Radiation is a therapeutic modality commonly used in the management of cancer. Although most patients experience some acute side effects, it is a rare and serious event when severe late side effects develop. Acute side effects during or in the immediate postirradiation period are mostly self-limiting or amenable to simple medical management. On the other hand, late side effects, occurring after this period, are slower to heal and may lead to chronic debility. For example, osteoradionecrosis is one serious late effect present in the minority of head-and-neck cancer patients treated with radiation. Although 85% of cases resolve with conservative management, the remainder become refractory and can progress to involve a more extensive area of bony and soft tissue..

In recent years, our understanding of the underlying mechanisms of late radiation-induced side effects has increased.. Although cellular depletion and tissue devascularization were originally thought of as being the predominant pathologic basis for these side effects, they represent merely a histopathologic marker for a far more complex and clinically diverse problem.. Both patient- and treatment-related factors seem to contribute to this process. It is now known that the size of the radiation treatment field, dose per treatment, and total dose are important factors that are associated with the occurrence of radiation-related side effects.. Also different tissues have various levels of tolerance to radiation damage, possibly because of the structural organization of that tissue. More specifically, tissues whose functional subunits are arranged in series tend to display a lower degree of radiation tolerance than those with parallel arrangement, because serially arranged subunits depend on the well-being of all subunits before and after them.. Patients' comorbid disease may also affect the ability to repair tissue damage caused by therapeutic radiation. Anecdotal data suggest a possible correlation between connective tissue diseases and increased radiosensitivity, though clinical evidence thus far has not conclusively confirmed any such relationship.. Recent evidence suggests a role of an impaired genomic repair capacity of radiation-induced DNA damage in some patients with severe radiation-related late side effects.

Hyperbaric oxygen therapy (HBOT) has been used in the past to assist in the repair of radiation-induced damage.. Besides improving temporarily the oxygenation of tissue and helping eradicate anaerobic bacteria, it is thought that high oxygen tension promotes neovascularization in damaged tissues of radiation-treated patients.. Studies have shown that HBOT effectively treats irradiated soft tissue necrosis and has also been used empirically to treat mandibular osteoradionecrosis, radiation cystitis, radiation proctitis, and other radiation side effects. HBOT has also been used for the other areas of problematic wound healing, such as ulcers in chronic diabetes and burns, besides its obvious role in the treatment of decompression disease.

Certain chemotherapies sensitize cells to effects of radiation through various mechanisms. Combination chemoradiotherapy plays a valuable role in tumor downstaging, increasing surgical resectability, and potentially improving long-term prognosis. However, associated with enhancing tumor response is a potentially equal sensitization of normal tissues to radiation resulting from a biologically more intense treatment. Recent data suggest that more intense therapy may prolong acute symptoms, leading to consequential late effects..

In this retrospective study, we aim to evaluate the efficacy of HBOT in the treatment of radiation-induced late side effects in a group of patients treated with radiation alone or in combination with chemotherapy.Of 105 eligible subjects, 30 had either died or were not contactable, leaving 75 who qualified for inclusion in this retrospective study. Patients answered a questionnaire documenting symptom severity before and after treatment (using Radiation Therapy Oncology Group criteria), duration of improvement, relapse incidence, and HBOT-related complications.

Results

The rate of participation was 60% (45/75). Improvement of principal presenting symptoms after HBOT was noted in 75% of head-and-neck, 100% of pelvic, and 57% of “other” subjects (median duration of response of 62, 72, and 68 weeks, respectively). Bone and bladder symptoms were most likely to benefit from HBOT (response rate, 81% and 83%, respectively). Fifty percent of subjects with soft tissue necrosis/mucous membrane side effects improved with HBOT. The low response rate of salivary (11%), neurologic (17%), laryngeal (17%), and upper gastrointestinal symptoms (22%) indicates that these were more resistant to HBOT. Relapse incidence was low (22%), and minor HBOT-related complications occurred in 31% of patients.
No serious, life-threatening complication arose from HBOT. A small number of patients experienced minor side effects. Auditory problems were most common (22%), and these ranged from hearing difficulties to ear pain during or shortly after HBOT. Only 1 patient had a serous effusion in 1 ear. No subjects in this study reported any persistent residual hearing problems. Three patients experienced visual complications: One patient developed lens swelling, and the other 2 patients experienced accelerated cataract formation. Lens swelling was short-lived, because the patient received ophthalmologic clearance to continue HBOT. Patients with accelerated cataract formation subsequently underwent surgery without additional problems. One patient suffered an episode of epistaxis, which never recurred on subsequent HBOT sessions.
Conclusion

