title: A randomised trial of secondary prophylaxis using granulocyte colony-stimulating factor ('SPROG' trial) for maintaining dose intensity of standard adjuvant chemotherapy for breast cancer by the Anglo-Celtic Cooperative Group and NCRN.
abstract: BACKGROUND
  Guidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI.
  
  
  METHODS
  Adult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups.
  
  
  RESULTS
  Most regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF.
  
  
  CONCLUSIONS
  Secondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.
authors.affiliation: Department of Surgery and Cancer, Imperial College, London.
authors.forename: R C F
authors.initials: RC
authors.lastname: Leonard
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas' Hospital and King's College London Biomedical Research Centre, London janine.mansi@gstt.nhs.uk.
authors.forename: J L
authors.initials: JL
authors.lastname: Mansi
authors.affiliation: Quantics Consulting Ltd, Edinburgh.
authors.forename: C
authors.initials: C
authors.lastname: Keerie
authors.affiliation: Quantics Consulting Ltd, Edinburgh.
authors.forename: A
authors.initials: A
authors.lastname: Yellowlees
authors.affiliation: Scottish Clinical Trials Research Unit, NHS National Services Scotland, Edinburgh.
authors.forename: S
authors.initials: S
authors.lastname: Crawford
authors.affiliation: Gloucestershire Centre for Clinical Oncology, Cheltenham General Hospital, Cheltenham.
authors.forename: K
authors.initials: K
authors.lastname: Benstead
authors.affiliation: Oncology Department, Northampton General Hospital NHS Trust, Northampton.
authors.forename: R
authors.initials: R
authors.lastname: Matthew
authors.affiliation: Ninewells Hospital and Medical School, Dundee.
authors.forename: D
authors.initials: D
authors.lastname: Adamson
authors.affiliation: Department of Clinical Oncology, Nottingham City Hospital, Nottingham.
authors.forename: S
authors.initials: S
authors.lastname: Chan
authors.affiliation: Arden Cancer Centre, University Hospital, Coventry, UK.
authors.forename: R
authors.initials: R
authors.lastname: Grieve
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D000069585:Filgrastim / Q000008:administration & dosage*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D055502:Secondary Prevention / Q000379:methods*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim
keywords: adjuvant chemotherapy; dose intensity; early breast cancer; growth factors; neutropaenia