title: Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
abstract: BACKGROUND
  Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone.
  
  
  METHODS
  This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820.
  
  
  RESULTS
  Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13%] vs 85 [corrected] [12%]), joint pain (41 [corrected] [6%] vs 38 [5%]), infection (31 [5%] vs 23 [corrected] [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]).
  
  
  CONCLUSIONS
  Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions.
  
  
  BACKGROUND
  Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022).
authors: Velindre Cancer Centre, Velindre Hospital, Cardiff, UK.
authors: Peter
authors: P
authors: Barrett-Lee
authors: Wales Cancer Trials Unit, Cardiff University, Cardiff, UK. Electronic address: casbardac@cardiff.ac.uk.
authors: Angela
authors: A
authors: Casbard
authors: Velindre Cancer Centre, Velindre Hospital, Cardiff, UK.
authors: Jacinta
authors: J
authors: Abraham
authors: South East Wales Trials Unit, Cardiff University, Cardiff, UK.
authors: Kerenza
authors: K
authors: Hood
authors: Cancer Research UK/Yorkshire Cancer Research Sheffield Cancer Research Centre, Weston Park Hospital, Sheffield, UK.
authors: Robert
authors: R
authors: Coleman
authors: Cancer Research UK Clinical Unit, Southampton General Hospital, Southampton, UK.
authors: Peter
authors: P
authors: Simmonds
authors: Wales Cancer Trials Unit, Cardiff University, Cardiff, UK.
authors: Hayley
authors: H
authors: Timmins
authors: Royal Cornwall Hospitals NHS Trust, Truro, UK.
authors: Duncan
authors: D
authors: Wheatley
authors: Arden Cancer Centre, University Hospitals Coventry & Warwickshire, Coventry, UK.
authors: Robert
authors: R
authors: Grieve
authors: Wales Cancer Trials Unit, Cardiff University, Cardiff, UK.
authors: Gareth
authors: G
authors: Griffiths
authors: Royal Adelaide Hospital, Adelaide, SA, Australia.
authors: Nick
authors: N
authors: Murray
mesh_terms: D000284:Administration, Oral; D000368:Aged; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D000077557:Ibandronic Acid; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000077557:Ibandronic Acid