title: Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.
abstract: BACKGROUND
  Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies.
  
  
  METHODS
  HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066.
  
  
  RESULTS
  Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related.
  
  
  CONCLUSIONS
  We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed.
  
  
  BACKGROUND
  Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.
authors.affiliation: Hyperbaric Medicine Unit, St Richard's Hospital, Chichester, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Glover
authors.affiliation: DDRC Healthcare, Plymouth, UK.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Smerdon
authors.affiliation: The GI Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: H Jervoise
authors.initials: HJ
authors.lastname: Andreyev
authors.affiliation: The GI Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Benton
authors.affiliation: Whipps Cross University Hospital, Leytonstone, London & East of England Hyperbaric Unit, Great Yarmouth, UK.
authors.forename: Pieter
authors.initials: P
authors.lastname: Bothma
authors.affiliation: London Diving Chamber, Hospital of St John and St Elizabeth, London, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Firth
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Lone
authors.initials: L
authors.lastname: Gothard
authors.affiliation: North West Emergency Recompression Unit, Murrayfield Hospital, Wirral, UK.
authors.forename: John
authors.initials: J
authors.lastname: Harrison
authors.affiliation: DDRC Healthcare, Plymouth, UK.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ignatescu
authors.affiliation: North of England Medical and Hyperbaric Services, Spire Hull & East Riding Hospital, Kingston-upon-Hull, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Laden
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Martin
authors.affiliation: Clinical Trials and Statistics Unit at the Institute of Cancer Research, London, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Maynard
authors.affiliation: The Diver Clinic, Poole, UK.
authors.forename: Des
authors.initials: D
authors.lastname: McCann
authors.affiliation: DDRC Healthcare, Plymouth, UK.
authors.forename: Christine E L
authors.initials: CEL
authors.lastname: Penny
authors.affiliation: The Diver Clinic, Poole, UK.
authors.forename: Spencer
authors.initials: S
authors.lastname: Phillips
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
authors.forename: Grace
authors.initials: G
authors.lastname: Sharp
authors.affiliation: Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. Electronic address: John.yarnold@icr.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Yarnold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D006471:Gastrointestinal Hemorrhage / Q000209:etiology / Q000628:therapy; D006801:Humans; D006931:Hyperbaric Oxygenation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010386:Pelvic Neoplasms / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000209:etiology / Q000628:therapy*; D011878:Radiotherapy / Q000009:adverse effects; D012007:Rectum; D011795:Surveys and Questionnaires; D063189:Symptom Assessment