Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

Complications of Radiotherapy
Christopher Prichard, M.D.
July 28, 2005

The history of radiation therapy really begins around the turn of the 20th century with the discovery of the x-ray tube by Röntgen in 1895. This is the famous first x-ray ever taken of Mrs. Röntgen’s hand. Just a year later was the first clinical application of the x-ray tube where the dermatologist Freund used it to treat a hairy nevus. In the early days of radiation, it was primarily used for dermatologic treatment. Some surgeons used it for application of cautery as well. In 1898, the Curies discovered radium as a radioactive element, and then really in the early 1920s the ideas of fractionation of radiotherapy came in to development.

Let’s discuss a brief review of radiation physics. Sources of radiation include both electromagnetic radiation and particle radiation. Electromagnetic radiation is generated by the accelerationof electrons to a linear accelerator, which then strikes a metal plate, usually tungsten, and emits photons of x-ray energy; and, in addition, a source of electromagnetic radiation (or gamma rays). In the head and neck, the most common gamma rays used are cobalt gamma radiation. Also, particle radiation can be used using subatomic particles, most commonly electrons, which can be accelerated to a linear accelerator. Protons are more complex because they weigh over 1800 times that of an electron, and so the equipment required to generate a proton beam is much more sophisticated so it is much more rarely used. Neutron radiotherapy is really not commonly used at all.

In addition to the characteristics of the radiation beam is the interaction of the energy with the tissue. The most common way that radiation interacts with the tissue is knownas the Compton effect, and that is that an x-ray or gamma ray which is incident upon its target tissue then transfers some of its energy into an outer electron of the atom of tissue, and this ejects what is known as the Compton electron, which then can inflict local damage and subsequent ionization on adjacent tissues. The energy that is lost goes towards ejection of the electron, and then a photon continues on with a lower energy level than the initial x-ray. But, it can go on to have subsequent Compton effects. Then the characteristics of x-rays or gamma rays which are favorable for radiotherapy and its skin-sparing properties. The Compton effect tends to be quite directional; and so the incident loss of energy at the skin tends to be minimal and decreases as you go up in increasing x-ray energy. In addition, there is a good penetration of tissue and we can predict a good dose depth of the majority of the radiation therapy with given energy beams. Typically there is good beam uniformity so there is an even distribution of the x-ray energy across the beam. This just demonstrates the principle of dose depth, that with increasing energy x-rays, you get an increased deposition at various depths; so higher energy x-rays can be used to deliver higher amounts of energy at deeper tissue levels.

In terms of radiation biology, the way that the radiation interacts with the tissue to cause cell killing is by DNA damage, and this occurs in two ways. The first is the indirect mechanism, which is the primary mechanism. The energy causes free radical formation of the oxygen and water in adjacent tissue areas, which then leads to primarily single-stranded DNA breaks. In addition, the energy can directly break the chemical bonds of DNA, causing DNA damage. Then after DNA damage, the cells undergo two types of death. In rapidly dividing cells, they undergo mitotic death, which is just basically that cells with significant DNA damage undergo cell death at the division of mitosis. If DNA damage is inflicted, the cell can institute its own programmed cell death pathways of apoptosis. It is important to note that with each dose of radiation therapy, there is a random cell kill, so a given fraction of any tumor cells will undergo death with radiation therapy. In terms of looking at a cure of a tumor, the factors that become important are the tumor size because only a fraction of the given tumor will die with each fraction of radiation, the overall radiation dose, and then the radiosensitivity of the individual cells and this is most dependent upon the oxygen status of the cells. Hypoxic tumor cells tend to be relatively radioresistant because of the inability to form free radicals and cause DNA damage. Also very important in the radiosensitivity of the cells is the stage in the cell cycle, with cells in the G2 phase being the most sensitive to radiation. In the S phase, as DNA is getting synthesized in the cell's machinery for DNA repair at its maximum, cells tend to be most resistant.

So these properties lead to what radiation therapists refer to as the four Rs: repair, reoxygenation, redistribution and repopulation. It is these principles that give way to the principle of fractionation in radiation therapy. The first “r” is repair of sublethal injury. That is, from one dose fraction of radiation to the next there is time cell to undergo repair of DNA damage that was not significant enough to cause cell death. In addition, in the interval, there is the ability for reoxygenation of cells, which previously might have been hypoxic, but that with killing of adjacent tumor cells may be better oxygenated and more susceptible to radiation. There is the ability for the cells to redistribute within the various stages of cell cycle which affects the sensitivity; and then there is the ability of the tumor to repopulate after a given fraction of cells are killed.

When you look at the complications of radiation therapy, they are really divided into acute tissue reactions and late tissue reactions. Acute tissue reactions typically occur during treatment or shortly thereafter, and they are really just related to the acute toxicity of the treatment from the radiation therapy. They generally resolve shortly after termination of the therapy, but they are significant in that they significantly affect the patient’s quality of life during the therapy, and they can become severe enough to interfere with treatment. Acute tissue reactions typically occur at sites where there are rapidly proliferating cells such as mucosal sites or skin. The late tissue reactions are defined in the literature as occurring more than 90 days after treatment. These are more often permanent and frequently irreversible complications, they tend to be more severe, and they tend to affect slowly dividing cells such as bone or cartilage as well as neurons. It is estimated that between 5 and 15% of head and neck radiotherapy patients will have late tissue complications.

So, first we will take a look at the acute tissue reactions and we will focus on the most common and usually significant, which is mucositis. There is also skin erythema or breakdown. Xerostomia is an interesting complication in that it tends to be acute as well as chronic. Taste loss, woundinfection, and fistulas are other examples of acute complications. Radiation mucositis typically beings at 1-2 weeks after the onset of radiation therapy, and a very conservative estimate is that it occurs in 80% of patients undergoing head and neck radiation. Typically, it is thought of as the four stages occurring of radiation mucositis: a inflammatory stage which presents with initial erythema, an epithelial stage in which pseudomembranes are formed, a bacterial stage in which there is Gram-negative bacilli overgrowth, and a healing stage. Trotti et al., reviewed the literature in a systematic review in patients undergoing radiation and/or chemotherapy. He thought that overall 80% of the patients developed radiation mucositis. It is significant to note that 100% of the patients who underwent accelerated fraction radiotherapy developed mucositis, and a third of these patients required hospitalization. In addition from the previous study, 11% of the patients that he reviewed actually required an alteration or a halt in their treatment due to their mucositis.

There are several modalities of treatment of radiation mucositis. The first is through direct cryoprotectants. There are also indirect protectants and antimicrobial therapy. The direct protectants are broken down into barrier agents such as sucralfate, which bonds and coats the ulcers formed from mucositis. The stimulant that we will focus on is the new free radical scavenger, amifostine, which has been shown to have some benefits as well in the treatment of radiation mucositis. The indirect protectants are divided into the growth factors, such as GCSF, which have been shown to have some benefit, but also there is concern that they may be protective for the tumor. There are the anti-inflammatory therapies and then finally the antimicrobial therapy there two are two main types of antimicrobial therapy, the broad spectrum, which consists of topical rinses such as Peridex, and then the narrow spectrum which is actually directed antibiotic therapy towards the Gram-negative bacilli that seem to overgrow in the patient who have radiation mucositis. Sutherland et al performed a meta analysis of all of the randomized control trials that have been performed for these various therapies of mucositis, and the findings were interesting. When looking at the subgroup analysis over all the randomized trials in the literature, only the narrow spectrum antibiotic lozenges, the PTA lozenges, were shown to have a statistically significant effect in the subgroup analysis. But it is notable that when looking at the patients’ perception of the severity of their mucositis, the direct cryoprotectants, such as sucralfate, were four times as efficacious in their overall evaluation of severity. From what they looked at in the literature, GCSF and the amifostine have some promising results, but it is still very early there are not really adequate trials, particularly of GCSF.

