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Authors : Dr. Suraj Agarwal, Dr. Samta Goel Mittal.

ABSTRACT

In addition to anti-tumor effects, ionizing irradiation causes damage in normal tissues located in the field of radiation. This becomes particularly evident in the head and neck region, a complex area composed of several dissimilar structures that respond differently to radiation: mucosal linings, skin coverings, subcutaneous connective tissue, salivary gland tissue, teeth, and bone/cartilage. Acute changes produced by radiotherapy are observed in the oral mucosa (erythema, pseudo membrane-covered ulceration), salivary glands (hyposalivation, changed salivary composition), taste buds (decreased acuity), and skin (erythema, desquamation).

Late changes can occur in all tissues although thorough protocols have been developed to minimize or manage the early and late oral sequelae of radiotherapy of the head and neck region, the consequences of radiation-induced salivary gland injury and the other oral sequelae of head and neck radiotherapy are still difficult to manage.This particular article deals with the radiation-related changes in the oral mucosa, salivary glands, taste, dentition, periodontium, bone, muscles, and joints which are discussed in the order that they appear.

Keywords: Mucositis, Xerostomia, Sialogogues, Radiation Caries, Osteoradionecrosis

INTRODUCTION

They can be divided into early (mucosa, taste, salivary glands), intermediate (taste, salivary glands), and late (salivary glands, dentition, periodontium, bone, muscles, joints) effects. 1

Oral Mucosa 1

Damage to oral mucosa is strongly related to radiation dose, fraction size, volume of irradiated tissue, fractionation scheme, and type of ionizing irradiation. Oral side-effects develop early during radiotherapy.

The acute mucosal response to radiotherapy is a result of mitotic death of epithelial cells, since the cell cycle time of the basal keratinocytes is about four days. Mucositis induced by radiotherapy is defined as the reactive inflammation of the oral and oropharyngeal mucous membrane during radiotherapy in the head and neck region. It is characterized by atrophy of squamous epithelial tissue, absence of vascular damage, and an inflammatory infiltrate concentrated at the basement region .Radiation mucositis is an inevitable but transient side-effect .

It is an integral part of radiotherapy in terms of morbidity, since during a course of curative radiation about 80% of the patients will develop pseudo membranous mucositis. The early radiation reaction causes local discomfort as well as difficulties in drinking, eating swallowing, and speech. Therefore, it can give rise to nutritional problems, and in severe cases nasogastric feeding, which is very uncomfortable, may become necessary. About 20-30% of the patients will need artificial feeding. Severe mucositis may necessitate an interruption of the course of radiotherapy and thus can serve as a dose-limiting factor. Such interruptions must be prevented, because they may result in prolongation of treatment time and thus a reduction in therapeutic effect.
 
Figure 1: Radiation induced mucositis


Various signs of mucositis may emerge during radiotherapy. The first clinical signs of mucositis occur at the end of the first week of a conventional seven-week radiation protocol (daily dose of 2 Gy, five times a week). There is no consensus regarding what is the first sign of mucositis. Some authors describe a white discoloration of the oral mucosa, which is an expression of hyperkeratinization as the first symptom, followed by or in combination with erythema .Others consider erythema to be the first reaction.

Briefly, mucositis generally persists throughout radiotherapy, it is maximum at the end of the irradiation period, and continues for one to three weeks after treatment has ceased .The severity of mucositis varies considerably between patients and may relate to the fractionation schedule applied. Accelerated fractionation results in a more rapid onset of mucositis. Furthermore, the mucosa of the oral cavity does not react in the same manner at all locations. Mucositis is most severe in the soft palate, followed, in order, by the mucosa of the hypopharynx, floor of the mouth, cheek, base of the tongue, lips, and dorsum of the tongue.

Patients with compromised oral mucous membranes secondary to alcoholism and/or excessive smoking exhibit the most severe mucosal changes. Other factors that may contribute to the development of mucositis include: an increase in the carriage rate of Gram-negative bacilli in the oropharynx. This marked increase in oral Gram-negative enterobacteria and pseudomonads has particularly been shown as a possible aggravating factor for development of oral mucositis. The most common infection in the oral cavity during or shortly after radiotherapy is Candidiasis.

