Hyperbaric Soft Tissue Radionecrosis

Etiology

Soft tissue radionecrosis can occur in any organ or tissue that has had substantial amounts of radiation exposure usual from therapeutic procedures for treating cancer. The initial radiation damage (acute phase) to the tissue is at the DNA level, and if the damage is severe enough, the 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 the normal tissue that is in the ionizing radiation field is damaged, then undesirable changes can take place in the tissue. Initially, there is edema and inflammation in the tissue from the radiation that results in the clinical erythema. After the initial radiation-induced erythema, then the tissue may develop an obliterative endarteritis that can increase hypoxia in the tissue with tissue fibrosis. These fibrotic tissue changes are a precursor for the development of the final delayed effects of radiation therapy. The damaged tissue has a lack of normal capillaries and arterioles and increases in the stroma that give the tissue its fibrotic appearance and texture. Such tissue is hypoxic because of the farther distance of diffusion for oxygen from the red blood cells going through the decreased number of capillary beds. 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 results 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 is dependent on the amount of radiation delivered, the type of ionizing radiation and the tissue that was radiated.

Pathophysiology

The dose of the radiation exposure is usually over 5000 cGy, but it can be seen in as little as 3000 cGy. Remember that 1 rad is equal to 1 cGy. The biologic effect of radiation is to cause DNA damage, lipid peroxidation, and protein denaturation. The cells exposed to the radiation will either die or dysfunction and then undergo cellular repair. The cells that are most damaged by radiation are the more rapidly dividing cells which are found in the dermis, mucosa, and vascular tissue. Endothelial cells are particularly prone to damage which results in the fibrotic changes and the lack of normal functioning cells in the radiation-damaged tissue. The cellular sensitivity to the radiation goes from tumor cells most sensitive, then endothelium, fibroblasts, muscle, and then nerve cells.

The acute clinical phase occurs during the first 6 months after the radiation therapy, which is commonly fractionally dosed. This phase may have no gross changes in the tissue but can cause dose-dependent changes. These changes clinically can be manifested by hair loss, erythema, blistering of the skin, and ulceration of the skin. 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 a chronic pulmonary fibrosis problem. 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's sign. Most of the time this symptom will resolve without treatment, but sometime the symptoms may persist 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 the soft tissue damage follows the principle that the cells that have a faster turnover rate or dividing at a faster rate have more sensitivity to the radiation and are more damaged than cells that are not undergoing division. Endothelial cells in the arterioles and capillary beds are particularly more sensitive to the radiation than stromal cells. This results in an obliterative endarteritis causing hypoxia in the tissue and the characteristic fibrotic changes to the stroma of the radiation damaged tissue. The arterioles may try to re-grow, but this proliferative endarteritis results in a disorganized telangiectatic growth of vascular tissue and often doesn’t provide adequate oxygenation of the tissue 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

It is important to take an adequate history and physical is determining when the radiation therapy was given, what type of ionizing radiation, and what was the accumulative dose of radiation that the tissue had received. Also, when the patient presents with a problematic wound, it is important to consider other factors that may be causing poor wound healing, for example, malnutrition, macro-vascular disease, tobacco use, diabetes, age, and repeated trauma to the tissue from shear injury and pressure. For example, a pressure ulcer in the pelvic area may not be healing not only from not offloading the tissue but also from the previous radiation therapy that the patient had for pelvic cancer. It is also important what surgical procedures have been done to the problematic wound, and one should anticipate problem wound healing in a surgical wound if the tissue has had previous radiation therapy, especially if there are fibrotic changes to the tissue.

The acute effects of radiation to soft tissues in the development of erythema, tissue edema, pigmentation changes to the skin, hair loss, and skin or mucosal ulceration. The acute effects of radiation therapy are usually self-limiting and are treated with supportive care and use of antibiotics if cellulitis infection develops because of the skin ulcerations becoming infected. Usually, the acutely damaged radiated tissue will recover within about one month with reduction of the inflammation, edema, and repair of the damaged endothelial cells. If the arterioles do not recover, then this precipitates a hypoxic environment to the tissue with fibrotic changes that can become permanent and lead to the delayed effects of radiation therapy. The delayed effects can cause wounds that are difficult to heal, and the tissue develops a progressive endarteritis and obliterative process of the arterioles which decreases the blood supply to the tissue, and the hypoxic environment causes the typical fibrotic change. Clinically the damaged skin tissue has a contracted look, woody feel to the tissue, and a waxy look to the skin. Telangiectasias are frequently seen in the surface and it is common for this skin to ulcerate with minor trauma or spontaneously. The delayed effects of radiation therapy can develop within 6 weeks to many years after the radiation therapy.

Evaluation

When evaluating a problematic wound in previously radiated tissue, it is important to determine that the problem is from soft tissue radionecrosis and not from another cause. Typically, the accumulative dose of radiation has been over 3000 cGy and more commonly is 5000 cGy. For example, a squamous cell carcinoma of the skin previously treated with 1000 cGy of radiation would be very unlikely to develop a future skin ulcer from the delayed effects of radiation therapy. More likely, in this scenario, the skin ulcer may represent a recurrence of the skin cancer and biopsy should be done.

