Minimally Invasive Isolated Limb Perfusion (MI-ILP) for Locally Advanced Melanomas and Sarcomas of the Extremity

Podsumowanie

This protocol presents a step-by-step guide for performing minimally invasive isolated limb perfusion (MI-ILP), a treatment option for patients with locally advanced melanomas and sarcomas of the extremities.

Streszczenie

Minimally invasive isolated limb perfusion (MI-ILP) is a treatment option for patients with locally advanced melanomas and sarcomas of the extremities. Briefly, the procedure starts with percutaneous access of the femoral or brachial vessels in the diseased extremity. It is then isolated from the rest of the body with a tourniquet. The catheters are connected to a heart-lung machine, and the extremity is perfused with a high dose of melphalan. In the literature, the reported overall and complete response rates for ILP are approximately 80% and 60%, respectively. Our previously reported results using MI-ILP, showed similar response rates. The objective of this manuscript is to provide a step-by-step guide on how to perform an MI-ILP. The purpose of this protocol is to enable local perfusion of the extremities with a high dose of chemotherapy without systemic leakage in a minimally invasive manner.

Wprowadzenie

The global incidence of melanoma is increasing and is particularly pronounced in the Western population, where one out of every 50 individuals will develop melanoma¹. Patients with cutaneous melanoma can develop in-transit metastasis (ITM), most often localized to the limb². These metastatic deposits appear as discrete tumor nodules within the subcutaneous or cutaneous tissue and arise between the primary melanoma site and the nearest regional lymph node basin. A compelling hypothesis implies that ITM develops after the entrapment and subsequent proliferation of tumor cell emboli in dermal lymphatic vessels between the primary tumor location and regional lymph nodules³. Surgical resection is an option for those patients with limited ITM, but when the tumor load is more extensive or when it is rapidly recurring, isolated limb perfusion (ILP) is an option.

ILP is an extremely effective regional treatment for advanced tumors but likely has no influence on the development of metastatic disease outside of the perfused region. The introduction of this technique dates back to 1958, when Creech and Krementz first described its principles⁴. The procedure consists of the isolation of the limb from the systemic circulation, achieved through the application of a pneumatic tourniquet or an Esmarch bandage, followed by its connection to an extracorporeal heart-lung machine. This allows for regional administration of heated chemotherapy (melphalan) at concentrations that would not be possible to give systemically⁵.

A minimally invasive counterpart is isolated limb infusion (ILI), where access is gained via percutaneous insertion of arterial and venous catheters via the contralateral groin. Subsequently, chemotherapy is then infused under tourniquet isolation in an ischemic environment for a duration of 20-30 min. Across various studies, overall tumor response rates for ILI and its counterpart ILP, have ranged between 40%-90%, whereas ILP generally yields higher response rates^6,7,8,9,10. ILI offers several advantages, including the possibility of repeating it more easily, its percutaneous vascular access, and, therefore, potentially fewer adverse events, such as wound complications. Furthermore, it does not necessitate the use of an extracorporeal oxygenator.

In 2016, Sahlgrenska University Hospital developed a technique that combined both methods, minimally-invasive limb perfusion (MI-ILP), with the goal of performing isolated limb perfusion, but with the advantage of doing this in a minimally invasive setting. In this procedure, the femoral vessels are percutaneously accessed in a similar way as in ILP. In this paper, we present the technical details of the procedure, which is of special interest to clinicians who treat melanoma ITM and sarcoma.

Protokół

The protocol adheres to the guidelines established by our Institution's Human Research Ethics Committee.

1. Anesthesia

1. Induce anesthesia according to the Institute's local protocol.

2. Set up

1. Calculate the leg volume of the patient (1 day preoperative):
   1. Lay the patient supine and draw a circular baseline starting in the groin. With 5 cm intervals, mark the patient's leg down to the ankle.
   2. If there is evidence of tumor load in the foot, include foot measurements by adding the length from the heel of the patient to the end of the first toe and the end of the fifth toe.
   3. Add all measurements in a spreadsheet with an underlying calculation model that summed the calculation of cones at the predefined levels of 5 cm.
2. Place a scintillation probe above the heart of the patient to enable capturing the percentage of leakage to the systemic circulation under the perfusion period.
3. Inject a small dose of 10 MBq Tc^99m marked albumin. To calculate the biological half-time, the activity is then measured for at least 20 min.

