Isolated hypoxic hepatic perfusion with melphalan in patients with irresectable ocular melanoma metastases

Abstract

Aim

Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metastatic disease in 80% of patients. Until now there has been no standard treatment available and these patients have a very poor prognosis (median survival 2–5 months). Isolated hepatic perfusion may be an option in patients with irresectable hepatic ocular melanoma metastases. The aim of this study was to evaluate applicability, toxicity and response in this selected group of ocular melanoma patients by treatment with isolated hypoxic hepatic perfusion with retrograde outflow (IHHP) with melphalan.

Methods

From September 2002 until July 2006 eight consecutive patients were included in this study. IHHP was performed with inflow via the hepatic artery and retrograde outflow via the portal vein during 25 min with 1 mg/kg melphalan. The perfusion was followed by a complete wash-out procedure.

Results

The median total operation time was 4 h with a median blood/fluid loss of 1100 ml. No postoperative mortality was observed. Median hospital stay was 9.5 days. Toxicity was moderate: WHO grade 3 leukocytopenia in 3 patients, grade 3 hepatic toxicity in 1 patient. In 37% of patients (3/8) a partial response could be demonstrated 3 months after IHHP. Stable disease was found in 3 patients and progressive disease in 2 patients. Median time to local progression was 6 months and the median survival was 11 months.

Conclusion

Melphalan-based IHHP with retrograde outflow is a safe treatment option for patients with irresectable ocular melanoma metastases. Survival benefit seems to be comparable to classical IHHP.

Introduction

Ocular melanoma is the most common (90%) primary intraocular malignancy in adults.¹ The incidence of uveal melanoma is reported to be 0.78 per 100,000 each year and has been stable during a long period in contrast with the marked increase in incidence of cutaneous melanoma.² Five-year survival rates range from 84% in small tumours to 47% in large tumours.³ After primary diagnosis approximately 40% to 60% of patients will ultimately develop metastases.⁴ In the case of metastases, survival is poor with median survival of 2–7 months.5, 6

There are no standard treatment options for this group of patients at this moment. Chemotherapeutic treatment often consists of dacarbazine (DTIC) in combination with other agents and studies based on these regimens reported poor results. Most regimens demonstrate response rates of 1–5% with survival rates no longer than the natural history.6, 7 Several groups have studied the use of chemotherapy in combination with immunotherapeutic agents like interferon. These studies showed increased toxicity with response rates of 0–15% without evidence of an impact on survival in a randomized trial.8, 9

Hepatic metastases are the sole site of metastases in about 70–80% of ocular melanomas cases. In the absence of effective systemic therapy this justifies the exploration of locoregional treatments.5, 6, 10 Surgery can only be performed in selected cases since most patients (>80%) have diffuse metastases. In highly selected patients in whom a R0 liver resection can be performed, survival rates ranging from 20 to 39 months11, 12, 13 have been observed. Since most patients do not have resectable tumours locoregional treatments, other than surgery, may be effective in this group of patients. Intrahepatic artery chemotherapy and chemoembolization has been explored in phase I/II studies, demonstrating response rates of 16–36%.14, 15, 16 Most regimens use cisplatin or fotemustine. Clinical feasibility was limited by dose limiting systemic toxicity, especially for cisplatin. Hepatic artery infusion (HAI) with fotemustine showed promising results in a large series of 101 patients.¹⁵ This study reported a response rate of 36% with a median survival of 15 months.

Isolated hepatic perfusion (IHP) is the modality that can expose tumours in the liver to the highest local concentrations of chemotherapeutic agents, whilst avoiding serious systemic adverse effects. IHP is already performed in several institutes worldwide in phase I and II studies with acceptable toxicity and morbidity.17, 18, 19, 20 Most of these patients have liver metastases of colorectal carcinoma origin. Earlier reports on IHP in selected melanoma patients were promising with respect to response rates.21, 22, 23, 24, 25 However, IHP is a major, expensive and complex surgical intervention, which until now was performed in patients only as a palliative treatment option. We recently reported our new perfusion technique with isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow.26, 27 It is easier to perform, less time consuming and less expensive and with less morbidity and mortality than the “classical” IHP. The major difference between this new technique and the classical IHP is that veno-venous bypass and the heart–lung machine is not required. It exposes the liver to a short period of hypoxia and the drainage of the liver is retrograde through the portal vein. We performed this IHHP with melphalan in a series of patients with ocular melanoma liver metastases. Here we present the results of the first 8 patients treated with this technique in our institute with a minimal follow-up of 1 year.