Hyperbaric oxygen therapy is a safe and effective treatment modality offering durable relief in the management of radiation-induced osteoradionecrosis either alone or as an adjunctive treatment. Radiation soft tissue necrosis, cystitis, and proctitis also seemed to benefit from HBOT, but the present study did not have sufficient numbers to reliably predict long-term response.

Hyperbaric oxygen treatment for radiation proctitis.
Woo TC, Joseph D, Oxer H
Int J Radiat Oncol Biol Phys 1997; 38:619-22.

Abstract
PURPOSE: Our objective was to assess, retrospectively, the efficacy of hyperbaric oxygen treatment in radiation proctitis in all patients who have completed treatment for this disease at the Fremantle Hyperbaric Oxygen Unit. This unit is the only one of its kind in Western Australia. METHODS AND MATERIALS: Patients were assessed by a review of hospital records, blood bank records, and clinic review (if this was convenient), and all patients responded to a telephone survey. Patients were questioned regarding radiation proctitis symptoms and the degree to which each had improved. RESULTS: Most patients had previously been treated with radiotherapy for prostate carcinoma. Patients with proctitis mainly suffered from bleeding, diarrhoea, incontinence, and pain. In more than half of these patients, symptoms partially or completely resolved after hyperbaric oxygen treatment. CONCLUSION: Radiation-induced proctitis is a difficult clinical problem to treat and will probably become more significant with the rising incidence of diagnosis of prostate cancer. Hyperbaric Oxygen should be considered in the treatment of radiation-induced proctitis. Further prospective trials with strict protocol guidelines are warranted

Medicare Accepted Indications

Soft Tissue Radionecrosis
Pathophysiology and Hyperbaric Effects

Soft tissue radionecrosis results from damage done to non-osseous tissues by ionizing radiation during the course of radiotherapy for cancer. The introduction of super voltage radiation therapy made the cure of solid tumors of the head, neck, and pelvis a reality. The powerful beams destroy some tumor masses. But the new therapy also exacts a toll on the body. Tissues in the path of the radiation beam suffer damage.

Once the patient is exposed to the radiation beam, tissue damage begins. The layer of endothelium supplying the irradiated area starts to proliferate, resulting in a proliferative endarteritis. This proliferation, most often noted in the capillaries, continues and interferes with the normal processes of supplying blood to irradiated areas. The tissue begins to manifest ischemic changes, and may become frankly necrotic. In irradiated areas, ischemia and necrosis can occur. Ischemic tissue may survive without adequate blood supply for a long period of time, until a traumatic or infectious incident triggers the events leading to extensive tissue death. There is no spontaneous resolution from the vasculitis and the inflammation progresses after completion of the radiotherapy. Surgeons attempting repair confront numerous complications. The area surrounding the lesion is also damaged. When attempting to graft to or rotate a flap, surgeons must connect to tissues that are ischemic and hypoxic. Procedures often fail because the tissue does not heal due to ischemia.
STRN Clinical Sequence

The clinical sequence of events can be divided into four periods:

Acute clinical period (first six months):

Acute organ damage accumulates, particularly appearing early when a fractionated administration of radiation dose is used. No clinical signs may arise during the first portion of this period, or the entire period, unless tissue therapy exceeded radiation tolerance limits.

Subacute clinical period (second six months):

Recovery from acute radiation damage ends. Persistence and progression of permanent residual damage becomes evident. Clinical changes arising from deterioration of the vasculature first appear.

Chronic clinical period (second to fifth years):

Further progression of permanent residual damage occurs, with increasing chronic organ damage. The most significant problems arising during this clinical period result from chronic deterioration of the microvasculature with resulting hypoperfusion and tissue hypoxia. Such developments trigger an increasing tissue fibrosis, parenchymal degeneration, and lower resistance to complicating factors that stress the compromised tissue. The latter include infection or trauma.

