Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

Ann Oncol. 2014 Mar;25(3):742-746. doi: 10.1093/annonc/mdt585. Epub 2014 Feb 7.

Abstract

Background: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM.

Patients and methods: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points.

Results: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths.

Conclusion: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental.

Eudract number and clinicaltrialsgov identifier: 2004-002245-12 and NCT00110123.

Keywords: chemotherapy; intra-hepatic treatment; liver metastases; uveal melanoma.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Disease-Free Survival
  • Female
  • Hepatic Artery
  • Humans
  • Infusions, Intra-Arterial
  • Liver / pathology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / secondary
  • Male
  • Melanoma / drug therapy*
  • Melanoma / mortality
  • Melanoma / pathology
  • Middle Aged
  • Nitrosourea Compounds / administration & dosage*
  • Nitrosourea Compounds / adverse effects
  • Nitrosourea Compounds / therapeutic use
  • Organophosphorus Compounds / administration & dosage*
  • Organophosphorus Compounds / adverse effects
  • Organophosphorus Compounds / therapeutic use
  • Prospective Studies
  • Survival Analysis
  • Uveal Neoplasms / drug therapy*
  • Uveal Neoplasms / mortality
  • Uveal Neoplasms / pathology
  • Young Adult

Substances

  • Antineoplastic Agents
  • Nitrosourea Compounds
  • Organophosphorus Compounds
  • fotemustine

Supplementary concepts

  • Uveal melanoma

Associated data

  • ClinicalTrials.gov/NCT00110123