In summary, although the etiopathogenesis of radiation mucositis still is not fully clear, it most likely can be considered as a four-step inflammation consisting of an inflammatory/ vascular phase, an epithelial phase, a bacterial phase, and a healing phase. This sequence of phases has been proposed by Sonis (1998) for chemotherapy-induced stomato-toxicity, but probably also holds true for radiation mucositis.

Prevention And Management 2,3

The use of various radiation treatment modalities and schedules of fractionation can play an important role in the prevention of mucositis. More recently, it has been claimed that new irradiation techniques like hyper fractionation and accelerated treatment improve local control in head and neck cancer.

The Consensus Development Panel of the National Institutes of Health (Consensus statement, 1990) stated that no drugs can prevent mucositis, an opinion that still holds true to date. Consequently, prevention of mucositis is still limited to reduction of its severity by oral care programs, relief of pain and discomfort, and/or strategies to eliminate micro-organisms that are thought to be involved in the development or promotion of radiation mucositis.

Most oral care programs aim at: removal of mucosal-irritating factors, cleansing of the oral mucosa, maintaining the moisture of the lips and the oral cavity, relief of mucosal pain and inflammation, and prevention or treatment of infection. Although it has been suggested that good oral hygiene may reduce the development and severity of mucositis. Some authors recommend discouraging the wearing of dentures during radiotherapy. Since denture surfaces may be colonized with Candida species, others recommend special attention to denture hygiene and removal of the appliance, at least at night.

In keeping with the aim of eliminating irritating factors, the use of tobacco, alcohol, and spicy and acidic foods should also be discouraged. For relief of pain and discomfort due to mucositis, several anaesthetics, analgesics, and mucosal-coating agents have been recommended. Periodic rinses with topical anaesthetics such as viscous xylocaine (lidocaine) and benzydamine have been proposed. Cytoprotectants, antibacterial have been used to prevent or reduce radiation mucositis.

The potential beneficial effects of aqueous chlorhexidine rinses to control chemotherapy-associated oral mucositis have been reported, but they are unable to control radiation mucositis. However, they still have value in plaque control in these patients. Because of the high carriage rate of Gram-negative bacilli found in many high-dose radiotherapy patients, it has been postulated that selective elimination of these oral Gram-negative bacilli has a prophylactic or ameliorating effect on the development of radiation mucositis.

Several authors have studied the radiation-mucositis-reducing effect of polymyxin E/tobramycin/ amphotericin B (PTA)-containing lozenges, pastilles, or paste The results have been very encouraging, in that eradication of Gram-negative bacilli (selective elimination of oral flora) was associated with at least some reduction of mucositis.

Taste Buds2

Alteration in taste is an early response to radiation and often precedes mucositis. Radiotherapy to the head and neck affects taste thresholds, food intake, chewing, and the hedonics of tasting and may result in weight loss. Most patients experience partial or complete loss of taste acuity during radiotherapy found that taste sensation decreases exponentially with a cumulative dose of about 30 Gy (3 weeks), 2 Gy per fraction, after which it becomes virtually absent. The loss in perception of all flavors rarely occurs .

Perception of bitter and acid flavors is more susceptible to impairment than perception of salt and sweet flavors .The loss of taste is not only a result of the effect of irradiation on the taste buds, but is also related to the reduction in salivary flow rate. A reduced salivary flow decreases transport and solubilization of gustatory stimulants, reduces the ability of saliva to protect the mucosa against bacteria, fungi, and variation in the oral pH, alters the ionic composition of saliva which is important for taste, and affects mastication, nutrition, and the hedonic aspects of tasting .Direct radiation damage to the taste buds or their innervating nerve fibers has been reported as the main cause of taste loss.

Histologically, taste buds showed signs of degeneration and atrophy at 10 Gy (2 Gy per day), while at therapeutic levels the architecture of the buds was almost completely destroyed .Loss of taste is usually transient. Taste gradually returns to normal or near-normal levels within one year after radiotherapy, although it can take as long as five years. The degree of taste recovery and the recovery time depend on the radiation dose received.

Taste impairment has profound effects on the nutritional status of the patient and is associated with weight loss through reduced appetite and altered patterns of food intake. This is due not only to the loss of taste per se, but to the non-equal impairment of the perception of the various flavors as well. Also, further studies are needed to evaluate the effect of irradiation on von Ebner's glands and the residual flow from these glands. This may be sufficient to obscure the interpretation of currently available data. If so, radiotherapy treatment plans should attempt to spare these glands if possible.

