title: Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  2004-002245-12 and NCT00110123.
authors: Oncology Department, University Hospital, Lausanne, Switzerland. Electronic address: serge.leyvraz@chuv.ch.
authors: S
authors: S
authors: Leyvraz
authors: Institut Curie, Paris, France.
authors: S
authors: S
authors: Piperno-Neumann
authors: EORTC Headquarters, Brussels.
authors: S
authors: S
authors: Suciu
authors: Centre du Cancer, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors: J F
authors: JF
authors: Baurain
authors: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors: M
authors: M
authors: Zdzienicki
authors: European Institute of Oncology, Milan, Italy.
authors: A
authors: A
authors: Testori
authors: Clatterbridge Centre for Oncology, Wirral, UK.
authors: E
authors: E
authors: Marshall
authors: West German Cancer Center, University of Essen Medical School, Essen, Germany.
authors: M
authors: M
authors: Scheulen
authors: University Hospital Bordeaux Saint André, Bordeaux.
authors: T
authors: T
authors: Jouary
authors: Léon-Bérard Cancer Centre, Lyon, France.
authors: S
authors: S
authors: Negrier
authors: Antwerp University Hospital, Edegem, Belgium.
authors: J B
authors: JB
authors: Vermorken
authors: Universitätsklinik Erlangen, Erlangen, Germany.
authors: E
authors: E
authors: Kaempgen
authors: Centre Jean Perrin, Clermont-Ferrand, France.
authors: X
authors: X
authors: Durando
authors: University Hospital Essen, Essen.
authors: D
authors: D
authors: Schadendorf
authors: EORTC Headquarters, Brussels.
authors: R Karra
authors: RK
authors: Gurunath
authors: Department of Hematology and Medical Oncology, Charité, CBF, Berlin, Germany.
authors: U
authors: U
authors: Keilholz
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D016019:Survival Analysis; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D055815:Young Adult; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine
keywords: chemotherapy; intra-hepatic treatment; liver metastases; uveal melanoma