title: TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.
abstract: Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent.
  
  
  
  Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA.
  
  
  
  
  
  
  
  757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA.
  
  
  
  Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable.
  
  
  
  Current Controlled Trials ISRCTN12808747.
  
  
  
  This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.
authors.affiliation: Department of Oncology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.|Cancer Research Unit, University of Warwick, Coventry, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: James
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pirrie
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Pope
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Barton
authors.affiliation: Health Economics Unit, University of Birmingham, Birmingham, UK.
authors.forename: Lazaros
authors.initials: L
authors.lastname: Andronis
authors.affiliation: Health Economics Unit, University of Birmingham, Birmingham, UK.
authors.forename: Ilias
authors.initials: I
authors.lastname: Goranitis
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Collins
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: McLaren
authors.affiliation: Department of Oncology, Belfast City Hospital, Belfast, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Department of Oncology, Royal Marsden Hospital, Sutton, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Parker
authors.affiliation: Department of Oncology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Emilio
authors.initials: E
authors.lastname: Porfiri
authors.affiliation: Institute of Cancer and Genetics, Cardiff University, Cardiff, UK.|Velindre Cancer Centre, Cardiff, UK.
authors.forename: John
authors.initials: J
authors.lastname: Staffurth
authors.affiliation: Pharmacy Department, City Hospital, Birmingham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stanley
authors.affiliation: Department of Oncology, The Christie Hospital, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: Wylie
authors.affiliation: Kent Oncology Centre, Maidstone Hospital, Kent, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Beesley
authors.affiliation: Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Birtle
authors.affiliation: Department of Oncology, St James' University Hospital, Leeds, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Oncology, Royal Derby Hospital, Derby, UK.
authors.forename: Prabir
authors.initials: P
authors.lastname: Chakraborti
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Russell
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Billingham
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D003362:Cost-Benefit Analysis; D004164:Diphosphonates / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D013326:Strontium Radioisotopes / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D013326:Strontium Radioisotopes; D043823:Taxoids; C000615489:Strontium-89; D000077143:Docetaxel; D000077211:Zoledronic Acid; D011239:Prednisolone