Hyperbaric Soft Tissue Radionecrosis

Etiology

Soft tissue radionecrosis can occur in any organ or tissue that has had substantial amounts of radiation exposure, usually from therapeutic procedures for treating cancer. The initial radiation damage (acute phase) to tissue occurs at the DNA level, and if the damage is severe enough, cells will not be able to recover. This will lead to cell death. If these are cancer cells, this is the desired effect of the radiation, but when normal tissue in the ionizing radiation field is damaged, undesirable changes can occur in the tissue. Initially, there is edema and inflammation in the tissue from radiation, resulting in clinical erythema. After the initial radiation-induced erythema, the tissue may develop obliterative endarteritis, which can increase hypoxia and fibrosis. These fibrotic tissue changes are a precursor for the development of the final delayed effects of radiation therapy. The damaged tissue lacks normal capillaries and arterioles and shows increased stroma, which gives the tissue its fibrotic appearance and texture. Such tissue is hypoxic because of the increased distance for oxygen diffusion from the red blood cells due to a decreased number of capillaries. Not only is there a lack of normal capillary beds, but the capillaries that are present are frequently disorganized and do not provide adequate perfusion of the tissue for normal oxygenation. The proliferative endarteritis and fibrosis result in tissue that is predisposed to tissue breakdown either spontaneously or, many times, in conjunction with trauma and/or infection. These delayed soft tissue radiation changes often happen 6 months to years after the initial radiation treatments.[5][6][7][8]

Epidemiology

In the United States, there are more than 1.2 million cases of invasive cancer diagnosed yearly, and about one-half of these patients will receive radiation therapy to help manage the cancer. About 3% to 5 % of the patients who have had radiation therapy for cancer will develop delayed effects of radiation therapy, such as soft tissue radionecrosis or problems with wound healing. The risk of developing this problem depends on the amount of radiation delivered, the type of ionizing radiation, and the tissue that was irradiated.

Pathophysiology

The radiation dose is usually over 5000 cGy, but can be as low as 3000 cGy. Remember that 1 rad is equal to 1 cGy. The biological effects of radiation include DNA damage, lipid peroxidation, and protein denaturation. The cells exposed to radiation will either die or become dysfunctional, then undergo cellular repair. The cells most damaged by radiation are the more rapidly dividing cells, found in the dermis, mucosa, and vascular tissue. Endothelial cells are particularly prone to damage, resulting in fibrotic changes and a lack of normal-functioning cells in radiation-damaged tissue. Cellular sensitivity to radiation varies: tumor cells are most sensitive, followed by endothelium, fibroblasts, muscle, and nerve cells.

The acute clinical phase occurs during the first 6 months after the radiation therapy, which is commonly fractionally dosed. This phase may show no gross changes in the tissue but can still cause dose-dependent effects. These changes can clinically manifest as hair loss, erythema, blistering, and skin ulceration. Lung tissue may develop radiation-induced pneumonitis that typically occurs 2 to 3 months after radiation therapy and is considered a subacute phase phenomenon. Clinically, the pneumonitis behaves like chronic bronchitis. This may gradually resolve or evolve into chronic pulmonary fibrosis. If radiation therapy damages the spinal cord, then demyelination can occur, and clinically, this causes electrical-like shocks down the legs when the spinal column is extended. This is known as Lhermitte sign. Most of the time, this symptom resolves without treatment, but sometimes it may persist for more than 6 months and become a chronic problem. These delayed effects of radiation therapy are typically seen more than 6 months after the radiation therapy but may occur 5 or more years later. The delayed effects of radiation therapy are dependent on the tissue that has been irradiated.

The pathology behind soft tissue damage follows the principle that cells with a higher turnover rate or dividing faster are more sensitive to radiation and more damaged than cells not undergoing division. Endothelial cells in the arterioles and capillary beds are particularly more sensitive to the radiation than stromal cells. This results in obliterative endarteritis, causing hypoxia in the tissue and characteristic fibrotic changes in the stroma of the radiation-damaged tissue. The arterioles may attempt to regrow, but this proliferative endarteritis results in disorganized, telangiectatic vascular growth and often fails to provide adequate oxygenation to maintain normal function. The relatively hypoxic and fibrotic tissue is now susceptible to tissue breakdown from trauma or infection. The resulting chronic wounds are very difficult to treat, and further surgical intervention and grafting may be problematic because of the underlying lack of vascularity of the tissue.

