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Isolated limb perfusion (ILP) for sarcoma


Medical editor Stephan Stoldt MD
Surgeon
Oslo University Hospital

Raphael Pollock, MD, PhD
MD Anderson Cancer Center

General

Isolated limb perfusion (ILP) is a treatment in which the blood circulation of the extremity is isolated. Local treatment with chemotherapy is applied in the isolated vessels by means of a heart-lung machine. This allows for administration of doses of tumor-toxic medication which are 15- to 20-fold higher than for systemic treatment. The treatment provides an increased local effect on the tumor with minimal systemic exposure.

Today, ILP is an alternative treatment strategy for advanced soft tissue sarcoma and for regionally advanced malignant melanoma limited to an extremity. In certain cases, the treatment is given to avoid amputation. In most cases, ILP leads to necrosis and shrinking of the tumor while in other cases it leads to complete remission of the tumor. The subsequent operation may be optimized. Important nerves and vein structures may be spared and a less mutilating operation may be performed.

Indications

  • All histological types of soft tissue sarcomas and fibromatosis
  • Curative:
    • Primary inoperable tumor necessitating amputation or mutilating surgery
    • Local relapse
  • Palliative:
    • For metastatic disease at the time of diagnosis if the tumor can only be removed by mutilating surgery or amputation

Goal

  • Avoid amputation
  • Reduce the mutilating effect of the operation
  • Curative treatment 
  • Palliation

Equipment/Medications

Equipment

  • Heart-lung machine, oxygenator, and heating system
  • Gamma detector
  • Software for continuous monitoring of possible leakage.
  • Surgery tray
  • Vascular instruments
  • Temperature probe
  • Tourniquet

Drugs

Melfalan is an appropriate medication for ILP treatment due to the short half-life, low endothelial toxicity, limited cell cycle specificity, and relative linear dosage response relationship for cytotoxicity.

Optimal dosage:

  • 10 mg/l extremity volume for upper extremity
  • 13 mg/l extremity volume for lower extremity

Tumor necrosis factor (TNF-a) leads to selective endothelial damage of tumor vessels and conserves normal vessels. The medication is very toxic when given systemically and can lead to septic shock.

Dosage for both upper and lower extremities:

  • 2-4 mg per perfusion regardless of extremity

Hyperthermia

Hyperthermia increases the tumor toxic effect of both melfalan and TNF.

Temperature above 41°C leads to high regional toxicity, therefore mild hyperthermia with temperatures between 38.5°-38.9°C is used.


Preparation

  • Vascular and neurological status must be assessed precisely.
  • The volume of the extremity must be calculated.
  • The surgery is carried out under general anesthesia.
  • The patient should be in the supine position with good access to the extremity.

Implementation

Vascular access

ILP can be carried out on the following blood vessels:

  • Upper extremity
    • Axillary
    • Brachial
  • Lower extremity
    • External iliac 
    • Femoral
    • Popliteal 

Iliacal access is often used during lower extremity perfusion.

  • A diagonal incision is made over the iliac fossa.
  • Fascia and muscles are incised.
  • Retroperitoneal dissection to the external iliac artery.
  • Vascular control is ensured proximally and distally with vessel loops. 
  • The side branches are ligated.
  • Heparin is given for anticoagulation.
  • Venous and arterial cannulas are inserted.
  • Tourniquet is applied proximally on the thigh.
  • Temperature probes are inserted in the extremity both in subcutaneous tissue and distally and proximally in muscle.

Perfusion

  • The cannulas are connected to the heart/lung machine.
  • Perfusion is performed at 400-500 ml/min for lower extremities and 150-300 ml/min for upper extremities.
  • TNF is added to the perfusion circuit and circulated for 30 minutes
  • The perfusion is heated to 38.5°-39.5°C.
  • Melfalan is added.
  • The duration of the perfusion with both medications is 60 minutes. Total duration of the entire perfusion is 90 minutes.

Monitoring leakage

  • Potential leakage is measured with radioactive labelled albumin injected into the perfusion circuit.
  • A gamma detector is placed over the heart.
  • Radioactivity of peripheral plasma is monitored continuously with special software.
  • For leakage > 10% it must be decided whether perfusion should be interrupted due to increased risk for systemic toxicity.

Conclusion of ALP

  • Perfusion is interrupted and the extremity is rinsed with 3-5 l Macrodex.
  • The pump is turned off and the turniquet and cannulas removed.
  • The blood vessels are sutured and blood supply is reestablished in the extremity.
  • The incision is closed.

Follow-up

The patient is mobilized on the first postoperative day.

Normal postoperative stay is 3-7 days depending on side effects and/or complications.

Local side effects

Side effects are graded according to the Wieberdinks classification:

Wieberdinks classification

Grade Description
I No reaction
II Mild edema and/or erythema
III

Prominent edema and/or erythema with blisters and some limited movement

IV

Extensive epidermolysis and/or noticeable damage to deep tissue causing

limited function, threatening, or open compartmental syndrome

V Reaction requiring amputation

  • Mild side effects usually develop 2-3 days after ILP in >90% of patients. Moderate to serious side effect appear in 25-40% of patients.
  • Extremity-threatening complications with serious tissue damage and serious edema occur in less than 10% of patients. In rare cases, amputation is necessary.

Most side effects after ILP treatment resolve spontaneously after 2-3 weeks.

Vascular complications such as thrombosis after arteriotomy occur in about 2.5%. The incidence of DVT is approximately 10% despite use of heparin during treatment. Nerve toxicity manifests as pain or paresthesia 2-3 weeks after treatment in about 25-40% of the patients. These disappear within a few months. Long-term neuropathy is more rare.

Systemic side effects

Most systemic side effects are caused by leakage from perfusion fluid into the general circulation during treatment. Despite complete isolation and thorough rinsing, there can 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 may cause serious cardiovascular metabolic and hematological complications.

Follow-up

The patient is examined clinically every other week and with MRI of the involved extremity 4 and 8 weeks after ILP. For stable tumor size, partial or complete response, local extirpation of the tumor is planned 10-12 weeks after ILP.

In certain palliative cases, ILP is not followed by surgery.


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