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
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.
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.
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.
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.
Bakker, DJ, Rijkmans BG: Hyperbaric oxygen in the treatment of radiation induced hemorrhagic cystitis, A report on 10 cases. In: Schmutz J, and Bakker DJ, eds: Proceedings of the Second Swiss Symposium on Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1989.
Beehner MR, Marx RE: Hyperbaric oxygen induced angiogenesis and fibroplasia in human irradiated tissues. In: Proceedings of the 65th Meeting of the American Association of Oral and Maxillofacial Surgery. Rosemont: AAOMS; 1983:78-79.
Charneau J, Bouachour G, Person B, et al.: Severe hemorrhagic radiation proctitis advancing to gradual cessation with hyperbaric oxygen. Digestive Diseases and Sciences 1991; 373-375.
Chuba PJ: Hyperbaric oxygen therapy for radiation-induced brain injury in children. Cancer 1997; 80(10):2005-2012.
Davis, JC: Soft tissue radionecrosis: the role of hyperbaric oxygen. HBOT Rev 1981;2:153-170.
Del Pizzo JJ: treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen: long-term followup. J Urol 1998;160(3):731-733.
Dusoleil A: Post-radiation duodenal ulceration treated with hyperbaric oxygen. Gastroenterol Clin Biol 1994;18(2):172-174.
Favre C: Hyperbaric oxygen therapy in a case of post-total body irradiation colitis. Bone Marrow Transplant 1998;21(5):519-520.
Feldmeier JJ, Heimbach RD, Davolt DA, Brakora MJ: Hyperbaric oxygen as an adjunctive treatment for severe laryngeal necrosis: a report of nine consecutive cases. Undersea and Hyperbaric Medicine 1993;329-335.
Granick MS: Radiation-related wounds of the chest wall. Clin Plast Surg 1993;20(3):559-571.
Glassburn JR, Brady LW, Plenk HP: Hyperbaric oxygen in radiation therapy. Cancer 1977;39:751-765.
Greenwood TW, Gilchrist AG: Hyperbaric oxygen and wound healing in post irradiation head and neck surgery. Br J Surg 1971;50:394.
Greenwood TW, Gilchrist AG: Hyperbaric oxygen and wound healing in post-irradiation head and neck surgery. Br J Surg 1973;394-397.
Guy J, Schatz NJ: Hyperbaric oxygen in the treatment of radiation-induced neuropathy. Ophthalmology 1986;1083-1088.
Hart GB, Mainous EG: Treatment of radiation necrosis with HBO. Cancer 1976;2580-2585.
Hart GB, Strauss MB: Hyperbaric oxygen in the management of radiation injury. In: Schmutz, ed: Proceedings, First Swiss Symposium on Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1986.
Heimbach RD: Radiation effect on tissues. In: Davis and Hunt, eds: Problem Wounds. The Role of Oxygen. New York, NY: Elsevier; 1988:53-63.
Kindwall EP, Goldman RW: Hyperbaric Medicine Procedures. Milwaukee, WI: St Luke’s Hospital; 1988.
Knighton DR, Silver LA, Hunt TK: Regulation of wound healing angiogenesis: effect of oxygen gradients and inspired oxygen concentrations. Surgery 1981;90:262-269.
Knighton DR, Hunt TK, Schenestuhl H, et al.: Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 1983;221:1283-1287.
Knighton, DR, Oredsson S, Banda M, Hunt TK: Regulation of repair, hypoxic control of macrophage mediated angiogenesis. In: Hunt TK, Heppenstall RB, Pines I, Rovee D, eds: Soft and Hard Tissue Repair. New York, NY: Praeger; 1984:41-49.
Leber KA: Treatment of cerebral radionecrosis by hyperbaric oxygen therapy. Stereotact Funct Neurosurg 1998;70(Suppl 1):229-236.
Lee HC, Liu CS: Hyperbaric oxygen therapy in hemorrhagic radiation cystitis: a report of 20 cases. Undersea Hyperb Med 1994; 21(#):321-327.
Levenback C: Enterovesical fistula following radiotherapy for gynecologic cancer. Gynecol Oncol 1994; 52(3):296-300.
Marx RE: Osteoradionecrosis: A new concept of its pathophysiology. J Oral Maxillofac Surg 1983;48:283.
Marx RE, Ehler WG, Tayapongsak PT: Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Surg 1990;519-524.
Marx RE, Johnson RP: Problem wounds in oral and maxillofacial surgery: the role of hyperbaric oxygen. In: Davis and Hunt, eds:Problem Wounds. The Role of Oxygen. New York, NY: Elsevier; 1988:123.
Marx RE, Johnson RP: Studies in the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg 1978;379-390.
Marx RE, Kline SN: Principles and methods of osseous reconstruction. In: International Advances in Surgical Oncology. New York, NY: Alan Liss, Inc.; 1983:167-228.
Marx RE: Radiation injury to tissue. In: Kindwall RP, ed: Hyperbaric Medicine Practice. Flagstaff, AZ: Best Publishing; 1994:447-504.
Matthews R, Rajan N: Hyperbaric oxygen therapy for radiation induced hemorrhagic cystitis. J Urol 1999; 161(2):435-437.
Neovius EB, Lind MG: Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients. Head Neck 1997; 19(4):315-322.
Pomeroy BD, Keim LW: Preoperative hyperbaric oxygen therapy for radiation induced injuries. J Urol 1998; 159(5):1630-1632.
Poulton TJ, Witcofsky RL: HBOT Therapy for experimental radiation myelitis. Undersea Biomed 1985;12:453-457.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a partial scale. Lancet 1974;2:81-84.
Thorn JJ, Kallehave F: The effect of hyperbaric oxygen on irradiated oral tissues: transmucosal oxygen tension measurements. J Oral Maxillofac Surg 1997; 55(1):1103-1107.
Weiss JP, Mattei DM, Neville EC, Hanno PM: Primary treatment of radiation-induced hemorrhagic cystitis with hyperbaric oxygen: a 10 year experience. J Urol 1994;1514-1517.
Weiss JP, Neville EC: Hyperbaric oxygen: primary treatment of radiation-induced hemorrhagic cystitis. J Urol 1989;142:43-45.
Williams JA, Clark D, Dennis WA, et al.: The treatment of pelvic soft tissue radiation necrosis with hyperbaric oxygen. Am J Obstet Gynecol 1992;412-416.