History and Physical

An adequate history and physical examination are essential for determining when radiation therapy was administered, the type of ionizing radiation used, and the cumulative radiation dose received by the tissue. When a patient presents with a problematic wound, clinicians should also consider factors that may contribute to poor wound healing, including malnutrition, macrovascular disease, tobacco use, diabetes, age, and repeated trauma caused by shear injury or pressure. For example, a pressure ulcer in the pelvic area may fail to heal because of inadequate offloading and prior radiation therapy for pelvic cancer. Clinicians should also determine which surgical procedures have been performed on the problematic wound and anticipate impaired healing of a surgical wound in tissue previously exposed to radiation therapy, especially when fibrotic changes are present.

Acute radiation effects on soft tissues include erythema, tissue edema, changes in skin pigmentation, hair loss, and skin or mucosal ulceration. These acute effects are usually self-limited and are treated with supportive care and antibiotics if cellulitis develops after infection of skin ulcerations. Acutely damaged irradiated tissue usually recovers within about 1 month, with reduced inflammation and edema and repair of damaged endothelial cells. However, failure of the arterioles to recover precipitates a hypoxic tissue environment with potentially permanent fibrotic changes and delayed radiation effects. Delayed radiation effects can cause difficult-to-heal wounds because progressive endarteritis and obliteration of the arterioles decrease the blood supply to the tissue, and the resulting hypoxic environment causes characteristic fibrotic changes. Clinically, damaged skin tissue has a contracted appearance, a woody feel, and a waxy appearance. Telangiectasias are frequently visible on the surface, and the skin commonly ulcerates after minor trauma or spontaneously. Delayed effects of radiation therapy can develop within 6 weeks or many years after treatment.

Evaluation

When evaluating a problematic wound in previously irradiated tissue, clinicians should determine whether soft-tissue radionecrosis or another condition is causing it. Typically, the cumulative radiation dose exceeds 3000 cGy, often reaching 5000 cGy. For example, skin affected by squamous cell carcinoma and previously treated with 1000 cGy of radiation would be very unlikely to develop a future ulcer due to delayed radiation effects. In this scenario, the skin ulcer is more likely to represent recurrent skin cancer, and clinicians should perform a biopsy.

When approaching a problematic wound in radiation-damaged tissue, it is best to take a systematic approach, starting with obtaining answers to the following questions:

• Is the macrovascular supply to the tissue adequate?
• Is there an active infection and have the host factors for wound healing been addressed (proper nutrition, tobacco use cessation, reducing pressure and avoidance of repeat trauma to the tissue)?
• Is the ulceration or symptom caused by recurring cancer?

For wounds affecting an extremity, macrovascular status can be evaluated by palpation of pulses, the ankle-brachial index, arterial duplex ultrasonography, and angiography when appropriate. Additionally, transcutaneous oxygen measurement can assess tissue oxygenation. A transcutaneous oxygen measurement greater than 40 mm Hg predicts a favorable likelihood of wound healing.

Wound cultures or bacterial cultures obtained from a tissue biopsy can help target antimicrobial therapy and tailor treatment for secondary infections, which are common in soft tissue radionecrosis. Determining whether tissue necrosis results from delayed radiation effects or a secondary infection is often difficult. Methicillin-resistant Staphylococcus aureus (MRSA) is particularly problematic due to its pathogenicity and antimicrobial resistance. Therapy should be tailored based on the antimicrobial sensitivity.

Cancer recurrence or secondary cancers should always be considered, and clinicians should have a low threshold for performing a biopsy. Radiation therapy damages DNA and can cause cellular mutations and carcinogenesis. Careful evaluation is therefore necessary when new or persistent symptoms develop in previously irradiated tissue.

ot all soft tissue radionecrosis is easily identified on clinical examination, and further imaging studies or procedures should be performed to adequately evaluate the patient’s symptoms. For example, hemorrhagic cystitis or proctitis can be a delayed radiation effect after treatment of pelvic cancers. Evaluation of hemorrhagic cystitis and proctitis often requires cystoscopy or colonoscopy for diagnosis and further treatment. A biopsy can be performed during such procedures to confirm the diagnosis and evaluate for cancer recurrence or secondary cancers. CT or MRI findings can often help confirm the diagnosis. Spinal cord demyelination caused by delayed radiation effects and electric shock–like pain radiating into the lower extremities during spinal extension can indicate soft tissue radionecrosis of the spine.