Prevention And Management 2,3

In most instances, taste gradually returns to normal or near-normal levels within one year after radiotherapy. Because of this transitory aspect, there is usually no need for treatment. Prevention of taste loss can best be accomplished through direct shielding of healthy tissue or placement of these tissues outside the radiation field by means of shielding or repositioning prostheses. Recently, a cytoprotection against the loss of taste was reported by the administration of amifostine during a course of radio chemotherapy.

However, the design of the latter is questionable, because a wide variety of treatment protocols was used. Since taste loss can result in weight loss, the importance of dietary counseling should be stressed. Food with pleasing taste, color, and smell and substitution of food aromas for the sense of taste may improve food intake.

Dietary counseling is also of great help in adapting to the taste of food, since in many patients the perception of the various flavors does not change to the same extent. Consequently, food that was enjoyed by the patient before radiation treatment can often have a less pleasant taste after treatment.

Thus, a basic meal plan including the addition of supplementary feedings should be started at the beginning of therapy and followed, with modifications, during at least the total period of treatment. As the taste perception, mostly gradually although not completely, returns to normal, dietary counseling often has to be continued until the complaints subside or the patient has adapted to the new situation. Attention also has to be paid to the level of hyposalivation, since insufficient moistening and lubrication of the oral tissues and food have a major negative impact on food intake and the ability of a patient to eat Some patients may be left with residual hypogeusia after radiotherapy.

Zinc supplements are reported to be helpful in increasing taste acuity in such patients. It is probably of more benefit in the acceleration of taste improvement in the post radiotherapy period than in the preservation of taste during radiotherapy.

Salivary Glands 1

Based on the slow turnover rates of their cells, the salivary glands are expected to be relatively radio-resistant. Yet the changes in quantity and composition of saliva that occur shortly after radiotherapy indicate that the gland tissue is an acutely responding tissue. It is not clear whether the direct effects of radiation on the secretory and ductal cells cause radiation damage of salivary gland tissue, or if it is secondary to injury of the fine vascular structures, increased capillary permeability, interstitial edema, and inflammatory infiltration.

In a human post mortem study, it has been assessed that, in the lower dose range (< 30 Gy), damage is reversible to a certain level, but after cumulative doses (> 75 Gy), an extensive degeneration of acini is observed, along with inflammation and fibrosis in the interstitium. As treatment continues, there is progressive degeneration of the acinar epithelium and development of interstitial fibrosis. Serous acinar cells appear to be more readily affected by irradiation than mucous acinar cells and ductal cells.
 
Figure 2: Salivary Gland- Chronic Radiation injury


Four phases in the radiation- induced loss of salivary gland function is observed. The first phase (0-10 days) was characterized by a rapid decline in flow rate without changes in amylase secretion or acinar cell number. The second phase (10-60 days) consisted of a decrease in amylase secretion and was paralleled by acinar cell loss.

Flow rate, amylase secretion, and acinar cell numbers did not change in the third phase (60-120 days).The fourth phase (120-240 days) was characterized by a further deterioration of gland function but an increase in acinar cell number, with poor tissue morphology. Depending on the localization of the radiation portals, a rapid decrease of the salivary flow rate is observed during the first week of radiotherapy, after which there is a gradual decrease to less than 10% of the initial flow rate.

Flow rate of parotid and submandibular-sublingual (SM/SL) saliva as a function of time after start of radiotherapy (conventional fractionation schedule, 2Gy per day, 5 days per week, total Dose 60-70 Gy). The parotid, submandibular, and sublingual glands are located in the treatment portal. Initial flow rates were set to 100%

Radiotherapy also results in a change of salivary composition. Saliva turns into a very viscous, white, yellow, or brown fluid. The obvious qualitative salivary changes are a reduced pH and buffering capacity, altered salivary electrolyte levels, and changed non-immune and immune antibacterial systems. The average pH decreases from about 7.0 to 5.0 .The reduced buffering capacity is primarily due to a reduction of bicarbonate concentration in parotid saliva. An increase in the concentrations of sodium, chloride, calcium, and magnesium has been reported, while the concentration of potassium is only slightly affected1.

