INTRODUCTION — Radiotherapy (RT) is an effective treatment for head and neck cancer (HNC). For early (T1 and T2) lesions, results are comparable to those obtained with surgery, and RT is preferred over surgery at some sites because of preservation of organ structure and function. For more advanced HNC, adjuvant RT can be administered postoperatively (either alone or with concomitant chemotherapy) or combined with chemotherapy as definitive therapy. There are both acute and long-term sequelae of RT for HNC that occur because of effects on normal tissues. The side effects of RT and their management will be reviewed here. ACUTE SIDE EFFECTS — Acute reactions that can occur during RT for HNC include mucositis, odynophagia, dysphagia, hoarseness, xerostomia, dermatitis, and weight loss. These effects occur to some degree in the majority of patients, but they are self-limited in duration. Acute complications can interfere with and delay treatment. Even short delays can be deleterious, interfering with local tumor control. In one study, for example, a five day delay in completing RT was associated with a 3.5 to 8 percent reduction in local control for laryngeal cancers. The effect was greater in tumors with a higher probability of local failure. In addition to treatment-related factors, the nature, frequency, and severity of complications are heavily influenced by tumor-related (eg, location, invasion of vital structures) and patient-related factors (eg, oral hygiene, nutritional status, continued tobacco use, history of diabetes or collagen vascular disease or HIV). The importance of smoking cessation — All patients should receive counseling about the importance of smoking cessation. Besides being a major risk factor for HNC, smoking can also influence cancer prognosis. When smoking is continued both during and after RT, it can increase the severity and duration of mucosal reactions, exacerbate xerostomia, and compromise oncologic outcome One study, for example, evaluated 115 patients with HNC who were treated with RT with or without 5-fluorouracil (5-FU). The 53 patients who continued to smoke during RT had significantly lower rates of complete response (45 versus 74 percent) and two-year survival (39 versus 66 percent) compared with the 62 patients who did not smoke or who had quit before treatment. Among nonsmoking patients, mortality rate was influenced by the duration since quitting smoking. Compared to patients who continued to smoke, the death rate was 40 percent lower in patients who had quit less than 12 weeks before and 70 percent lower in patients who had quit more than one year before diagnosis. Dermatitis — Radiation damage to stem cells in basal layers of the skin can give rise to a sunburn-like desquamation. This can be aggravated by chemotherapeutic agents such as 5-FU, doxorubicin, and methotrexate, among others. Prior to initiating RT, patients should be instructed about appropriate skin care and avoidance of exposure to potential chemical irritants. They should also limit direct sun (UV) and wind exposure, and refrain from application of lotions, ointments, or fragrances to the head and neck region to minimize the bolus effect that might alter the depth at which the maximum RT dose is delivered. A number of commercially available skin care products can be used during RT to provide lubrication and protect the skin. These include aloe vera-based gels and water-based lotions. However, none of these preparations promotes or accelerates healing of radiation-induced dermatitis. Prophylaxis of salivary gland dysfunction — The degree of xerostomia resulting from RT for HNC depends upon the volume of salivary tissue irradiated. Temporary loss of saliva is significant after about 10 Gy is delivered to the salivary glands, while administration of approximately 40 to 50 Gy causes permanent loss of function. Alteration in taste can also occur and decreased oral intake may also contribute to decreased saliva production. Patients should be instructed to drink adequate fluids and to rinse and gargle with a weak solution of salt and baking soda several times daily (one-half teaspoon of salt and one teaspoon of baking soda added to one quart of water). This regimen can refresh the mouth, loosen thick, tenacious oral secretions, and alleviate mild mucositis pain. Amifostine — Another important adjunctive drug that may diminish RT-related xerostomia is amifostine. The benefit of amifostine was shown in a landmark trial of 315 patients receiving RT alone (60 to 70 Gy in 1.8 to 2.0 Gy daily fractions), who were randomly assigned to amifostine (200 mg/m2 per day 30 minutes prior to each radiation dose) or no amifostine. Amifostine reduced the incidence of significant acute xerostomia from 78 to 51 percent, and the incidence of significant chronic xerostomia at 12 months from 57 to 34 percent. Amifostine had no impact on mucositis or on tumor control at two years Whether amifostine is effective at diminishing xerostomia in patients undergoing chemoradiotherapy is uncertain; the results from four randomized trials are conflicting:
Summary — Taken together, the data supporting the benefit of amifostine for patients undergoing RT or chemoradiotherapy for HNC are somewhat conflicting. Despite a recommendation by ASCO that amifostine be considered to reduce the incidence of xerostomia in patients receiving RT for HNC, the inconvenience and cost of daily IV infusions and side effects have limited its widespread use. Nonetheless, it should be considered in select patients who are likely to be long-term survivors, are at risk for xerostomia based upon RT fields and/or dose, and who might tolerate the added toxicity of amifostine. A possible alternative is subcutaneous administration during RT, which appears to provide similar protection as the IV route, and is more convenient, less expensive, and possibly better tolerated The benefit of amifostine for patients undergoing chemoradiotherapy is less certain. The most well-conducted study in the setting of concurrent chemoradiation is negative. One interpretation is that the additional salivary toxicity added by adding chemotherapy to RT is not protected by amifostine; alternatively, the degree of benefit even in patients undergoing RT alone may be substantially less than was suggested in the Brizel trial Pilocarpine — Prophylactic pilocarpine (5 mg orally three times daily during RT and for three months thereafter) can reduce xerostomia severity in patients undergoing RT for HNC. In one report from the Radiation Therapy Oncology Group (RTOG), 249 such patients were randomly assigned to pilocarpine 5 mg four times daily or placebo. Compared to placebo, salivary function was significantly preserved in the treated group at six but not at three months. However, a second study of 139 patients found no difference in xerostomia at 1,3 or 6 months after treatment with either placebo or pilocarpine three times a day, and no difference in mucositis. The RTOG study assessed the impact of salivary function on short term quality of life measures, and found no benefit to improved salivation. It is possible that a difference may be seen with longer term follow-up, after full healing of affected mucosa. In contrast to its demonstrated efficacy in the setting of established xerostomia, prophylactic administration of pilocarpine was not shown to be beneficial in at least one placebo-controlled trial [ Future therapies — It is possible that future modalities will provide added benefit. As an example, prevention of xerostomia has been accomplished in a small preliminary series with surgical transfer of a submandibular salivary gland to the submental space, outside the RT field, prior to starting RT Mucositis — Radiation-induced loss of stem cells in the basal layer interferes with the replacement of cells in the superficial mucosal layers when they are lost through normal physiologic sloughing. The subsequent denuding of the epithelium results in mucositis, which can be painful and interfere with food intake and nutrition. Chemotherapy can have a similar effect on the mucosa. Mucositis usually develops two to three weeks after starting RT. The incidence of mucositis is variable depending upon the field, total dose and duration of RT, as well as the concomitant administration of chemotherapy. In one series, clinically significant mucositis occurred in 64 percent of patients receiving RT to the head or neck for any malignancy . Mucositis is managed symptomatically with scrupulous oral hygiene, dietary modification, and topical anesthetics. Topical anesthetics may be combined with an antacid suspension and/or diphenhydramine (for local drying effect) with or without nystatin in a "cocktail," commonly termed "Miracle Mouthwash". One such cocktail used for local pain control consists of 2 percent viscous lidocaine; diphenhydramine; and Maalox (sometime termed Miracle mouthwash and available commercially as FIRST®-Mouthwash BLM). Other "cocktails" add dexamethasone solution as an antiinflammatory, or antibiotics such as tetracycline. Care should be advised for patients using rinses containing lidocaine to avoid further trauma to the anesthetized mucosa. Acidic or spicy foods, sharp foods (eg, chips), caffeine, alcoholic beverages and alcohol-containing mouth washes should be avoided in symptomatic patients. In addition, secondary bacterial, fungal (eg, oral candidiasis), and viral (eg, herpes simplex virus) infections should be treated with appropriate antimicrobials. A variety of other agents have been evaluated either prophylactically or after the onset of symptoms; their role in the treatment of radiation-induced mucositis is uncertain. Sucralfate — The bulk of evidence from placebo-controlled trials suggests that prophylactic sucralfate mouth washing during RT does not reduce the degree of mucositis Amifostine — In contrast, amifostine may provide benefit. In one randomized study of 26 patients receiving accelerated RT (64 Gy in 3.5 weeks) for HNC, twice daily amifostine markedly reduced the incidence, severity, and duration of mucositis compared to placebo. However, tolerance of amifostine was poor; vomiting, generalized erythema and liver enzyme elevation prevented the continuation of amifostine in five of 13 patients. Similar benefit with less toxicity was noted in a trial that randomly assigned 50 patients with advanced HNC to conventional fractionation RT (60 to 74 Gy in daily 2 Gy fractions) and concurrent weekly carboplatin with or without amifostine (300 mg/m2 IV daily). In addition to fewer treatment interruptions and less severe mucositis (grade four in 5 versus 52 percent at week five), amifostine was also associated with a significant reduction in the incidence of xerostomia at three months follow-up (27 versus 74 percent). A third larger trial, with xerostomia as the end point, failed to demonstrate a reduction in mucositis with amifostine, despite finding less acute and chronic xerostomia. Published guidelines from ASCO do not recommend amifostine to prevent RT-related mucositis, but do recommend its use be considered to decrease the incidence of acute and late xerostomia. The benefit of amifostine in patients undergoing chemoradiotherapy remains uncertain. Helium-neon laser therapy — Several controlled trials have provided evidence that pretreatment with low energy helium-neon laser therapy (LEL) reduces mucositis associated with chemotherapy. In a double-blind, multicenter study, 30 patients with carcinoma of the oropharynx, hypopharynx and oral cavity that was treated with RT alone were randomized to LEL or placebo light treatment, starting on the first day of RT and before each session. LEL therapy was associated with significant reductions in the frequency of both grade III mucositis (8 versus 35 percent) and severe pain (2 versus 24 percent). While the results of this single-institution study are encouraging, the general application of LEL for prophylactic treatment for RT-induced mucositis cannot be advocated until its safety and efficacy are verified in a multiinstitutional trial. Furthermore, a better understanding of the mechanism of action and the potential interaction with RT is necessary. Limitations of LEL treatment include the need for specialized equipment and lack of information on treatment-related complications. GM-CSF — Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), given either subcutaneously (5 µg/kg for five days) or topically (400 µg/day) beginning with the experience of oral pain or after the administration of a portion of the RT dose, significantly reduced the severity of mucositis in pilot studies . However, at least two randomized trials have failed to confirm a benefit for topical GM-CSF in this setting KGF — Other growth factors including keratinocyte growth factor (KGF) may accelerate epithelial restoration. However, cytokines modulate the radiation response in both normal and cancerous cells, raising the concern that they may protect the tumor cells. Furthermore, systemic administration of cytokines causes significant side effects. These studies are ongoing. Topical protectants/anesthetics — A mucosa-adhesive, water-soluble film, containing topical anesthetics and antibiotics (tetracaine, ofloxacin, miconazole, guaiazulene, and triacetin) may be beneficial for symptom control. Others have shown efficacy for topical application of tetracaine gel alone. Neither of these products is available in the United States. In addition, two nonprescription products, Oratect® gel and Gelclair® (maltodextrin) gel, may provide a temporary protective barrier for inflamed mucosal tissues, especially the lips, especially if applied prior to eating. Benzydamine is an NSAID with topical
antiinflammatory, analgesic, anesthetic, and antimicrobial activity. In a
double-blind placebo-controlled trial, benzydamine oral rinse (15 ml for 2
minutes, 4 to 8 times daily) during RT was associated with significantly
better freedom from ulceration (33 versus 15 percent), and a delay in the
use of systemic analgesics during conventional ( Clinical practice guidelines developed by
the Mucositis Study Section of the Multinational Association of Supportive
Care in Cancer and the International Society for Oral Oncology recommend
the use of benzydamine for prophylaxis of radiation-induced mucositis in
patients with head and neck cancer receiving moderate dose RT ( Glutamine — A small pilot trial randomized 17 patients with HNC who were receiving primary or adjuvant RT to oral glutamine (2 g in 30 mL normal saline four times daily) or placebo during therapy. The glutamine group had a shorter duration and severity of objective mucositis (maximum grade 1.6 versus 2.6). Despite the above measures, pain may be significant during and shortly after the course of RT. Long acting opiates should be used as needed during the treatment period. For patients who cannot swallow, long-acting morphine or oxycodone pills, or transdermal fentanyl may provide good pain relief. Short acting opiates should be used for breakthrough pain. Zinc sulfate — A beneficial role for prophylactic oral zinc sulfate was suggested in a trial that randomly assigned 30 patients receiving RT for HNC to zinc sulfate (220 mg [50 mg elemental zinc] three times daily) or placebo, during and for six weeks after RT. The severity of mucositis was significantly less in the zinc group (grade 3 or 4 in 0 versus 8 patients); furthermore, mucositis developed later, and started to improve earlier with zinc. These results require independent confirmation. Despite these measures, pain may be significant during and shortly after the course of RT. Long acting opiates should be used as needed during and after the treatment period. For patients who cannot swallow long-acting morphine or oxycodone pills, transdermal fentanyl may provide good pain relief. Short-acting opiates should be used for breakthrough pain. Intravenous hydration, oral liquid nutritional substitutes, and gastric feeding tubes should be used to treat dehydration and malnutrition (see below). Nutritional disturbances — A variety of factors can contribute to nutritional deficiency in patients with HNC who receive RT. Many patients present with weight loss related to dysphagia and/or odynophagia. This problem is often compounded by significant nutritional deficiencies associated with lifestyle before diagnosis, and treatment-related dysphagia if RT is delivered to large areas of the oral-pharyngeal mucosa or salivary glands. Nutrition and swallowing should be assessed prior to starting RT in order to determine the need for intervention and to provide instructions about appropriate food choices and methods to promote mastication and deglutition [41]. In general, frequent, small portion meals consisting of soft solids and liquids are recommended. Patients experiencing significant weight loss (ie, greater than 5 to 10 percent) or recurrent episodes of dehydration require alternative methods of feeding such as a nasogastric tube or a gastrostomy tube. LATE EFFECTS — In general, acute side effects from radiation are a result of parenchymal cell loss and they resolve as these cells are replaced. In contrast, late effects are thought to arise as a result of injury to stromal elements or supporting tissues such as the vasculature. By comparison, the magnitude of late complications with radiation therapy (RT) for head and neck cancer (HNC) is more influenced by fraction size than that of acute complications. This relationship has led to the evaluation of hyperfractionated regimens in an attempt to reduce some late toxicities. Established xerostomia — Xerostomia often improves with time, but it can be a long lasting or even permanent problem. Commercially available salivary substitutes or artificial saliva (oral rinses containing hyetellose, hyprolose, or carmellose), relieve the discomfort of xerostomia by temporarily wetting the oral mucosa. Although they can provide temporary relief especially prior to eating, many patients must take frequent sips of water to remain comfortable. In addition to being inconvenient, this can lead to secondary problems such as nocturia from late night fluid intake in men with prostatic hypertrophy and men and women with small bladder capacity. A commercially available oral moisturizer (Optimoist) produces significant benefit for patients undergoing RT for HNC as well as for for those with Sjögren's syndrome. In a series of 24 patients, whole unstimulated salivary flow rate improved from 0.12 to 0.24 mL/min after two weeks of therapy. Candida colonization decreased in 43 percent, and swallowing objectively improved in 75 percent. Sialagogues — Untreated or unaffected residual salivary tissue is the target for sialagogues. Salivary stimulants can be characterized as gustatory, tactile, or pharmacologic. Gustatory stimuli such as acidic or bitter substances are most effective at stimulating salivary flow. Sweet substances such as sugar-free hard candy also stimulate the flow of saliva, but to a lesser extent. Chewing sugarless gum can provide both gustatory and tactile stimuli to salivary flow. Pharmacologic sialagogues are typically agonists of the muscarinic (M3) receptor, and include pilocarpine and cevimeline. Of these, pilocarpine has been the most extensively investigated. Pilocarpine — Oral pilocarpine is effective for established xerostomia. In one study, 207 patients who had received 40 Gy of RT to the head and neck were randomized posttherapy to pilocarpine or placebo. Compared to placebo, pilocarpine was associated with greater improvement in oral dryness (44 versus 25 percent), speech (33 versus 18 percent), and mouth/tongue comfort (31 versus 10 percent). Six and 29 percent of the patients in the 5-mg and 10-mg pilocarpine groups, respectively, withdrew from the study because of adverse effects, predominantly sweating. In general, functional improvement ceases after drug withdrawal. However, at least some retrospective data suggest that the effect may be more persistent when pilocarpine is used throughout RT, and then stopped three months after the completion of therapy. However, randomized trials have not been conducted to answer the question of optimal timing of pilocarpine use. In addition to sweating, other adverse effects of pilocarpine include tachycardia, hypertension, flushing and increased bowel and bladder motility. We recommend the routine use of pilocarpine except in patients with uncontrolled asthma, acute angle glaucoma, or known hypersensitivity to pilocarpine in whom it is contraindicated. It is not clear whether it is preferable to start pilocarpine in conjunction with RT or after RT. Cevimeline — Cevimeline (Evoxac®) is another acetylcholine analog which has a high affinity for the M3 muscarinic receptors on salivary gland, but a low affinity for the M2 muscarinic receptors of heart and lung tissue. Because of its more favorable risk to benefit ratio, this drug has become the sialogogue of choice for patients with Sjogren's syndrome. Cevimeline is under active investigation for treatment of RT-induced xerostomia, but at present, no data are available
Acupuncture — Acupuncture may
provide meaningful palliation for patients with pilocarpine-resistant
xerostomia, although the duration of benefit is unclear. In one report, 50
patients with xerostomia following RT for HNC underwent acupuncture (three
or four weekly treatments, followed by monthly sessions). A clinical
response, defined by a
Amifostine — As noted above, the prophylactic use of amifostine during RT has been associated with a significant reduction in the incidence of xerostomia in patients treated with RT at least two trials Published guidelines from ASCO recommend that amifostine be considered in such patients to decrease the incidence of acute and late xerostomia [12]. In contrast, the utility of prophylactic amifostine in patients undergoing chemoradiotherapy is uncertain. Osteoradionecrosis — Osteoradionecrosis of the jaw (ORN) is a severe complication of RT for HNC. The presentation of post-RT ORN ranges from small asymptomatic bone exposures that remain stable for months to years and heal with conservative management, to severe necrosis necessitating surgical intervention and reconstruction. Depending on the location and extent of the lesion, symptoms can include pain, bad breath, dysgeusia, dysesthesia or anesthesia, trismus, difficulty with mastication, deglutition, and/or speech, fistula formation, pathologic fracture, and local, spreading, or systemic infection. The mandible is the most frequently affected bone, because in the majority of patients treatment for HNC, a large part is inevitably exposed to high RT doses. Maxillary ORN is reported infrequently, usually in the setting of irradiation for nasopharyngeal cancer (in which both jaws are at risk) Mandibular ORN occurs in 5 to 10 percent of patients treated with conventional RT or high dose rate brachytherapy, and is severe in about 2 percent. The incidence of this complication appears to be higher with hyperfractionated regimens, especially with a short interfraction interval. In one study of 168 patients with oral cancer treated with hyperfractionated or conventional RT, the incidence of ORN was higher with hyperfractionated therapy (23 versus 9 percent). Tooth extraction and dental disease in irradiated regions are major factors in the development of both mandibular and maxillary ORN Although opinion differs as to preirradiation versus postradiation, many authors report that postirradiation extraction of diseased and nonrestorable teeth produces a higher rate of mandibular ORN Furthermore, at least some data suggest that mandibular ORN associated with postirradiation extraction more often requires radical resection than cases of ORN that develop after preirradiation extraction (45 versus 12 percent, respectively) Repair of nonrestorable and diseased teeth prior to RT may reduce the risk of this complication However, most authorities do not recommend the preirradiation extraction of healthy or restorable teeth Treatment — For mild osteoradionecrosis, treatment with conservative debridement, antibiotics, and occasionally ultrasound is usually successful. Some authors advocate pentoxifylline and vitamin E. However, when bone and soft tissue necrosis are extensive, radical resection of the mandible with immediate microvascular reconstruction may provide better results. Persistent ORN, despite aggressive treatment, should raise the suspicion of recurrent cancer Hyperbaric oxygen therapy (HBO) has been suggested as a beneficial therapeutic maneuver in patients developing ORN of the jaw after RT. ORN may be triggered by a predominantly fibro-atrophic mechanism. At least in theory, HBO simulates the function of monocytes and fibroblasts, increasing collagen synthesis and vascular density Despite this theoretical rationale, the available data are conflicting as to clinical benefit, both for prevention and therapy of ORN Benefit was called into question in a randomized multicenter trial in which 68 patients with overt mandibular ORN were randomly assigned to receive 30 to 40 exposures to HBO or a placebo at 2.4 absolute atmosphere for 90 min Healing rates were equivalent and in fact trended toward worse with HBO as compared to placebo (19 versus 32 percent, p = 0.23). Although this was only a single study and did not include patients receiving HBO prior to dental extraction, it raises doubt as to the efficacy of HBO for ORN. Likewise, the protective benefit of HBO as a means of reducing the incidence of ORN prior to dental extraction in irradiated patients is also uncertain, and is discussed in detail below. Thus, the benefit of HBO in preventing or treating ORN remains unproven RT-induced fibrosis — A serious complication of RT in the treatment of cancer patients is the late onset of fibrosis in normal tissues including the neck, pharynx, esophagus, and temporomandibular joint. Although no therapy has been consistently effective at reversing fibrotic complications, treatment with pentoxifylline with and without tocopherol has produced some striking regression of subcutaneous fibrosis. In one study, 43 patients who had received RT for HNC or breast cancer an average of 8.5 years previously and who had symptomatic fibrosis involving the skin and underlying soft tissues were treated with pentoxifylline (800 mg/day) and vitamin E (1000 IU/day) for at least six months. The fibrosis had gradually worsened prior to therapy. The mean measurable surface area of fibrosis fell by 53 and 66 percent at 6 and 12 months, respectively, and patients reported improved symptoms of edema, plexitis, restricted movement, and signs of inflammation. The benefit of combined therapy was confirmed in a follow-up placebo-controlled trial involving 24 women with skin and soft tissue fibrosis after RT for breast cancer. However, a similar degree of benefit has been shown for pentoxifylline alone in patients with radiation-induced soft tissue injury. The mechanism of benefit from pentoxifylline in this setting may involve inhibition of transforming growth factor beta (TGF-beta) . This cytokine is hypothesized to be a master switch for the fibrotic process following radiation. Site specific effects — A number of other late sequelae can occur at various sites within the head and neck. Oral cavity — Radiation to the oral cavity can induce changes in taste and tongue pain. Taste gradually returns in most patients over a six month period, although in some patients taste incompletely recovers. Likewise, tongue pain generally diminishes gradually in the weeks and months after RT, often in a fluctuating manner. Xerostomia, oral thrush, and spicy foods may act as triggers for pain exacerbations. High dose RT can cause fibrosis of the muscles of mastication and lead to a slowly evolving inability to open the mouth (trismus or lockjaw). Eating is made difficult by the restricted range of motion of the jaw movements, although in most instances, speech articulation is not affected. Trismus is particularly common in patients who undergo retreatment with RT, occurring in 15 to 30 percent of cases. Jaw exercises and the use of a dynamic opening device (Therabite) can minimize the severity of trismus. Pentoxifylline may be of benefit Dental disorders — Dental status has a profound impact on posttreatment quality of life among patients with head and neck cancer. Patients with head and neck cancer often have poor preexisting dentition and dental health. Furthermore, the decrease in saliva and changes in its chemical composition can alter the microbial flora of the mouth, and increase the risk of dental caries. Aggressive dental prophylaxis can reduce this problem; in addition, the repair of preexisting diseased and nonrestorable teeth prior to RT will reduce the risk of osteoradionecrosis (see above]. For these reasons, all patients receiving RT to the maxilla, mandible, or salivary glands should undergo a comprehensive pretherapy dental evaluation. All indicated extractions and/or restorative work should be completed prior to RT and the patient given instructions on the maintenance of oral hygiene and fluoride prophylaxis. A delay of approximately two weeks is required between extractions and the beginning of RT to permit proper healing. The edentulous patient should be evaluated for retained root tips, alveolar hyperplasia, maintenance of oral hygiene, and assessment for prosthodontics. Reduced quantity and altered composition of saliva is known to result in dental caries. Methods to reduce xerostomia are likely to also reduce RT-related dental caries. For example, preliminary evidence suggests a possible benefit of amifostine in the prevention of postradiotherapy dental caries. This report evaluated the preradiotherapy and postradiotherapy dental status of 35 patients with HNC who were randomly assigned to receive amifostine or placebo for prevention of radiation induced xerostomia. At one year following the completion of radiation, significantly fewer amifostine-treated patients had either new caries or required tooth extractions (2 of 17), compared to the placebo group (11 of 18). Patients requiring dental extractions in a previously irradiated area of mandible or maxilla are at risk to develop osteoradionecrosis (ORN). A benefit for pre-extraction HBO in this setting was supported by one small randomized study of HBO plus perioperative versus penicillin alone, and by several retrospective or small studies However, at least two series of conservative approaches to dental extractions in irradiated patients without HBO show low rates of development of ORN (2 and 0 percent in 187 and 72 patients, respectively. In addition, there did not appear to be any benefit from HBO in established ORN in the previously described placebo-controlled trial of HBO in 68 patients with osteoradionecrosis after radiotherapy for HNC, 22 of whom had necrosis due to dental extraction