Treatment / Management

Conventional therapies for nonhealing wounds and bleeding problems associated with soft tissue radionecrosis are often unsatisfactory and unsuccessful in controlling symptoms. Because the tissue lacks adequate vascularity to deliver oxygen and nutrients for healing, surgical interventions are more likely to fail and may contribute to further tissue damage and breakdown. Radiation-damaged tissue is also more prone to infectious complications, especially after a surgical procedure.

Hyperbaric oxygen therapy is helpful in treating soft-tissue radionecrosis by improving tissue oxygenation. More importantly, a course of 30 to 40 treatments, usually at 2 to 3 atmospheres absolute (ATA) for 90 to 110 minutes, stimulates angiogenesis. The new capillary beds and granulation tissue provide a more robust blood supply and durable improvement in tissue oxygenation. Clinically, these changes improve chronic wound healing, increase tissue elasticity, reduce fibrosis, and alleviate conditions such as xerostomia (dry mouth caused by decreased saliva production). Common sites of soft tissue radionecrosis treated with hyperbaric oxygen therapy include the head and neck, breast or chest wall, and pelvic organs such as the bladder and rectum. However, any organ or tissue within the radiation field can be damaged and may be treatable with hyperbaric oxygen therapy.[9][10][11](A1)

Hyperbaric oxygen therapy generally has an approximately 80% response rate, with improvement in symptoms of soft tissue radionecrosis, but the tissue never returns to normal. Clinical improvements include reduced fibroatrophic changes in the tissue, relief of xerostomia, improved granulation of wound tissue, reduction or resolution of bleeding from ulcerated mucosal tissue, improved osteocyte function in radiation-damaged bone, and improved neurologic symptoms associated with radiation myelitis.

Hyperbaric oxygen therapy transiently improves oxygenation of damaged tissue during treatment. After 20 to 30 treatments, angiogenesis is stimulated, with the formation of new capillary beds and granulation tissue that provide a more robust blood supply for wound healing. Typically, hyperbaric oxygen therapy is administered at 2 to 3 ATA for 90 to 110 minutes with 5- to 10-minute air breaks every 30 minutes to reduce the risk of oxygen toxicity. A pressure of 2.4 ATA is often chosen to maximize the benefits of hyperbaric oxygen therapy while minimizing the risk of oxygen toxicity seizures. Approximately 20 daily treatments are required before clinical evidence of improved angiogenesis and symptom relief becomes apparent. Clinical improvements include increased elasticity of fibrotic tissue, improved granulation of the wound bed, and relief of xerostomia (dry mouth caused by decreased saliva production). Benefits may plateau after 30 to 40 treatments or more. Common sites of soft tissue radionecrosis requiring treatment with hyperbaric oxygen therapy include the head and neck, breast or chest wall, and pelvic organs such as the bladder and rectum. However, any organ or tissue within the radiation field can be damaged and may be treatable with hyperbaric oxygen therapy. Clinical parameters, transcutaneous oxygen measurements, and fluorescent angiography can be used to monitor treatment response.

Hyperbaric oxygen therapy generally has an approximately 80% response rate, with improvement in symptoms of soft tissue radionecrosis, but the tissue never returns to normal. Clinical improvements include reduced fibroatrophic changes in the tissue, increased tissue elasticity, relief of xerostomia, formation of granulation tissue in chronic wounds, reduction or resolution of bleeding from ulcerated mucosal tissue, improved osteocyte function in radiation-damaged bone, and improved neurologic symptoms associated with radiation myelitis.