The concentrations of immunoproteins (e.g., sIgA), lysozyme, and lactoferrin are increased. The decrease in salivary flow rate, however, is greater than the increase in immunoproteins and lysozyme levels, and this result in a significant immunoproteins deficit. Since oral clearance and immunologic mechanisms are potent means of host protection, their compromise is intrinsically related to changes in the oral flora of irradiated patients. One of the major radiation-induced changes in the oral flora is a pronounced increase in acidogenic, cariogenic microorganisms, at the expense of non-cariogenic micro-organisms. The most clinically significant changes are the increase of Streptococcus mutans, Lactobacillus species, and Candida species

The major changes in the oral flora as a result of hyposalivation after radiotherapy are observed in the period from the onset of radiotherapy to three months after completion.
 

Table 1: Consequences of Radiation-induced Hyposalivation

Dryness of the mouth                                   Burning sensation

Thirst                                                            Taste disturbances

Difficulties in oral functioning                     Alterations of soft tissues

Difficulties in wearing dentures                   Shift in oral microflora

Nocturnal oral discomfort                            Radiation caries

Mucus accumulation                                    Periodontal disease



The above Table shows a list of the consequences of radiation induced hyposalivation. Oral function (speech, chewing, and swallowing) is hampered because of, e.g., insufficient wetting and lubrication of the mucosal surfaces. Moreover, swallowing and chewing are impeded because of insufficient moistening of food by saliva. The increased viscosity and reduced flow of saliva cause intolerance to prosthetic appliances. Saliva is an effective lubricant at the denture-mucosal interface.

With lesser amounts of saliva present, retention of the denture is poor and more friction is produced during function, which may easily traumatize the vulnerable irradiated oral mucosa. Many patients suffer from nocturnal oral discomfort. They are often awakened at night by a serious dryness of the mouth or have to get up frequently because of polyuria due to polydipsia throughout the day. The oral mucosa can have a dry, atrophic, pale, or hyperemic appearance. The mucosa of the tongue can exhibit similar features or appear fissured. The lips may be dry, cracked, or fissured. These changes in the oral mucosa are, in general, typical for xerostomia of any origin.

Composition (buffer capacity, pH, immunoproteins, and oral clearance) may result in rapidly progressing radiation caries, along with a greater incidence of periodontal infections. The caries susceptibility is further increased by altered eating habits. Due to the radiation-mediated changes such as mucositis, atrophy of oral mucous membranes, hyposalivation, and taste loss, the diet of irradiated patients shifts to softer, sticky, carbohydrate rich foods, with an increase in the frequency of intake—all of which promote caries. The average daily energy intake is about 300 kcal lower in irradiated patients with dry mouth symptoms.

Prevention And Management 2,3,4
The most effective intervention for reduced salivary gland function is its prevention, because once chronic hyposalivation occurs, treatment essentially relies upon stimulation of the residual secretory capacity of the salivary glands, the use of saliva replacements if the result of stimulation of the residual salivary flow is insufficient, or possibly, in future, by gene transfer to repair hypofunctional gland parenchyma or to produce secretory transgene products.

Surgical transposition of the submandibular salivary glands outside the treatment portals has also been described as a successful method for the prevention of hyposalivation, but its indications are limited. At present, prevention of radiation damage to salivary glands is best accomplished by meticulous treatment planning and beam arrangement designed to spare as much of the parotid and submandibular glands as possible Changing a conventional schedule of fractionated radiotherapy into a schedule of continuous, hyperfractionated, accelerated radiotherapy (CHART) results in some sparing of salivary gland function, but the effect is insufficient to be of clinical significance.

A better option might be to attempt to spare one of the parotid glands by three-dimensional treatment planning and conformal dose-delivery techniques. This has been shown not only to reduce the radiation-induced impairment of salivary gland function, but also, concomitantly, to improve the xerostomia- related quality of life when compared with conventional radiotherapy.

Second to meticulous treatment planning and beam arrangement, the greatest potential to prevent salivary glands from post-radiotherapy functional loss comes from sialogogue studies. Of the sialogogues, pilocarpine has been most extensively studied. Administration of pilocarpine or pure cholinergic sialogogues to stimulate any residual function of the salivary gland post radiotherapy is worthwhile to a limited extent, because the functional gain ceases as soon as the administration of the sialogogue is stopped.