after RT. This study did not include patients receiving pre-extraction HBO. Oropharynx — Radiation of the oropharynx can lead to mucosal inflammation, edema, fibrosis, pharyngeal stenosis, and soft tissue necrosis. Mild dysphagia, requiring change in diet, pharyngeal strengthening, or swallowing retraining is fairly common, particularly when RT is used with surgery and/or chemotherapy. One report evaluated 46 patients receiving hyperfractionated RT with concomitant chemotherapy; 82 percent (52 percent of whom had cancer of the oropharynx) were still restricting their diet to soft foods 12 months after treatment; this was partly attributable to swallowing difficulties In a subsequent study by the same group using the same dose of radiation but less dose intensive chemotherapy, only 47 percent of treated patients were still restricting their diet to soft foods one year after treatment Partial or total oropharyngeal stricture may occur in more severe cases. These strictures can sometimes be treated with balloon or other methods of dilation, but they may be permanent. A small number of patients may be chronically dependent on gastrostomy feedings for nutrition. Severe pharyngeal or laryngeal edema may interfere with respiration and, if severe, may require temporary, and occasionally, long term tracheostomy. Pharyngeal edema, strictures, and other forms of radiation-induced dysfunction predispose patients to aspiration that can lead to pneumonitis or infectious pneumonia. As in the oral cavity, soft tissue necrosis of native or grafted tissue may occur. These necrotic areas may improve spontaneously with or without antibiotics, but healing may be hastened with hyperbaric oxygen therapy Larynx — Radiation or chemoradiation to the larynx may result in hoarseness or airway edema, both acutely and chronically. In extreme cases of airway edema, tracheostomy may be needed. Hoarseness generally improves over time, although about one-half of patients with early vocal cord cancers will have chronic hoarseness. This may be worse with stripping of the vocal cord rather than biopsy, and in patients who continue to smoke after treatment is completed Osteoradionecrosis or chondroradionecrosis may also result from laryngeal radiation. Chondroradionecrosis, like bone and soft tissue necrosis, may improve with hyperbaric oxygen treatment Thyroid dysfunction — Irradiation of the low neck is associated with hypothyroidism. The incidence varies widely, and is dose-dependent, as well as time dependent, increasing with time elapsed since treatment. RT-induced hypothyroidism develops at a median of 1.4 to 1.8 years (range 0.3 to 7.2 years). It is more common in patients undergoing both neck surgery and RT, but is not higher in patients who undergo chemotherapy in addition to radiation compared to radiation alone. Although some studies suggest that this complication is more frequent in women than in men this is not a universal finding Neck — Neck irradiation may lead to severe consequences, particularly in conjunction with surgery. Neck immobility can result in stiffening of muscles and/or pain, and in severe cases, flexion contractures. Edema of the neck is common after radiation. In time, this edema may harden, leading to neck stiffness. In severe cases, in particular when accompanied by neck dissection, or in the case of reirradiation, neck and facial edema may be extremely severe and cosmetically significant. Treatment of the low neck produces apical pulmonary fibrosis in all patients.
One of the primary causes of stroke is carotid artery stenosis. Most patients with HNC have other risk factors for cerebrovascular disease as well (particularly smoking), making it difficult to define the contribution from prior neck irradiation. This issue was addressed in a cohort study of 44 HNC survivors who received unilateral neck radiotherapy between 1974 and 1999, and then underwent bilateral carotid duplex sonography. The incidence of significant carotid artery stenosis on the irradiated sides (8 of 44, 18 percent) was nonstatistically significantly higher than on the nonirradiated heminecks (3 of 44, 7 percent). The rates increased over time elapsed since RT, and were higher in those who had undergone a neck dissection as compared to those who did not (7 of 22 [32 percent] versus 1 of 22 [4 percent]). The authors suggested that carotid artery screening be considered for asymptomatic survivors of irradiation and neck dissection for HNC.
Carotid rupture and fistula are rarely observed after definitive RT with or without concomitant chemotherapy but may be more common when there is tumor invading the carotid sheath or extending into and occupying a large volume of the soft tissue of the neck. Patients with osteoradionecrosis of the temporal bone following definitive treatment for nasopharyngeal cancer are also at risk of carotid artery rupture The most common angiographic abnormality seen in one study was one or more pseudoaneurysms. Although this devastating complication can sometimes be managed with endovascular therapy, it recurs in up to 25 percent of patient
|
50 Gy), but not accelerated fractionation (
2.2 Gy daily) RT.