Here, we present a protocol how to perform an isolated liver perfusion (IHP) with melphalan and we also discuss IHP as a treatment option for liver metastases of uveal melanoma.
Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation.
In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.
Uveal melanoma is the most common primary intraocular malignancy in adults, with the incidence being highest in Caucasian populations 1. Local treatment consists of enucleation or local plaque radiation therapy 2,3. Irrespective of local treatment, metastatic disease will ultimately develop in about 35-50% of the patients 4,5. The liver is the most common site of metastases and approximately 50% of the patients present with isolated liver metastases. The median overall survival (OS) for patients with liver metastases is 6-12 months 4. Several different systemic and regional treatment strategies have been explored, but survival rates have not improved 2.
Treatment with systemic chemotherapy, both single substance (Dacarbazine or Temozolomide6) or combination treatments (BOLD regimen7, gemcitabine with treosulfan 8), shows response rates of less then 10 %. Hepatic intra-arterial chemotherapy (HIA) has shown a slightly higher overall response rate compared to systemic chemotherapy, but no increase in overall survival 9. Transarterial chemoembolization (TACE) with cisplatin and carboplatin showed a partial response in 57% of patients with a median survival of 9 months10. Selective internal radiation therapy (SIRT) has shown a partial response in 62% of patients with a median survival of 7 months 11. In a study on liver resection, including 255 patients, an overall survival of 14 months was reported; in 76 of the patients where a microscopically complete resection was possible, the survival was 27 months 12.
Isolated hepatic perfusion (IHP) is a regional treatment option, originally developed by Ryan and Ausman. The rationale behind the technique is to surgically isolate and perfuse the liver with a high dose of a chemotherapeutic agent while avoiding systemic toxicity 13. In addition, concurrent hyperthermia mediates an increased uptake of the chemotherapeutic agent by changes in tumor blood flow and cellular membrane permeability 14. Complete vascular isolation is confirmed with a radioactive tracer technique using Tc-99 labeled human serum albumin 15. A retrospective phase II study has shown a potential survival benefit of 14 months (26 vs. 12 months) for patients that underwent IHP compared to the longest survivors with uveal melanoma liver metastases in Sweden 16.
Here we present the technique of IHP with a short review of current results and future perspectives.
Patients provided written informed consent and the study was approved by the Regional Ethical Review Board at the University of Gothenburg.
1. Anesthesia
2. Isolation of the Liver and Cannulation of Vessels
3. The Perfusion
4. End the Perfusion and Remove Catheters
5. Postoperative Care
An initial report included 22 patients treated with melphalan with or without TNF-alpha. The results showed an overall response rate of 62%, including two patients with CR (10%), and a median overall survival of 11 months 20. A subsequent study reported on the outcome of 29 consecutive patients treated using melphalan alone. The outcome was very similar with a 62% overall response including 10% complete response and a median survival of 12 months 21.
In a study by Rizell et al., 20 patients with uveal melanoma were included. The patients were divided into three different time eras, and the results showed a decrease in mortality from 27% to 0% due to improved patient selection and technical development 22.
The knowledge about IHP is primarily based on smaller retrospective single institution series, and the published results are listed in Table 1. In summary, the overall response rate is 33-100%, including a 0-20% complete response rate. The post-operative mortality is 6% and the median survival is 12 months.
Author | n | Type | ORR | CR | Median survival | Mortality |
Alexander et al. 2000 | 22 | IHP | 62% | 10% | 11 months | 5% |
Alexander et al. 2003 | 29 | IHP | 62% | 10% | 12 months | 0% |
Noter et al. 2003 | 8 | IHP | 50% | 0% | 10 months | 0% |
Pingpank et al. 2005 | 10 | PHP | 50% | 20% | N/A | 0% |
Rizell et al. 2008 | 27 | IHP | 70% | 7% | 13 months | 22% |
Verhoef et al. 2008 | 4 | IHHP | 100% | 0% | 9 months | 0% |
van Iersel et al. 2008 | 12 | IHP | 33% | 0% | 10 months | 0% |
van Etten et al. 2009 | 8 | IHHP | 37% | 0% | 11 months | 0% |
Weighted mean | 120 | 59% | 7% | 12 months | 6% | |
Olofsson et al. | 34 | IHP | 68% | 12% | 24 months | 0% |
Table 1: Results of isolated hepatic perfusion. Publications with clinical outcomes reported for patients with isolated liver metastases treated with different modalities of isolated hepatic perfusion. ORR = overall response rate; CR = complete response; IHP = isolated hepatic perfusion; IHHP = isolated hypoxic hepatic perfusion; PHP = percutaneous hepatic perfusion; N/A = Not available.
