Hyperbaric oxygen therapy for radiation-induced injury: evidence is needed
Authors: Carien L Creutzberg
Journal: The Lancet Oncology (2015)

Many patients with gynaecological cancers, colorectal cancers, and genitourinary cancers receive radiation therapy as primary or adjuvant treatment. Despite improvements in radiation techniques, a substantial subgroup of these patients have chronic radiation-induced gastrointestinal symptoms that strongly affect their daily lives. Hyperbaric oxygen therapy is one of the few treatments for patients with severe radiation-induced symptoms, which include proctitis and cystitis with bleeding. However, evidence of its efficacy is weak and is based almost solely on small retrospective studies. One randomised trial (HORTIS),1Clarke RE Tenorio LM Hussey JR et al.Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up.Int J Radiat Oncol Biol Phys. 2008; 72: 134-143Summary Full Text Full Text PDF PubMed Scopus (197) Google Scholar in which hyperbaric oxygen therapy is compared with sham treatment in 120 evaluable patients with chronic radiation-induced proctitis, included crossover of patients who had sham treatment to hyperbaric oxygen therapy shortly after completion of initial treatment. Although a significant (albeit modest) improvement on the Late Effects Normal Tissue scoring system (LENT SOMA) and on a bowel bother scale was noted in patients who received hyperbaric oxygen therapy, no data on longer-term benefit are available because of the early crossover. Results of a small, randomised study2Alvaro-Villegas JC Sobrino-Cossio S Tenorio-Tellez LC et al.Argon plasma coagulation and hyperbaric oxygen therapy in chronic radiation proctopathy, effectiveness and impact on tissue toxicity.Rev Esp Enferm Dig. 2011; 103: 576-581Crossref PubMed Scopus (11) Google Scholar of hyperbaric oxygen therapy versus argon plasma coagulation for patients with radiation proctopathy suggested a better and faster response with argon plasma coagulation than with hyperbaric oxygen. Sucralfate enemas and antibiotics are other therapies for radiation proctitis with some evidence of efficacy.3Stacey R Green JT Nonendoscopic therapies for the management of radiation-induced rectal bleeding.Curr Opin Support Palliat Care. 2013; 7: 175-182Crossref PubMed Scopus (4) Google Scholar Systematic assessment and treatment of chronic radiation-induced bowel dysfunction using a comprehensive management algorithm,4Andreyev HJ Davidson SE Gillespie C et al.Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer.Gut. 2012; 61: 179-192Crossref PubMed Scopus (192) Google Scholar has proven to be effective in a randomised trial.5Andreyev HJ Benton BE Lalji A et al.Algorithm-based management of patients with gastrointestinal symptoms in patients after pelvic radiation treatment (ORBIT): a randomised controlled trial.Lancet. 2013; 382: 2084-2092Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar This algorithm suggests the use of hyperbaric oxygen therapy for patients with rectal bleeding. However, the authors of two systematic reviews6Bennett MH Feldmeier J Hampson N et al.Hyperbaric oxygen therapy for late radiation tissue injury.Cochrane Database Syst Rev. 2012; 5 (CD005005)Crossref Scopus (157) Google Scholar, 7Hoggan BL Cameron AL Systematic review of hyperbaric oxygen therapy for the treatment of non-neurological soft tissue radiation-related injuries.Support Care Cancer. 2014; 22: 1715-1726Crossref PubMed Scopus (26) Google Scholar of hyperbaric oxygen therapy for patients with radiation-related tissue injuries concluded that evidence was too limited and that more clinical trials were needed to assess both its long-term benefit and cost-effectiveness.8Guo S Counte MA Romeis JC Hyperbaric oxygen technology: an overview of its applications, efficacy, and cost-effectiveness.Int J Technol Assess Health Care. 2003; 19: 339-346Crossref PubMed Scopus (13) Google Scholar In The Lancet Oncology, Mark Glover and colleagues9Glover M Smerdon G Andreyev HJ et al.Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial.Lancet Oncol. 2015; (published online Dec 15.)http://dx.doi.org/10.1016/S1470-2045(15)00461-1PubMed Google Scholar report the results of the randomised HOT2 trial of hyperbaric oxygen therapy versus sham treatment for patients with chronic bowel dysfunction after pelvic radiotherapy. 84 patients were randomly assigned (2:1) to receive 40 exposures of hyperbaric oxygen therapy or sham treatment in 8 weeks. With changes in the bowel component and rectal bleeding score of the Inflammatory Bowel Disease Questionnaire from baseline to 12 months after start of treatment set as the primary endpoint measures, the investigators found no evidence of a benefit from hyperbaric oxygen therapy. Mark Glover and colleagues are to be applauded for the sham-controlled study design and 12-month follow-up in what has been a long-awaited confirmatory trial of the efficacy of hyperbaric oxygen therapy in this setting. The strength of this study is the standardised analysis and treatment guided by the Royal Marsden algorithm for all included patients, ensuring that patients with other causes of bowel symptoms were excluded and given relevant treatments. This approach might have led to a highly selected study population of patients with long-lasting, difficult symptoms, but these are the typical patients who would qualify for referral for hyperbaric oxygen therapy. The negative results of the HOT2 trial are disappointing for clinicians and patients who hoped for proof of efficacy of hyperbaric oxygen therapy, a form of therapy that is often tried as a last resort. Yet the publication of negative trial results are important to avoid publication bias of efficacy and to give a compelling rationale to plan future phase 3 trials. The results are especially relevant with respect to the burden that undergoing hyperbaric oxygen therapy can be for patients (at least 6–8 weeks of daily treatments, with risk of [transient] vision changes and ear problems) and for health-care providers, given the significant cost of hyperbaric oxygen therapy. The mechanism by which hyperbaric oxygen therapy is thought to promote the repair of damaged tissue is by restoring oxygen tension, which stimulates angiogenesis and improves tissue function in chronic hypoxic, atrophic, fibrotic, and damaged mucosal tissue. One of the secondary endpoints in the HOT2 trial was photographic evidence of changes in images of rectal mucosa taken through flexible sigmoidoscopy; assessment of this endpoint would have added essential information about the degree of tissue healing and allowed a direct assessment of changes in response to hyperbaric oxygen. The question remains whether the results of the HOT2 trial should be understood as hyperbaric oxygen therapy having a transient and too weak an effect on the atrophic and vulnerable mucosa to result in measurable improvement or whether the results seem to refute the putative mechanism by which oxygen therapy is thought to promote tissue healing. The results of the HOT2 trial do, however, give compelling and urgent rationale for more well designed clinical trials of hyperbaric oxygen therapy. Random assignment of patients with chronic radiation-induced bowel dysfunction to a sham treatment is difficult, whereas a comparison of hyperbaric oxygen therapy to other treatment approaches might be more acceptable and enable larger trials. All patients with serious chronic radiation-induced bowel problems should be assessed and managed by an expert multidisciplinary team.4Andreyev HJ Davidson SE Gillespie C et al.Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer.Gut. 2012; 61: 179-192Crossref PubMed Scopus (192) Google Scholar Both symptom-related endpoints and endpoints related to tissue healing would be essential in further trials of hyperbaric oxygen therapy for radiation proctopathy, as symptoms can relapse and remit, and proof of the mechanism and degree of tissue improvement with hyperbaric oxygen therapy is needed. I declare no competing interests. Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trialWe 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. Full-Text PDF Open Access