title: A randomised phase 2 trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor-prognosis germ cell tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604).
abstract: BACKGROUND
  Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required.
  
  
  OBJECTIVE
  To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial.
  
  
  METHODS
  We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres.
  
  
  METHODS
  BEP (bleomycin 30,000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15,000 IU).
  
  
  METHODS
  Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates.
  
  
  CONCLUSIONS
  A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS.
  
  
  CONCLUSIONS
  The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial.
  
  
  RESULTS
  In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration.
  
  
  BACKGROUND
  ISRCTN53643604; http://www.controlled-trials.com/ISRCTN53643604.
authors.affiliation: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, UK. Electronic address: robert.huddart@icr.ac.uk.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Huddart
authors.affiliation: Medical Research Council Clinical Trials Unit, London, UK.
authors.forename: Rhian
authors.initials: R
authors.lastname: Gabe
authors.affiliation: Medical Research Council Clinical Trials Unit, London, UK.
authors.forename: Fay H
authors.initials: FH
authors.lastname: Cafferty
authors.affiliation: Medical Research Council Clinical Trials Unit, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Pollock
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: White
authors.affiliation: St. Bartholomew's Hospital, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shamash
authors.affiliation: University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cullen
authors.affiliation: Medical Research Council Clinical Trials Unit, London, UK.
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stenning
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001761:Bleomycin / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D005047:Etoposide / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D001761:Bleomycin; D014750:Vincristine; D005047:Etoposide; D016190:Carboplatin; D002945:Cisplatin
keywords: Metastatic germ cell tumour; Poor prognosis; Randomised trial