Risks associated with hyperbaric oxygen therapy include hypoglycemia in patients with diabetes, especially those taking insulin or hypoglycemic agents; barotrauma to the ears; pneumothorax; oxygen toxicity seizures; and, rarely, pulmonary oxygen toxicity. Patients with cancer who previously received bleomycin chemotherapy are at increased risk of pulmonary fibrosis, even when chemotherapy was administered long before hyperbaric oxygen therapy. Prior bleomycin therapy is a relative contraindication, but some clinicians may treat patients when the benefits outweigh the risks. Active cisplatin therapy is a contraindication because concurrent hyperbaric oxygen therapy increases the risk of bladder toxicity. A history of spontaneous pneumothorax with underlying lung disease and air trapping is also a relative contraindication. Chest radiography, CT, and a xenon washout nuclear medicine study can be performed to evaluate for blebs, pulmonary disease, pneumothorax, and air trapping. Clinicians must weigh the risks of treatment against the potential benefits.

Results from mostly anecdotal reports and prospective studies described the potential benefits of hyperbaric oxygen therapy for cerebral radionecrosis, which is very difficult to treat with standard corticosteroid therapy and surgical procedures. Further research is needed to develop consensus statements regarding optimal treatment and the role of hyperbaric oxygen therapy. Theoretically, hyperbaric oxygen therapy may promote angiogenesis and repair of cerebral radionecrotic tissue. The use of hyperbaric oxygen therapy with stem cells to repair damaged tissue also warrants further research. Hyperbaric oxygen therapy is theorized to sensitize stem cells to damaged tissue, allowing them to differentiate into the cell types most needed for tissue repair.[12][13](B3)

Differential Diagnosis

The differential diagnosis of soft tissue radionecrosis should include other causes of tissue necrosis. Necrotizing infections, especially Staphylococcus spp and Streptococcus spp. infections can cause tissue necrosis and should be ruled out through infectious disease evaluation of the wound and deep tissue cultures. Superficial wound cultures are often inadequate and may yield false-negative results or isolate organisms that merely colonize the wound. Arterial insufficiency ulcers and tissue necrosis from macrovascular insufficiency must be considered, especially in patients with risk factors such as smoking, hypertension, and diabetes mellitus.

Soft tissue radionecrosis may also present as tissue at risk for hemorrhage due to proliferative arteritis and fragile telangiectasias that tend to bleed. Hemorrhagic cystitis is a complication of pelvic radiation, and the delayed effects may be very difficult to treat and often lead to further bladder damage after fulguration or cauterization procedures. Proctitis is also a delayed manifestation of soft tissue radionecrosis that can result in significant rectal bleeding. Bleeding may be severe enough to require repeated blood transfusions and can cause significant morbidity. Clinicians should evaluate for recurrent cancer, secondary carcinoma, or a precancerous adenomatous polyp as the cause of bleeding. Cystoscopy or colonoscopy with biopsy is often required to rule out cancer and confirm soft tissue radionecrosis as the cause of the patient's symptoms.

Surgical Oncology

Common forms of soft tissue radionecrosis include central nervous system radionecrosis (cerebral radionecrosis and radiation myelitis of the spinal cord), radiation cystitis with hemorrhage, radiation proctitis, vaginal radionecrosis, and laryngeal radionecrosis. The morbidity associated with these conditions is substantial, with 50% of patients experiencing complications if a subsequent surgical procedure is needed in the irradiated field. Approximately 6000 to 30,000 patients develop this condition annually in the US. Radiation cystitis with hemorrhage can be improved in about 80% of patients, with resolution or significant reduction of hematuria. Among patients with resolution, the recurrence rate is about 0.12 recurrences per patient-year.

Prognosis

The beneficial effects of hyperbaric oxygen therapy are sustained because robust angiogenesis improves the blood supply and granulation of wounded tissue. Hyperbaric oxygen therapy is most beneficial when used in combination with appropriate surgical technique, as demonstrated by Marx's extensive work on osteoradionecrosis of the mandible and the development of the Marx protocol. Results from this work demonstrated the benefit of administering 20 to 30 hyperbaric oxygen treatments before reconstructive surgical procedures or jaw debridement, with an additional 10 treatments to promote healing of postoperative tissues and grafts through robust angiogenesis. Results from the 1993 study showed a reduction in wound dehiscence from 48% in the control group to 11% in the treated group, a reduction in infection from 24% to 6%, and a reduction in delayed healing from 55% to 11%. About 80% of patients with hemorrhagic cystitis due to soft-tissue radionecrosis have a favorable response, with reduced or resolved hemorrhage. If hemorrhage does not improve, clinicians should consider repeat cystoscopy with biopsy to evaluate for recurrent cancer.