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 from recurring cancer?

The macrovascular status, if wound in the extremities, can be evaluated with palpation of pulses, ankle brachial index, arterial duplex and angiography may be appropriate. Also, transcutaneous oxygen measurement (TCOM) can be done to assess the oxygenation of the tissue, and the TCOM should be greater than 40 mm Hg PaO2 to predict a good chance of wound healing.

Wound cultures or bacterial cultures on tissue biopsy can be helpful to target antimicrobial therapy and treatments tailored to secondary infections which are common in soft tissue radionecrosis. Often, it is difficult to determine if the tissue necrosis is from the delayed effects of radiation or secondary infection. Methicillin-resistant Staphylococcus aureus (MRSA) is especially problematic because of its pathogenicity and antimicrobial resistance. Therapy should be tailored based on the antimicrobial sensitivity.

Cancer recurrence or secondary cancers should always be considered, and there should be a low index of suspicion for doing a biopsy. Radiation therapy causes damage to DNA and can cause cell mutation and carcinogenesis.

Not all soft tissue radionecrosis is easily identified on clinical exam, and further imagining studies or procedures should be done to do adequate workup of the patient’s symptoms. For example, hemorrhagic cystitis or proctitis can be a delayed effect of radiation therapy for pelvic cancers. Evaluation of hemorrhagic cystitis and proctitis will often require cystoscopy or colonoscopy for diagnosis and further treatment. A biopsy can be done during such procedures to confirm the diagnosis and help to look for cancer recurrence or secondary cancers. Often the diagnosis can be confirmed by CT exam or MRI scanning. Demyelination of the spinal cord in the setting of delayed effects of radiation therapy and electrical pains into the lower extremity with the extension of the spine can be characteristic of soft tissue radionecrosis of the spine.

Treatment / Management

Conventional therapies for nonhealing wounds and bleeding problems as is seen in soft tissue radionecrosis are not satisfactory and many times are unsuccessful in the control of symptoms. Because the tissue is lacking in adequate vascularity to provide oxygen and nutrients for the tissue to heal, surgical interventions have a higher rate of failure, and may contribute to further tissue damage and breakdown. Radiation damaged tissue is also more prone to infection complications, especially after surgery.

Hyperbaric oxygen therapy is helpful in treating soft tissue radionecrosis by the improved oxygenation of the damaged tissue in part, but more importantly, over the course of 30 to 40 treatments usually at 2 to 3 atmospheres absolute (ATA) for 90 to 110 minutes, angiogenesis is stimulated. The new capillary beds and granulation tissue that is formed have a more robust blood supply and durable improvement in the tissue with improved oxygenation. This improvement in the tissue is clinically manifested in chronic wound healing, more elastic and less fibrotic texture of the tissue, and problems such as xerostomia (dry mouth because of lack of saliva production) resolving with hyperbaric oxygen therapy. Common sites of soft tissue radionecrosis treated with hyperbaric oxygen therapy are head and neck, breast or chest wall, pelvic organs such as bladder and rectum, but any organ or tissue that was in the radiation field can be damaged, and thus treatable with hyperbaric oxygen therapy.[9][10][11](A1)

Hyperbaric oxygen therapy, in general, has an approximately 80% response rate with an improvement of the patient’s symptoms of soft tissue radionecrosis, but the tissue never recovers to what would be considered normal tissue. Clinically what is seen is an improvement of the fibroatrophic changes of the tissue, for example, improvement of xerostomia, improve granulation of wounded tissue, reduction or resolution of hemorrhaging from ulcerated mucosal tissue, improved osteocyte functions in radiation damage bone, and improvement of the neurologic symptoms seen in radiation myelitis.

Hyperbaric oxygen therapy is helpful in treating soft tissue radionecrosis by the improved oxygenation of the damaged tissue transiently during the treatment, and after 20 to 30 treatments, angiogenesis is stimulated with the formation of new capillary beds and granulation tissue that has a more robust blood supply for wound healing. Typically, hyperbaric oxygen therapy is done at 2 to 3 ATA pressure 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 for treatment to the maximized benefit of hyperbaric oxygen therapy, but minimize the risk of oxygen seizures. It takes about 20 daily treatments to start to see clinical evidence for improved angiogenesis and improvement of the symptoms of soft tissue radionecrosis. This improvement in the tissue is clinically manifested by more elasticity to the fibrotic tissue, improved granulation of the wound bed, and improvement in xerostomia (dry mouth because of lack of saliva production). It may take 30 to 40 or more treatments before the benefits of hyperbaric oxygen therapy plateaus. Common sites of soft tissue radionecrosis needing treatment with hyperbaric oxygen therapy are head and neck, breast or chest wall, pelvic organs, such as bladder and rectum, but any organ or tissue that was in the radiation field can be damaged, and thus treatable with hyperbaric oxygen therapy.  Not only clinical parameters can be followed for response to therapy, but improvement in transcutaneous oxygen measurement and florescent angiography can be followed.

Hyperbaric oxygen therapy, in general, has approximately 80% response rate with an improvement of the patient’s symptoms of soft tissue radionecrosis, but the tissue never recovers to what would be considered normal tissue. Clinically, what is seen is an improvement of the fibroatrophic changes of the tissue, for example, improvement of tissue elasticity, resolution of xerostomia, formation of granulation tissue in chronic wounds, reduction or resolution of hemorrhaging from ulcerated mucosal tissue, improved osteocyte functions in radiation damage bone, and improvement of the neurologic symptoms seen in radiation myelitis.

The risk of hyperbaric oxygen therapy includes hypoglycemia in diabetic patients, especially if taking insulin and/or hypoglycemic agents, barotrauma to the ears, pneumothorax, and oxygen toxicity seizures and rarely pulmonary oxygen toxicity. Cancer patients who have a history of having had bleomycin chemotherapy are at increased risk of pulmonary fibrosis even though the chemotherapy was administered remotely from getting the hyperbaric oxygen therapy. This has been a relative contraindication, but some physicians will treat the patient if the benefits outweigh the risk. A patient actively receiving cis-platin is at high risk of bladder toxicity if also getting hyperbaric oxygen therapy and this a contraindication. Also, a relative contraindication is if the patient has had a history of spontaneous pneumothorax with underlying lung disease with air trapping. Chest x-ray, CT scan, and Xenon washout nuclear medicine study can be done to look for blebs, pulmonary disease, pneumothorax, and air trapping. As with any procedure, the risk of the treatment must be weighed against the benefit.

There are mostly anecdotal cases and prospective studies on the benefit of the treatment of cerebral radionecrosis which is very difficult to treat with standard steroid therapy and surgery. Further study is needed in this area to make consensus statements as to the best therapy and how hyperbaric oxygen therapy should be used. From a theoretical standpoint, the use of hyperbaric oxygen therapy should be beneficial for the angiogenesis and repair of cerebral radionecrotic tissue. An interesting area that will need further research is the use of hyperbaric oxygen therapy with stem cells in the repair of the damaged tissue. It is theorized that hyperbaric oxygen therapy helps to sensitive the stem cells to seek out damaged tissue so that the stem cells they can differentiate into the cells that are most needed for the repair of the tissue.[12][13](B3)

Differential Diagnosis

The differential diagnosis of soft tissue radionecrosis should take into account of other causes of tissue necrosis. Necrotizing infections, especially Staphylococcus and Streptococcus infections can cause tissue necrosis and should be ruled out by infectious disease evaluation of the wound and deep tissue culture. Superficial wound cultures are often inadequate and result in falls negatives and isolation of organisms that may be just colonizing the wound. Arterial insufficiency ulcers and tissue necrosis from macrovascular insufficiency must be considered especially in a patient with risk factors such as smoking, hypertension and Diabetes mellitus.  Sometimes soft tissue radionecrosis presents as tissue that is at risk for hemorrhage from proliferative arteritis and telangiectasis that are more fragile and 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 damage to the bladder which occurs after flugration treatments or cauterization. Proctitis is also a delayed soft tissue radionecrosis that can result in significant rectal bleeding.  Such bleeding problems can severe enough to require repeated blood transfusion and significant morbidity. It is always important when dealing with such situation to make sure that there is not a recurrence of cancer or a secondary carcinoma or precancerous adenomatous polyp causing the bleeding. Cystoscopy or colonoscopy with biopsy is often required to rule out cancer and to confirm the diagnosis of soft tissue radionecrosis as the cause of the patient's symptoms.

Surgical Oncology

Common forms of soft tissue radionecrosis are central nervous system (CNS) radionecrosis (cerebral and myelitis of spinal cord), radiation cystitis with hemorrhage, radiation proctitis, vaginal radionecrosis and laryngeal radionecrosis. The morbidity for these patients is substantial with 50% of the patients having complications if future surgery is needed in the radiated field. Annually there are 6000 to 30,000 patients annually developing this condition in the United States. Radiation cystitis with hemorrhage can be improved in about 80% of the patients with resolution or significant reduction of the hematuria. Of the patients with resolution, the recurrence rate is about 0.12 patients per year.

Prognosis

The beneficial effects of hyperbaric oxygen therapy are sustained effects because of the robust angiogenesis that takes place in the tissue with the improved blood supply and the improved granulation of the wounded tissue. Hyperbaric oxygen therapy is most beneficial when used in combination with a good surgical technique which has been demonstrated by the extensive work done by Dr. Marx on osteoradionecrosis of the mandible and the development of the Marx protocol. He demonstrated the benefit of treating the patient with initial 20 to 30 hyperbaric oxygen treatments before reconstructive surgery or bone debridement of the jaw, with additional ten treatments to help the post-surgical tissue and grafts to heal with robust angiogenesis. In his 1993 study, he had a reduction of wound dehiscence from 48% of controls to 11% in the treated group, reduction of infection from 24% to 6% and delayed healing from 55% to 11%. About 80% of the patients with hemorrhagic cystitis from soft tissue radionecrosis will have a positive response, and their hemorrhage problems will be reduced or cease. It is recommended that if the hemorrhage problems don't improve, then repeat cystoscopy should be considered with biopsy to look for cancer recurrence.