title: A randomised controlled trial of intravenous zoledronic acid in malignant pleural disease: a proof of principle pilot study.
abstract: BACKGROUND
  Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans.
  
  
  METHODS
  We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated.
  
  
  RESULTS
  Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI -4.7 to 13.0)) or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates.
  
  
  CONCLUSIONS
  This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further.
  
  
  BACKGROUND
  UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.
authors.affiliation: Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom; North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Amelia O
authors.initials: AO
authors.lastname: Clive
authors.affiliation: Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom; North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Hooper
authors.affiliation: North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Edey
authors.affiliation: North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Morley
authors.affiliation: North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Zahan-Evans
authors.affiliation: Cobalt Health, Cheltenham, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Hall
authors.affiliation: Cobalt Health, Cheltenham, United Kingdom.
authors.forename: Iain
authors.initials: I
authors.lastname: Lyburn
authors.affiliation: Department of Statistics, University of West of England, Bristol, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: White
authors.affiliation: Bristol Cancer Institute, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Braybrooke
authors.affiliation: North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Iara
authors.initials: I
authors.lastname: Sequeiros
authors.affiliation: North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lyen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Milton
authors.affiliation: Pragmatic Clinical Trials Unit, Queen Mary University of London, London, United Kingdom.
authors.forename: Brennan C
authors.initials: BC
authors.lastname: Kahan
authors.affiliation: Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom; North Bristol Lung Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Nick A
authors.initials: NA
authors.lastname: Maskell
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004417:Dyspnea / Q000150:complications; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology*; D010865:Pilot Projects; D010994:Pleura / Q000187:drug effects / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011788:Quality of Life; D012449:Safety; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid