Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial

Abstract

BackgroundUveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months).Methods/DesignThis is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography–computed tomography (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 sample size is 78 patients throughout five years.DiscussionPatients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.Trial registrationClinicalTrials.gov registration number: NCT01785316 (registered 1 February 2013). EudraCT registration number: 2013-000564-29.

The biology of uveal melanoma

“…Hepatic intra-arterial chemotherapy improves progression-free survival but not overall survival [61]. A phase II trial reveals a 14-month gain in survival [62], indicating that isolated hepatic perfusion is active on established liver metastases [63, 64]. A phase III trial is presently recruiting [62].…”

Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma

“…Isolated hepatic perfusion (IHP) techniques allow for complete vascular isolation of the liver so that high doses of cytotoxic agents can be delivered directly to the liver while minimizing systemic toxicity. IHP with melphalan has emerged as a viable treatment option for ocular melanoma, with up to 70% of patients demonstrating treatment response and median overall survival extending from 10 to 24 months . Minimally invasive percutaneous approaches to hepatic perfusion have also been developed to minimize perioperative morbidity with encouraging results .…”

“…Inclusion criteria included serum bilirubin < 2.0 mg/dL, platelet count > 150 000/L, serum creatinine < 1.5 mg/dL, and limited extrahepatic disease. Some protocols limit IHP to patients with < 50% tumor replacement in the liver . Our experience also dictates that the volume of hepatic disease predicts response and ability to tolerate the therapy .…”

“…Some protocols limit IHP to patients with < 50% tumor replacement in the liver. 13,16 Our experience also dictates that the volume of hepatic disease predicts response and ability to tolerate the therapy. 27 Most patients thought to be potential candidates for IHP are taken to the operating room for exploration for extrahepatic disease, intraoperative biopsy to evaluate for fibrosis, steatosis, cirrhosis or sinusoid liver congestion of unaffected liver, and to grossly evaluate the color and consistency of the liver intraoperatively.…”

“…8 Isolated hepatic perfusion (IHP) is a surgical procedure that allows for complete isolation of the liver to allow administration of high doses of chemotherapy to be delivered directly to liver metastases while limiting systemic toxicity. 9 Numerous studies have evaluated IHP with the drug melphalan for ocular melanoma with encouraging results [10][11][12][13][14][15][16][17][18][19] Unfortunately, this is a complex procedure associated with significant morbidity and potential for liver toxicity. As a result, a number of patients are not candidates for the procedure due to existing hepatic dysfunction or large volume of disease, leaving them with few treatment options.…”