title: Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy.
abstract: OBJECTIVE
  Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the beta-emitting isotope yttrium-90 ((90)Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues.
  
  
  METHODS
  We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A.
  
  
  RESULTS
  Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80).
  
  
  CONCLUSIONS
  Radioembolization with (90)Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.
authors.affiliation: Medicine Department, Institut Jules Bordet, Brussels, Belgium. alain.hendlisz@bordet.be
authors.forename: Alain
authors.initials: A
authors.lastname: Hendlisz
authors.forename: Marc
authors.initials: M
authors.lastname: Van den Eynde
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.forename: Geert
authors.initials: G
authors.lastname: Maleux
authors.forename: Bieke
authors.initials: B
authors.lastname: Lambert
authors.forename: Jaarke
authors.initials: J
authors.lastname: Vannoote
authors.forename: Katrien
authors.initials: K
authors.lastname: De Keukeleire
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.forename: Luc
authors.initials: L
authors.lastname: Defreyne
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Philippe
authors.initials: P
authors.lastname: Delatte
authors.forename: Thierry
authors.initials: T
authors.lastname: Delaunoit
authors.forename: Nicola
authors.initials: N
authors.lastname: Personeni
authors.forename: Marianne
authors.initials: M
authors.lastname: Paesmans
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
authors.forename: Patrick
authors.initials: P
authors.lastname: Flamen
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary / Q000628:therapy*; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D004621:Embolization, Therapeutic; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D007269:Injections, Intra-Arterial; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy*; D008297:Male; D008863:Microspheres; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000008:administration & dosage*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015021:Yttrium Radioisotopes; D005472:Fluorouracil