This is some data in support of the free radical scavenger amifostine. The patients were randomized to receive amifostine who were receiving concomitant chemoradiation. You will see that their outcomes were grade II mucositis at week #3 and then grade IV mucositis at week #5. There was an over 10-fold reduction in the mucositis at week #3 and week #5 as well, and these were statistically significant. Also of note in the study, the treatment duration of the patients who received amifostine was significantly lower, and this is thought to be due to a reduced number of halts of treatment due to the severity in mucositis.

So, in conclusion, for the treatment of mucositis, randomized controlled trials have not conclusively demonstrated the benefit for a specific modality. But it has suggested that sucralfate, the antibiotic lozenges, and then local care will improve patients’ symptoms. The newer therapies, with GCSF and particularly amifostine, likely add benefit; but it is still fairly early. Some more randomized trials are really needed to clarify the issue.

Another important complication is postradiation xerostomia, and this is an interesting complication. Xerostomia is a complication that is both acute and chronic. There are well documented changes in saliva that occur postradiation in patients who receive over 45 gray at radiation, they had about 10% of what their basal salivary production rate is, so there is significantly diminished salivary flow rate. The saliva is more acidic and has reduced buffering capacity, and it has less antimicrobial defenses than normal saliva would have. It has been shown that there is an alteration in the form of the oral florain these patients towards more cariogenic bacteria species, such as Strep mutans, as well as overgrowth of lactobacillus and Candida.

Xerostomia significantly alters the patient’s quality of life. It causes significant globus discomfort and pain and leads to a more significant increase in the rate of caries formation. There are more frequent oral infections and difficulty with speaking, eating, chewing, and tasting that result from the xerostomia. Pathologically, the parotid glands are most frequently involved, though all salivary glands can be involved. The xerostomia can be reversible at low doses, such as less than 30 gray. Histologically, the serous cells are more affected than the mucous cells, and long term you see acinar degeneration and interstitial fibrosis. So the treatment aside from topical symptomatic treatment, such as oral washings, topical oral gels, and frequent drinking primarily is aimed at sialagogues. And the most common sialagogue use is pilocarpine or Salagen. This is a cholinergic sialagogue. In a randomized trial by Dr. Johnson out of Pittsburgh, they showed that using 5 mg three times a day of Salagen, there was an increase in overall improvement, comfort, dryness, and speaking ability with the patients who were given the 5 mg dose of a placebo. In the 10 mg dose group, the patients really had too many significant side effects to continue with that dosage, but it is interesting to note that fewer of the patients being treated with pilocarpine 5mg withdrew due to adverse effects than in the placebo group. That definitely was not the case in the 10 mg dosage group. In addition, amifostine has been shown to provide benefit for xerostomia in head and neck radiation patients. Antonadou et al looked at patients with grade II xerostomia, which would be deemed moderate xerostomia by the patient and clinician’s estimation. At three months out and 18 months out, there was a reduction from one-third to one-sixth in the amifostine grip over controls, and this was statistically significant. So, amifostine, a free radical scavenger does appear to have significant benefit in both the treatment of mucositis as well as xerostomia.

Really, the principal treatment for xerostomia from radiation therapy is prevention. Formulating the radiotherapy dose so that the parotids can be spared that is really the best treatment there is for xerostomia. With new conformal radiotherapy techniques, such as intensity modulated radiation therapy (IMRT), this is becoming more and more possible. IMRT basically allows the delivery of an isodose of radiation over concave shapes, so it allows the radiation therapist to try to tailor the radiation therapy to the shape of the tumor and spare the adjacent parotids.

Eisbruch and Wolf et al at Michigan where they took patients who were requiring head and neck radiation in which they were able to use IMRT and spare one side of the face in terms of the parotid gland, but it would be included within the treatment portal of the other side. Then they subsequently measured the salivary production rate in these patients on the spared and treated sides after stimulated salivary flow, and you can see here that no significant difference obviously in the pretreatment. But at completion of therapy, and at three months, six months, and one year post treatment, there was significant improvement in salivary flow on the side in which the parotid was able to be spared using the IMRT protocols.

