title: 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial.
abstract: BACKGROUND
  Follicular lymphoma has been shown to be highly radiosensitive with responses to doses as low as 4 Gy in two fractions. This trial was designed to explore the dose response for follicular lymphoma comparing 4 Gy in two fractions with 24 Gy in 12 fractions
  
  
  METHODS
  FORT is a prospective randomised, unblinded, phase 3 non-inferiority study comparing radiotherapy given as 4 Gy in two fractions with a standard dose of 24 Gy in 12 fractions. Entry criteria included all patients aged over 18 years, having local radiotherapy for radical or palliative local control, with follicular lymphoma or marginal zone lymphoma, who had received no previous treatment for at least 1 month before. The primary outcome was time to local progression analysed on an intention-to-treat basis. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Radiotherapy target sites were randomised (1:1) with minimisation stratified by histology (follicular lymphoma vs marginal zone lymphoma), treatment intent (palliative or curative) and centre. This trial is registered with ClinicalTrials.gov number, NCT00310167.
  
  
  RESULTS
  299 sites were randomly assigned to 24 Gy and 315 sites to 4 Gy between April 7, 2006, and June 8, 2011, at 43 centres in the UK. After a median follow-up of 26 months (range 0·39-75·4), 91 local progressions had been recorded (21 in the 24 Gy group and 70 in the 4 Gy group). Time to local progression with 4 Gy was not non-inferior to 24 Gy (hazard ratio 3·42, 95% CI 2·09-5·55, p<0·0001). Eight (3%) of 282 patients in the 24 Gy group and four (1%) of 300 in the 4 Gy group had acute grade 3-4 toxic effects. Four (1%) patients in the 24 Gy group and four (1%) patients in the 4 Gy group had late toxic effects. Mucositis was the most common event in the 24 Gy group (two patients with acute mucositis and two with late mucositis; all grade 3) and was not reported in the 4 Gy group. The most common acute effect was pain at the site of irradiation (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3), and the most common late effect was fatigue (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3).
  
  
  CONCLUSIONS
  24 Gy in 12 fractions is the more effective radiation schedule for indolent lymphoma and should be regarded as the standard of care. However, 4 Gy remains a useful alternative for palliative treatment.
  
  
  BACKGROUND
  Cancer Research UK.
authors.affiliation: Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Electronic address: peterhoskin@nhs.net.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hoskin
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Kirkwood
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Bilyana
authors.initials: B
authors.lastname: Popova
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: Weston Park Hospital, Sheffield, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Robinson
authors.affiliation: Velindre Hospital, Cardiff, UK.
authors.forename: Eve
authors.initials: E
authors.lastname: Gallop-Evans
authors.affiliation: Kent and Canterbury Hospital, Canterbury, UK.
authors.forename: Stewart
authors.initials: S
authors.lastname: Coltart
authors.affiliation: Christie Hospital, Manchester, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Illidge
authors.affiliation: Southend General Hospital, Southend, UK.
authors.forename: Krishnaswamy
authors.initials: K
authors.lastname: Madhavan
authors.affiliation: New Cross Hospital, Wolverhampton, West Midlands, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brammer
authors.affiliation: Mount Vernon Cancer Centre, Northwood, Middlesex, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Diez
authors.affiliation: Leeds General Infirmary, Leeds, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jack
authors.affiliation: Clatterbridge Centre for Oncology, WirralI, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Syndikus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D018579:Patient Selection; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011878:Radiotherapy / Q000009:adverse effects; D011879:Radiotherapy Dosage; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom