To avoid amputation
- Curative treatment
- Heart/lung machine such as roll pump, oxygenator, and warming system
- Gamma detector
- Software for continual monitoring of possible leakage.
- Surgery tray
- Vein instruments
- Vascular cannulas
- Temperature probes
- Warming blanket
Melfalan is a suitable medication for ILP treatment because of its short half-life, low endothelial toxicity, limited cell cycle specificity, and relative linear dose response conditions of cytotoxicity.
- 10 mg/l extremity volume for upper extremity
- 13 mg/l extremity volume for lower extremity
Tumor necrosis factor (TNF-a) is used only for melanoma metastases with tumor size > 2 cm in diameter. TNF leads to selective endothelial damage to tumor veins and conserves normal ones. The medication is very toxic when given systemically and can lead to septic shock.
Dosage for both upper and lower extremity:
- 2–4 mg per perfusion regardless of extremity
Hyperthermia increases the toxicity effect of both melfalan and TNF.
Temperatures over 41°C lead to high regional toxicity, therefore mild hyperthermia with temperatures between 38.5-39.5°C are used.
- Vascular and neurological status must be assessed carefully.
- The volume of the extremity is calculated.
- The procedure is carried out under general anesthesia.
- Supine position with good access to the extremity to be treated.
ILP can be carried out via the following veins:
- Upper extremity:
- Axillary vein
- Brachial vein
- Lower extremity:
- External iliac vein
- Femoral vein
- Popliteal vein
Iliac access is used often for lower limb perfusions.
- A diagonal incision is made across the iliacal fossa.
- The fascia and muscles are cut.
- Dissection down to the external iliac veins.
- Vascular control is secured proximally and distally with vessel loop.
- The side branches are ligated.
- Anticoagulation with heparin is administered.
- Venous and arterial cannulas are inserted.
- A tourniquet is placed proximally on the thigh.
- Temperature probes are inserted in the extremity both in subcutaneous tissue and in the muscle distally and proximally.
- The cannulas are connected to the heart/lung machine.
- Perfusion is maintained at 400–500 ml/min for lower extremity and 150–300 ml/min for upper extremity.
- For large melanoma metastases TNF is added to the perfusion and circulated for 30 minutes.
- The perfusion is heated to 38.5–39.5°C.
- Melfalan is added.
- The duration of the perfusion with melfalan is 60 minutes. Total duration of the entire perfusion when TNF is added to melfalan is 90 minutes.
Monitoring of leakage
- Potential leakage is measured with radioactive-labeled albumin, which is injected into the perfusate.
- A gamma detector is placed over the heart.
- Radioactivity in perpheral plasma is monitored continually with specialized software.
- For leakage > 10 %, it must be decided whether the perfusion should be interrupted due to risk of systemic toxicity.
Completion of ILP
- The drug perfusion is stopped and the extremity is perfused with 3-5 L Macrodex.
- The pump is turned off and the tourniquet and cannula removed.
- The veins are sutured and the circulation is reestablished in the extremity.
- The incision is closed.
The patient is mobilized from the first postoperative day.
Normal postoperative stay is 3 to 7 days depending on side effects and/or complications.
Local side effects
Side effects are graded according to the Wieberdink's classification:
Mild edema and/or erythema
Prominent edema and/or erythema with blisters and some limited movement.
Comprehensive epidermolysis and/or visible damage to deep tissue leading to limited function,
threatening or developed compartmental syndrome.
Reaction requires amputation.
- Mild side effects develop usually after 2 to 3 days after ILP in 90% of patients. Moderate to serious side effects involve 25 to 40 % of patients.
- Extremity-threatening complications with serious tissue damage and edema occur in less than 10 % of patients. In rare cases, amputation is necessary.
Most side effects after ILP treatment spontaneously regress after 2 to 3 weeks.
Vascular complications such as thrombosis after arteriotomy occur in about 2.5 %. The incidence of DVT is about 10 % despite heparinization during the treatment. Nerve toxicity manifests itself as pain or paresthesia 2 to 3 weeks after treatment in 25 to 40 % of patients. These usually regress within a few months. Long-term neuropathy occurs more rarely.
Systemic side effects
Most systemic side effects are caused by leakage from the perfusion fluid to the circulation system during treatment. Despite complete isolation and thorough rinsing afterwards, there may still be remains of medication in the tissue or in intravascular components which can spread to the entire body when circulation is reestablished.
Systemic toxicity from melfalan perfusion is limited if the systemic leakage does not surpass 10%.
Systemic leakage of TNF can lead to serious cardiovascular, metabolic, and hematological complications.
The patient is checked clinically every other week for 3 months. Thereafter every third month for 1 year. Follow-up with MRI of the extremity is performed after 4 and 8 weeks and only when a large volume is involved.
For partial remission or locoregional relapse, new ILP treatment should be considered.