That means that the patients have to use these sialogogues, with all their side-effects, for the rest of their lives. Probably, a significant part of the beneficial effect of pilocarpine on post-irradiation xerostomia can be attributed to stimulation of the minor salivary glands, since the minor palatal glands have been shown to have a greater resistance to and ability to recover from irradiation than serous parotid glands.

A more persistent effect of pilocarpine can be observed when its administration is started before radiotherapy, continued during radiotherapy, and then stopped three months post radiotherapy. In such a case, the observed sparing effect on salivary gland function lasted for a much longer period of time, but the sparing effect was observed in only those patients in whom at least a part of the salivary glands was not included in the treatment portals.

Subjectively, it has been shown that amifostine has a potential to reduce xerostomia during and after radiation treatment. Unfortunately, this drug has also been shown to have the undesirable effect of tumor protection. Thus, caution must be exercised, since most clinical studies do not have the power to evaluate the influence of amifostine on the therapeutic index.

Unfortunately, the treatment of hyposalivation still has to be palliative to some extent, because salivary glands are usually located within the treatment portals for head and neck cancer, and because, at present, only part of the irradiation injury to salivary glands can be resolved in the clinic. This treatment consists of good oral hygiene practices, stimulation of residual salivary gland tissue (sialogogues), and symptomatic relief of oral dryness. Sialogogues can be divided into gustatory, tactile, and pharmacological substances.

With regard to gustatory stimuli, acid-tasting substances, in particular, are used as candies to increase salivary secretion. Bitter-tasting substances also stimulate salivary secretion, whereas sweet-tasting substances stimulate salivary flow to a lesser extent and can even exacerbate the sensation of a dry mouth. A combination of tactile and gustatory stimuli is found in chewing gum. In all compositions of gustatory sialogogues, the sugar-free ones are widely recommended.
 

Table 2: Some frequently used gustatory and tactile sialogogues

Gustatory and Tactile Sialogogues

Acid-tasting substances:

  1. Vitamin C tablets
  1. Citric Acid crystals
  1. Acid (sugar-free) sweets
  1. Lemon pastilles
  1. Lemon slices
  1. Acid or effervescent drinks (lemon juice, citric acid, buttermilk)
  1. Cotton-wool gauze soaked in a citric acid and glycerin solution

 

Miscellaneous substances:

  1. Sugar-free chewing gum
  1. Sugar-free sweets
  1. Dried pieces of reed root (calami rhizome)
  1. Vegetables or fruits
 

TABLE 3: Common Pharmacological Sialogogues

Pharmacological Sialogogues

  1. Pilocarpine hydrochloride, pilocarpine nitrate
  1. Anetholetrithione
  1. Carbachol
  1. Cevimeline
  1. Folia Jaborandi and tinctura Jaborandi
  1. Betanechol chloride
  1. Neostigmine, neostigmine bromide, pyridostigmine bromide,
  1. destigmine bromide
  1. Trithioparamethoxyphenylpropene
  1.  Benzapyrone
  1.  Potassium iodide
  1.  Nicotinamide and nicotine acid


Stimulation of the residual capacity by acupuncture has led to some promising results and may be of help for certain patients in the future. This procedure, however, needs further study. When stimulation of residual secretion is insufficient to relieve patients' complaints, one is left with a purely symptomaticapproach. For such patients, the stored autologous saliva collected before irradiation or the saliva from other patients (saliva bank) might be a worthwhile solution), but many patients regard this treatment as gruesome.

Therefore, many rinsing solutions have been developed to moisten the dry, irritated, vulnerable mucosa with the aim of reducing secondary effects. The simplest technique is frequent moistening of the mouth with water, tea, and saline, solutions containing sodium (bi) carbonate and sodium chloride, or diluted milk of magnesia. Mouthwashes containing irritating substances (sharp tastes, alcohol) must be avoided because of their effect on the thin, dry, atrophic mucosa.

An important disadvantage of all these mouthwashes is the necessity of frequent applications because of poor retention properties. For this reason, many clinicians treat xerostomia with more viscous glycerin-containing mouthwashes, which require less frequent application. Furthermore, complex saliva substitutes have been developed that contain agents not only to impart viscosity and to keep soft tissues moist but also, via inorganic substances, to retard enamel solubility.