Late clinical period (after five years):

Clinical developments resemble those in the chronic clinical period, but progress more slowly. The additional effects of damage from aging also impact the body. Radiation carcinogenesis can manifest during this period and physicians should be alert to signs of new cancers.

Soft tissue radionecrosis generally develops quite slowly. Very few recognizable skin, or other soft tissue changes arise during the first six to 12 months after radiation. At times, early atrophy begins, and frank ulceration may appear. Ulcerations develop during the subacute clinical period. They develop when the degree of radiation-induced vascular damage is so great that significant ischemia and tissue hypoxia occur, particularly over radionecrotic bone (see Protocol for Osteoradionecrosis). The most significant problem occurring in the subacute clinical period involves surgery. Incisions made through irradiated tissue may not heal. After the first post-irradiation year, ulcerations occur most frequently. In this phase, many ulcers lead to progressive skin necrosis. They heal with difficulty or not at all. The nature of the damage, and the lack of effective surgical procedures or medical therapy to reverse it, makes managing irradiation sequelae difficult.

Treatment with hyperbaric oxygen therapy (HBOT) has remarkably changed the treatment of soft tissue necrosis disease. HBOT allow tissues and vessels to be hyperoxygenated. By providing inhaled 100 percent oxygen under pressure, the arterial PO2 is raised five to 10 times above normal. This strategy promotes healing. For example, HBOT causes a marked increase in oxygenation of oxygen depleted, and therefore, marginally viable tissue. Due to the very high oxygen concentrations achievable intravascularly with HBOT, the diffusion distance of oxygen into the tissues is increased two to three times. As a result, a much larger volume of tissue becomes oxygenated by the remaining blood vessels. The hyperoxia stimulates fibroblast proliferation and collagen synthesis, which provide a matrix for the development of new blood vessels into the area at a faster rate than the usual.

HBOT’s main influence on tissue damaged by irradiation is angiogenesis, thereby promoting tissue healing. Beehner and Marx and Marx alone demonstrated this effect in several elaborate studies. The researchers measured transcutaneous oxygen levels, then showed that the angiogenic effect began and progressed through a repeatable, phased course.
Angiogenesis Enhanced by HBOT

Lag phase

No measurable angiogenesis marks the lag phase, but a period of preparatory collagen synthesis and early capillary budding occurs. Because capillary flow is not yet re-established, tissue oxygen levels TCP02 in subjects at sea level (breathing room air) remain unchanged. TCP02 consistently measured 30 percent (±5 percent) in the non-irradiated, control tissue until the eighth exposure to HBOT.

Growth phase

Between the 18th and 23rd hyperbaric exposures, a rapid rise in TCP02 occurs to a maximum of 82 percent (±4 percent) of non-irradiated control tissue. During this phase, visible signs of angiogenesis appear. The geometric rise occurs because of capillary budding from pre-existing vessels into adjacent tissues. Fibrous tissue forms (fibroplasia), an important sign of wound healing, and clinicians observe more organized collagen production, and with more numerous cells.

Plateau phase

During this phase, the TCP02 values level off at 80 to 85 percent of those in non-irradiated tissue. Knighton has shown that the steep oxygen gradients created in tissues drove angiogenesis through macrophage chemotaxis, and by stimulating macrophage-derived angiogenesis factor. Long-term follow-up in the plateau phase further showed the stability of the induced angiogenesis. In repeat measurements conducted yearly for up to four years after HBOT, TCP02 values remained at their elevated levels. That result demonstrated that the angiogenesis was permanent. The clinical impact of these discoveries was clear. Delays between completion of a full course of HBOT, and the performance of reconstructive surgery do not adversely effect surgical outcome.
Radiation Cystitis

A particularly debilitating soft tissue radionecrosis occurs in the bladder with hemorrhagic cystitis. Radiation cystitis should be treated as soon as recognized. Secondary infection is almost always present. None of the earlier therapies such as the intravascular instillation of formalin or silver nitrate, the systemic use of steroids or antibiotics, the hydrostatic dilatation of the bladder, or the bilateral ligation of the hypogastric arteries proved effective in studies. Hart and Strauss and Weiss and Neville all showed marked improvement of patients with radiation cystitis who underwent HBOT. Hypervascularity of the bladder wall was diminished, symptomatic relief was obtained, and clinical remissions were evident. The rationale for the use of HBOT in radiation enterocolitis and proctitis follows that of radiation cystitis.

