The principle objective of this research is to more precisely determine the degree of benefit that hyperbaric oxygen therapy affords in the treatment of late radiation tissue injury.

The study has eight components. Seven involve evaluation of established radionecrosis at varying anatomic sites (mandible, larynx, skin, bladder, rectum, colon, and GYN). The eighth will investigate the potential of hyperbaric oxygen therapy to prevent late radiation tissue injury.

This study will also generate more precise benchmarking data as to the complications associated with hyperbaric exposure, including incidence and degree of morbidity.

Background and Rationale

Radiation therapy is a key component of the control and eradication of malignant disease. Adequate tumorcidal doses may, however, result in damage to surrounding healthy tissue.

Therapeutic radiation injuries to non-target tissues can be divided into acute, sub-acute, and delayed complications.(1) Acute injuries are considered a direct cellular toxicity, self-limiting, and in most cases successfully managed symptomatically. Sub-acute injuries are typically identifiable in only a few organ systems, e.g., radiation pneumonitis. These, too, are generally limited but occasionally evolve to late complications. Late changes may occur months or even years after completing radiotherapy.

The incidence of late radiation injury is related to both total radiation exposure(2) and the length of time a patient is out from completing radiotherapy. (1) The higher the dose, the longer the interval from exposure, the greater the risk. In many cases, resulting radionecrotic lesions seriously impair form and function, and require extensive surgical correction or repair.(3,4) Such surgery is fraught with complications, (3,4) hence the inclusion of a prophylactic hyperbaric oxygen arm.

Study Type

HORTIS has been developed as a multi-center study of international participation, involving a randomized, double blind, placebo-controlled clinical trial, with patient cross-over option.

Patient Eligibility

Patients are eligible to enter the HORTIS trial if they have a history of exposure to therapeutic radiation, and have developed clinically manifest late radiation tissue injury (HORTIS I-VII).

A separate group of patients are eligible to be enrolled if they have likewise been irradiated, have not developed clinically manifest radionecrosis, and face surgical intervention within or through a previously radiated portal (HORTIS VIII).

Patients would be considered ineligible if they are considered to be at specific risk for hyperbaric-hyperoxic related complications.

Treatment Plan

Patients will be initially randomized to receive either oxygen at 2.0 atmospheres absolute (ATA), or air at 1.0 ATA.

The therapeutic algorithm is personalized to each patient's degree of response at specific points during their course of hyperbaric exposure. The total number of exposures will vary from between 20 and 40.

Data Collection

Data are entered into a central electronic HORTIS database, accessible via the Internet. HORTIS investigators will be responsible for entering all required data.

Assessment of change, and clinical outcomes, are determined by each patient's referring/specialty physician, who will remain blinded as to the initial randomization sequence.  A Quality of Life questionnaire will compliment the clinical data by providing patient-specific impressions of the value of this therapy.

Data Analysis

All data analysis is undertaken in Columbia, South Carolina, by faculty and graduate students at the Biostatistical Department, The School of Public Health at The University of South Carolina, USA. Statistical procedures used in the analysis of data will include simple tests of two proportions (comparing the proportion that heal in the treatment and control groups); chi-square tests of independence when the outcome is classified into more than two levels, and multiple logistic regression, to adjust for other (demographic) factors when comparing the two groups.

Publication

The results of HORTIS research will be published in an English specialty journal specific to the anatomic sites/medical specialties involved. A separate paper is planned for each of the eight HORTIS arms. Papers will be submitted for publication once a mean follow-up of approximately 12-18 months has been achieved. A follow-up report will be generated at a mean follow-up of 4-5 years.

Recently results for HORTIS IV (radiation proctitis) have been published in the International Journal of  Radiation Oncology Biology Physics Vol 72; No 1, 2008.  click here The results indicate very favorable results two years after treatment with a course of HBO.

References

1. Rubin P, Casarret GW. Clinical Radiation Pathology, Vol. 1. Philadelphia, PA. W. B. Saunders, 1968:58-61.

2. Curi MM, Dib LL: Osteoradionecrosis of the jaws: a retrospective study of the background factors and treatment in 104 cases. Journal Oral Maxillofacial Surgery 1997;55:540-544.

3. Joseph DL, Shumrick DL: Risks of head and neck surgery in previously irradiated patients. Arch Otolaryn 1973;97:381-384.

4. Samuels L, Granick MS, Ramasastry S, et al: Reconstruction of radiation-induced chest wall lesions. Annals of Plastic Surgery 1993;31(5):399-405.

5. Bolis G, et al: The impact of whole abdomen radiotherapy on survival in advanced ovarian cancer patients with minimal residual disease after chemotherapy. Gynecology, Oncology 1980;39:150-154.

6. Marx RE, Ames JR: The use of hyperbaric oxygen in bony reconstruction of the irradiated and tissue-deficient patient. Journal Oral Maxillofacial Surgery 1982;41:351-357.

7. Hart GB, Mainous EG: The treatment of radionecrosis with hyperbaric oxygen. Cancer 1976;37:2580-2585.

8. Marx RE: Osteoradionecrosis: a new concept of its pathophysiology. Journal Oral Maxillofacial Surgery 1983;41:283-288.

9. Marx RE: A new concept in the treatment of osteoradionecrosis. Journal Oral Maxillofacial Surgery 1983;41:351-357.

10. Bevers RF, Bakker DJ, Kurth KH: Hyperbaric oxygen treatment for haemorrhagic radiation cystitis. Lancet 1995;346:803-805.

11. Woo TCS, Joseph D, Oxer H: Hyperbaric oxygen treatment for radiation proctitis. Int. Journal Radiation Oncology Biology Physics 1997;38(3):619-622.

12. Williams J, Clarke D, Dennis WA, et al: The treatment of pelvic soft tissue radiation necrosis with hyperbaric oxygen. American Journal Obstetrics &Gynecology 1992;167(2):412-416.

13. Feldmeier JJ, Heimbach RD, Davolt DA, et al: Hyperbaric oxygen as an adjunctive treatment for severe laryngeal necrosis: a report of nine consecutive cases. Undersea & Hyperbaric Medicine 1993;20(4):329-335.