Now we will review the late tissue reactions association with radiotherapy. The late tissue reactions seem to typically again occur in cells which are slowly dividing, such as cartilage bone, neurons; and this is a list of some of the significant late term complications.

Fortunately, ocular complications, injury to the spinal cord, or brain necrosis are very, very rare late complications. Perhaps the most significant yet still relatively common complication in terms of late tissue reactions is radionecrosis either of the bone or of cartilage. That is what our patients experienced. Osteoradionecrosis by definition is an area of non-healing exposed bone in a patient with a history of radiation therapy that persists for more than three months without any evidence of tumor recurrence. By far the most common site where osteoradionecrosis occurs is in the mandible. though really any bone of the head and neck could be involved.

It is estimated throughout the literature that between as low as 1 and as high as 38% of the estimates given in patients with head and neck radiation had developed osteoradionecrosis. In this series by Howe, 100% presented with foul odor, up to three-fourths presented with exposed bone, and half had severe pain and discharge and fistulas at the time of presentation.

Osteoradionecrosis can be subdivided into a spontaneous type and a traumatic type. The spontaneous typically occurs less than two years from radiation therapy, and it is really thought to be due to just overwhelming cell killof osteocytes; whereas the traumatic type is typically much more delayed, is a mixture of cell death, and cell injury from trauma, and typically presents more than two years out. Dental extraction is the most common source of delayed trauma, which leads to traumatic osteoradionecrosis. There are several risk factors for osteoradionecrosis that are cited, including increasing dosage of radiation or radiation that is delivered by brachytherapy. It is thought that perhaps hyperfractionation of radiation leads to osteoradionecrosis. Then increasing age or history of trauma, alcohol and tobacco status, and nutritional status are risk factors as well. In addition, the primary site of the tumor and its proximity to bone are risk factors for development of osteoradionecrosis. It used to be thought that osteoradionecrosis was an infectious process, a cycle of radiation followed by trauma, followed by infection that could not be controlled. But really, the current thinking is that it is a cycle of radiation therapy causing chronic tissue hypoxia, hypovascularity of the tissue microvasculature, and hypocellularity of the tissue regions. This all leads to a diminished ability of bacteriocidal killing, a diminished ability to heal wounds and an overall metabolic demand outweighing the supply. All of these factors lead to subsequent tissue necrosis.

Histologically there is destruction of osteocytes and an absence of new osteoid or osteoblasts, and there is a thickening fibrotic process within the vessels with endarteritis. The treatment of osteoradionecrosis focuses around three aspects. One is prevention, and the mainstay of this is a thorough dental evolution. Number two is elimination of the necrotic bone due to debridement. Number three is an improvement in the vascularity of the tissue either through therapy such as hyperbaric oxygen or microvascular free flap reconstruction. It is interesting to note that infection control, which was once thought to be the mainstay, is really seen as an adjunctive therapy in the treatment of osteoradionecrosis.

The dental management of these patients requires aggressive oral hygiene. Studies done at M.D. Anderson have shown that the topical application of a 1% sodium fluoride gel significantly reduces the incidence of osteoradionecrosis. In the series by Daly at Anderson, it dropped it from 39% to 25%. Also important is the extraction of poor at-risk dentition, and the timing of the extraction is critical. It is important that extraction be done pre-radiation therapy if possible.

There is a two-fold increase in the incidence of osteoradionecrosis if extraction is performed after the radiation therapy, and there is a very high risk if extraction is performed during the radiotherapy protocol. It is important to allow adequate healing time after the extraction. In the series done by Marx, if the patients were allowed to have 21 days of healing after dental extraction it eliminated the risk of osteoradionecrosis, although this obviously must be balanced against the delay of tumor therapy: this encourages us to get rapid dental evaluations for our patients who will be candidates for radiation.