Figure 1: Schematic picture of the veno-venous bypass system and the perfusion system. The red line represents the catheter in the hepatic artery and the blue one represents the catheter in the caval vein. They are connected to a perfusion system consisting of an oxygenator, a roller pump and a heating unit. The black lines represent the veno-venous bypass system connected to a roller pump.
Patients with metastatic uveal melanoma have few therapeutic options. Chemotherapy 6, immunotherapy 23 and targeted therapy 24 have not been able to show improved OS. For patients with few liver metastases, liver resection is an option 12. Other treatments include hepatic intra-arterial chemotherapy (HIA) 9, transarterial chemoembolization (TACE) 25 and selective internal radiation therapy (SIRT) 26.
IHP is a major and complex surgical intervention and since the first report by Ausman there have been many developments in the surgical technique. In 2004, van Etten and colleagues reported the first clinical results using the isolated hypoxic hepatic perfusion (IHHP) technique 27. In the early 1990s, three independent groups developed a novel percutaneous hepatic perfusion (PHP) system using extracorporeal chemofiltration 28-30. No studies comparing these techniques to IHP have been performed. The reports so far do not seem to be in favor of any specific technique.
Patient selection is of high importance for this treatment. Since it is a local treatment, there should be no evidence of extrahepatic disease. Due to the risk of developing hepatic failure, no more than 50 % of the liver volume should be replaced by tumour 22. Patients should have a good performance status (ECOG 0-1) and no heart-, lung-, kidney- or liver disease that could increase the risk of severe morbidity after surgery.
In a recent phase II trial from our group, a median survival of 26 months was shown, implying a potential survival benefit of 14 months compared with a control group 16. To verify this finding, a multicenter randomized phase III trial between IHP and Best Alternative Care (BAC) has recently started in Scandinavia (the SCANDIUM trial, ClinicalTrials number: NCT01785316). The BAC treatment may include all other treatment options, either existing or experimental, with the notion that cross-over is not allowed from the BAC to IHP group. Inclusion criteria include biopsy verified liver metastases and no evidence of extra-hepatic tumor manifestations by PET-CT. The primary endpoint is overall survival at 24 months with secondary endpoints including response rate, progression-free survival and quality of life. The planned inclusion is 78 patients during 5 years.
In summary, there still exists no treatment that in phase III trials has shown any prolonged overall survival for patients with uveal melanoma liver metastases. IHP is an interesting and promising regional therapy where potential benefits in survival are currently being investigated in a randomized trial (the SCANDIUM trial).
The authors have nothing to disclose.
Lennart Wiman (photographer) is acknowledged for excellent video recording.
Wire re-inforced catethers | Medtronic Inc, Minnesota, USA | 12-18Fr | |
Stöckert S5 | Sorin Group, Mirandola, Italy | Heart-lung machine | |
Rotaflow | Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany | Centrifugal pump | |
HU 35 | Maquet cardiopulmonary AG, Hirrlingen, Germany | Heater unit | |
Flexbumin 200 g/l | Baxter Medical AB, Kista, Sweden | ||
Tribonat | Fresenius Kabi AB, Uppsala, Sweden | ||
Heparin LEO, 5000 IE/ml | LEO Pharma AB, Sweden | ||
Ringer Acetate | Baxter Medical AB, Kista, Sweden | ||
Vasculosis | Cis-Bio International, Gif-Sur-Yvette, France | 99mTc-albumin | |
MedicView | SystemData AB, Gothenburg, Sweden | Leakage monitoring system | |
Alkeran | Aspen Europe GmbH, Bad Oldesloe, Germany | melphalan |