title: A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma.
abstract: BACKGROUND
  Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5-monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of 1 mM for six or more hours, significantly enhances the efficacy of 5-FU.
  
  
  METHODS
  5-FU/FA was given as follows: days 1 and 2-FA 250 mg/m2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m2 by intravenous bolus (i.v.b.) over 15 minutes and subsequently 5-FU 400 mg/m2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g i.v.b. over 15 minutes followed by 12 g ivi over 12 hours.
  
  
  RESULTS
  Thirty patients were entered into the study. Median survival was nine months (range 1-51+ months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another.
  
  
  CONCLUSIONS
  HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.
authors.affiliation: Imperial Cancer Research Fund Medical Oncology Unit, Churchill Hospital, Oxford, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: P A
authors.initials: PA
authors.lastname: Philip
authors.forename: D J
authors.initials: DJ
authors.lastname: Propper
authors.forename: J P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: M P
authors.initials: MP
authors.lastname: Saunders
authors.forename: N P
authors.initials: NP
authors.lastname: Bates
authors.forename: M A
authors.initials: MA
authors.lastname: Taylor
authors.forename: D
authors.initials: D
authors.lastname: Madigan
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D002955:Leucovorin; D005472:Fluorouracil; D006918:Hydroxyurea