Marx described a protocol for treatment of osteoradionecrosis, which really revolves around the response to hyperbaric oxygen. It is a staging as well as treatment protocol. He described stage I osteoradionecrosis as ORN that is treated initially with 30 divesof HBO and local wound care and, if it appears to be improving, then another 30 dives are given. Fifteen percent of his series had resolution of the osteoradionecrosis with this therapy alone. If this fails, then it is upstaged to stage II in which debridement with sequestrectomy is required plus the hyperbaric oxygen therapy and primary mucosal closure. Then, subsequently if these patients break down to reveal exposed bone or if there is pathologic fracture, fistula, or evidence of resorption of the inferior border of the mandible, then it is increased to stage-III, which is where our patient would fit in. These patients really require radical resection of the necrotic bone with reconstruction, and Marx in his protocol gave an additional 20 divesof HBO. In a systematic review of the literature, looking at the randomized controlled evidence of hyperbaric oxygen, there are really only three randomized trials—they are all performed by Dr. Marx—but they do support the benefit of hyperbaric oxygen in osteoradionecrosis. The outcomes in these studies were complete mucosal coverage, the attainment of bony continuity, and the successful healing of tooth sockets. Then as you see in these studies, there was a relative benefit to the patients who received hyperbaric oxygen as an adjunct to their therapy.

So in summary, radiation therapy induces acute and late tissue reactions leading to complication. Prevention really is the cornerstoneof the management of these complications, as management once they occur is very difficult. Understanding the mechanism of the complications provides the best treatment alternatives for newer therapies. Good examples are hyperbaric oxygen aimed at the hypervascularity and osteoradionecrosis, and free radical scavengers such as amifostine and new radiotherapy protocol such as IMRT, can assist with the prevention of long-term complications. Given the importance of radiation currently in the management of head and neck cancer, understanding these complications is crucial for the head and neck surgical oncologist.

Case Presentation:

Mr. G. is a 70-year-old male who presented to the VAMC otolaryngology clinic for routine post-therapy cancer surveillance. He has a history of SCCA of the tongue (stage unknown), treated with surgical resection with split-thickness skin graft, neck dissection, and XRT 5 years prior at an outside hospital. He complains of facial swelling of the jaws and increased pain in the teeth.

Past medical history is notable only for hypertension. The patient has a 75 pack-year smoking history and formerly drank several drinks daily, but he has not used alcohol and tobacco since his cancer diagnosis. He takes no medications regularly and has been on a course of ciprofloxacin for his teeth pain.

Physical examination revealed significant dental caries. His graft was well-healed and there were no oral lesions suspicious for recurrence. He had notably viscous saliva. He had prominent submental fibrosis, but otherwise no lymphadenopathy

The patient was evaluated in conjunction with OMFS. He underwent full-mouth dental extraction with alveoloplasty. At the time of surgery he was noted to have significant amounts of necrotic alveolar bone which was debrided. He was started on clindamycin and peridex washes, and subsequently developed an oro-cutaneous fistula in the right submandibular region. He continued to have a fistula and exposed alveolar bone 6 weeks post-op. He was admitted for IV antibiotics and referred to Hermann for hyperbaric oxygen therapy (HBO). Bilateral PETs were placed by otolaryngology for HBO.

After 10 dives the patient was taken back to the OR and had further debridement and mucosal flap closure. On POD 8 he was noted to have mucosal breakdown and purulent drainage with a palpable step-off. Panorex confirmed a pathologic fracture of the mandible.

The patient underwent mandibulectomy with biphasic external pin fixator placement. He developed a small area of dehiscence intraorally and was treated with linezolid. He was discharged home on POD #26. He had a small area of dehiscence for 6 months, which ultimately closed. He underwent a total of 32 dives of HBO at Hermann. He did well for 2 years, and subsequently was fitted for dentures contrary to the advice of OMFS. He recently developed another small area of exposure over the posterior mandible, which spontaneously closed.

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