3. Femoral access

1. Localize the superficial femoral or brachial vein using ultrasound guidance. Make a small 5 mm incision with a scalpel in the skin. Puncture the superficial artery first with a special needle (20 G, 12 cm) at approximately 15 cm below the inguinal ligament and place a 0.018" introducer guidewire.
2. Place a micro-introducer (4 French, 10 cm).
3. Remove the 0.018" introducer guidewire and the inner dilator.
4. Introduce a 0.035" exchange guidewire via the 4 French introducer and verify its position by fluoroscopy.
5. Perform adequate predilation of the entry tract with several dilators over the exchange wire.
6. After sufficient pre-dilatation, introduce a 12-14 Fr minimally invasive cannula and place it over the exchange wire into the vein. Flush the venous catheter with heparin saline. Then secure it with a skin suture.
7. Cannulate slightly proximal to the venous level, in a similar fashion, the superficial femoral artery.
8. Puncture the artery with a 20 G angiography needle and place a 0.018" introducer guidewire.
9. Remove the needle and place a 10 cm long 4 Fr mini access introducer over the wire. Remove both the guidewire and the inner dilator of the introducer.
10. Confirm vascular access by aspirating blood via the introducer, as well as, hand injection of a small dose of iodinated contrast under fluoroscopy.
11. Introduce a 0.035" exchange wire via the 4 French introducer and verify its position by fluoroscopy. Remove the introducer.
12. Place with a pre-closing technique two ProGlide sutures. Place the first one at the 10 o'clock position and the other at the 2 o'clock position. Do not tighten the sutures, but clamp the suture limbs slightly away from the puncture site.
13. Place a 10-12 Fr minimal invasive cannula over the guidewire into the superficial femoral artery.

4. Isolating the leg

1. Connect the arterial and venous catheters to the perfusion system, which consists of a heart-lung machine equipped with a pump, heat exchanger, oxygenator, and volume reservoir.
2. Isolate the limb by applying two Esmarch tourniquets around the limb, proximal to the catheters.
3. Remove the clamps from the arterial and venous cannulas to the shunt site. Start the perfusion and adjust the flow rate until a steady state level is reached, usually between 500 and 1,200 mL/min.
4. Insert three thermistors for temperature monitoring at three different locations: ingoing blood cannula, subcutaneously 15 cm above the knee joint, and subcutaneously 15 cm below the knee joint.
5. If the foot has no tumor load, isolate it by wrapping an Esmarch tourniquet around it.
6. To maintain temperature, wrap a sterile green drape around the leg to maintain temperature. Aim for a temperature of 39 C for the ingoing blood.

5. The perfusion (Figure 1)

1. Inject a high dose of 100 MBq Tc^99m marked albumin in the perfusion system. The leakage rate is now calculated by measuring the transference from this radiotracer between the systemic circulation and the circulation in the isolated limb.
2. When a steady-state of the flow is established and no leakage is present, infuse melphalan at a dose of 10 mg/L limb volume for lower limbs and 13 mg/L limb volume for upper limbs during 10 min.
3. For patients with sarcoma, bulky tumors, or re-perfusions, give TNF-alpha (1-4 mg) as a bolus dose 10-15 min before starting the melphalan infusion.
4. After melphalan infusion, continue the perfusion for another 45 min.

6. End of the perfusion and vessel closure

1. After a total perfusion time of 55 min or 65 min (in those patients treated with TNF-alpha), rinse the leg with 3 L of Ringers Acetate and massage the leg to help empty the venous reservoir.
2. Disconnect the arterial and venous catheter from the perfusion system and remove the temperature probes and the Esmarch tourniquets.
3. Remove the arterial catheter first and use the suture-mediated closure device to close the vessel.
4. Remove the venous catheter and apply pressure to the groin for 5-10 min.

7. Postoperative care

1. Extubate the patient and transfer them to the post-operative care unit for 4-6 h.
2. Give thrombosis prophylaxis with Xarelto 10 mg for 4 weeks.
3. Follow the patient up at the surgical outpatient department at 1-, 3- and 12-months post-operative to assess toxicities (according to the Wieberdink classification scale) and response rates.

Wyniki

We have previously published the results of the first six patients treated with MI-ILP (five femoral and one brachial) between June 2016 and March 2017 at Sahlgrenska University Hospital¹¹. Patients who were 18 years or older with a locally advanced tumor of the extremity that had an indication for ILP were included in the study. Patients were excluded if they had a previous lymph node dissection, current lymph node disease, or severe atherosclerosis, as this could potentially complicate percutane...

Dyskusje

Patients with ITM have a poor prognosis and their treatment remains challenging. A key factor in treating these patients is aiming for local control. In a minority of these patients, surgical excision can be used when the tumor load is limited. When patients have more extensive disease or when ITMs are rapidly recurring, surgical resection is not possible. In these patients, isolated limb perfusion is an effective treatment option, with a high overall response rate of around 80%¹⁰. Despite its hig...

Materiały

Name	Company	Catalog Number	Comments
0.018” introducer guidewire
0.035” exchange guidewire
10-12Fr BioMedicus Nextgen Pediatric Arterial cannulae.	Medtronic, Minneapolis, MN, USA	96820-110 (10Fr); 96820-112 (12Fr)
12-14 Fr BioMedicus  NextGen Pediatric Venous Cannulae	Medtronic, Minneapolis, MN, USA	96830-112 (12Fr); 96830-114 (14Fr)
Esmarch tourniquets	McKesson	16-50409
Micro-introducer, 4 Fr, 10 cm	MAK, Merit Medical, USA	MAK401	Includes: (1) Co-axial introducer/dilator pair; (2) 21G Needle; (3) Guide wire
PerClose ProGlide closure devices	Abbott	12773-02	Includes:  (1)Perclose Suture-Mediated Closure and repair device; (2) suture trimmer; (3) snared knot pusher
Special Needle (20G, 12 cm)	Mediplast AB, Sweden	662620091