Treatment should begin in the ischemic phase of the disease rather than in the necrotic phase. Goals of therapy include the decrease or resolution of the symptoms of diarrhea and hematochezia.

In 1948, Boden first reported radiation myelitis of the cervical spinal cord following radiation therapy for pharyngeal carcinoma. Similarly, radiation encehalopathy has been reported following radiation therapy for brain tumors. Differentiating the encephalopathy from the recurrence or extension of the initial brain tumor proves difficult, generally requiring biopsy. Normal neurons are themselves structurally fairly resistant to usual therapeutic doses of radiation. The pathology of radiation injury to the nervous system usually involves interstitial support tissue damage and microvascular endothelial injury. These insults cause thrombosis with secondary regional ischemia, an impairment to which neurons are very sensitive.

Poulton and Witcofski and Hart and Strauss reported successful results using HBOT for radiation myelitis and for radiation encephalitis. Patients with established neurological deficits did not show any response. Those treated within one year of onset of symptoms showed prompt cessation of progression of their disease, followed by some improvement. Patients with symptomatology of less than six months duration had marked improvement in function. Two patients with encephalopathy were treated with a combination of vasodilators and HBOT, and both showed a marked improvement in cerebral function.

Soft tissue radionecrosis is a complication of modern radiotherapy that is amenable to treatment with hyperbaric oxygen therapy. One of the primary mechanisms of action of radiotherapy is damage to the irradiated small blood vessels, a progressive obliterative endarteritis with fibrosis. This damage worsens over time, so ischemia of the soft tissue can develop weeks to years after the initial radiotherapy. The radiation injury produces a hypovascular area of tissue that can neither sustain nor repair itself. The damage may be overt, with spontaneous hypoxic tissue necrosis, or may be subclinical until minor trauma or surgery reveals the inability to heal. Bone is the most commonly affected tissue; skin is the most commonly affected soft tissue. Other radiosensitive soft tissues such as the rectum, bladder, and nervous system can also be damaged. Research has demonstrated that HBOT reverses hypoxia, induces the release of macrophage-derived angiogenesis factor, and promotes angiogenesis into these compromised areas (Beehner and Knighton, 1981-1983). No other therapy reverses the adverse effects of radiation.

Multiple animal and human studies support the use of HBOT for soft tissue radionecrosis. In controlled animal studies, Marx and Ehler demonstrated the neo-angiogenesis effect in rabbits, with the HBOT group showing a 600 to 900 percent increase in angiogenesis compared to the controls (p<0.001). Using a rat model, Greenwood and Gilchrist showed that HBOT reduced tissue necrosis by 60 percent in skin flaps made into previously irradiated areas. Marx and Johnson demonstrated multiple effects in their clinical study of 536 patients, confirming the angiogenic effect of HBOT through direct measurement of the oxygen tension in the irradiated zone both pre- and post-HBOT. These researchers also confirmed the changes by tissue biopsy. In a human randomized prospective study using bone graft take as a marker for angiogenesis, Marx and Kline showed that the use of HBOT increased the success rate from 66 percent in the control group to 92 percent in the HBOT group. In a randomized, prospective study of 160 irradiated patients, Marx showed that his HBOT treatment group had 11 percent wound dehiscence, compared to 48 percent for the control group (p=0.001). He also found a wound infection incidence of 6 percent in the HBOT group compared to 24 percent in the control (p=0.005), and an 11 percent incidence of delay in healing with HBOT compared to 65 percent in the control group (p=0.005). Excellent results using HBOT in radionecrosis of the bladder (Weiss), rectum (Charneau), optic chiasm (Guy), vagina (Williams), neck (Feldmeier), and chest (Hart) have also been reported.

The use of hyperbaric oxygen therapy in soft tissue radionecrosis is well supported in the medical literature. Basic science studies, controlled animal evaluations, controlled human studies, and extensive clinical experience all support the significant benefits of HBOT. We recommend that it remain an approved indication.