These substitutes are based on either carboxymethylcellulose (CMC). The addition of fluoride to saliva substitutes increases the potentially enamel-remineralizing properties of the saliva substitute. Mucin-containing saliva substitutes are usually preferred over CMC-containing substitutes, by patients with both Sjogren's syndrome and radiation-induced xerostomia. In addition, it has been suggested that mucin-based artificial saliva is also more effective in restoring normal oral flora, an effect that has not been observed with other types of saliva substitutes.

When compared with the CMC substitutes, mucin-containing substitutes have superior rheological and wetting properties. More recently, a promising substitute which contains xanthan gum as a base has been developed. It mimics natural saliva better than the CMC-based substitutes. In addition to the more 'liquid-like' saliva substitutes, more 'gel like' saliva substitutes have been developed of which the polyglycerylmethacrylate-based substitute holds promise, particularly when used at night and when daily activities are at a low level. Often patients object to the taste or inconvenience of using artificial saliva, and return to the use of water.

Based on the literature, the following recommendations for the treatment of hyposalivation have been proposed

Severe hyposalivation:

A saliva substitute with gel-like properties should be used during the night and when daily activities are at a low level. During the day, a saliva substitute with properties resembling the viscoelasticity of natural saliva, such as substitutes which have xanthan gum and mucin (particularly bovine submandibular mucin) as a base, should be applied.

Moderate hyposalivation:

If gustatory or pharmacological stimulation of the residual salivary secretion does not provide sufficient amelioration, saliva substitutes with a rather low viscoelasticity, such as substitutes which have carboxymethylcellulose, hydroxypropylmethylcellulose, mucin (porcine gastric mucin), or low concentrations of xanthan gum as a base, are indicated. During the night or other periods of severe oral dryness, the application of a gel is helpful.

Slight hyposalivation:

Gustatory or pharmacological stimulation of the residual secretion is the treatment of choice. Little amelioration is to be expected from the use of saliva substitutes.

Dentition 1

During and following a full course of radiotherapy, many patients experience an increased dental sensitivity to temperature changes and to sweet- and sour-tasting foods which possibly is related to the loss of the protective layer of saliva. The most threatening complication for the dentition, however, is radiation-related caries. Radiation caries is a highly destructive form of dental caries which has a rapid onset and progression. Dental caries may become evident as early as three months following the initiation of radiotherapy.

In severe cases, a previously healthy dentition can be completely lost within a year. Clinically, three types of caries lesions can be observed. All three types of lesions can be observed within the same mouth. In view of the rapid progression, it is surprising that there is rarely any acute pain associated with radiation caries, even in its most severe manifestations.
 
Figure 3: Radiation Caries


The first type is a frequently observed lesion that starts on the labial surface at the cervical area of the incisors and canines. Initially, the lesion extends superficially around the entire cervical area of the tooth, and then progresses inward, often resulting in complete amputation of the crown. In the region of the molars, complete amputation of the tooth occurs less frequently; however, the caries tends to spread over all surfaces of the molar with changes in translucency and color leading to increased friability and breakdown of the tooth.

Occasionally, only a rapid wearing away of the incisal and occlusal surfaces of the teeth is seen either with or without cervical lesions. The second type of lesion is a generalized superficial defect that first affects the buccal and later the lingual or palatal surfaces of the tooth crowns. The proximal surfaces are less affected. This lesion often begins as a diffuse, punctate defect and then progresses to generalized, irregular erosion of the tooth surfaces. In this type of lesion, decay localized at the incisal or occlusal edges is often observed. The result is a destruction of the coronal enamel and dentin, especially on the buccal and palatal surfaces. The third type is less frequently observed. It consists of a heavy brown-black discoloration of the entire tooth crown, accompanied by wearing away of the incisal and occlusal surfaces.

Besides the rapid onset and progression, radiation caries is most commonly found on tooth surfaces (buccal, labial, lingual, palatal, incisal, occlusal) that are normally relatively immune to dental caries. The areas just below the contact points seem to be the last areas to be affected by radiation caries. Furthermore, the mandibular anterior teeth, which normally are the teeth most resistant to caries, are equally if not more affected by radiation caries. The characteristic attack on normally caries-immune, self-cleansing areas may be caused by changes in salivary flow and consistency that give rise to accumulation of a highly acidogenic dental plaque on these surfaces, and the result is a rapid decalcification of enamel.

In general, there is agreement that odontogenic cells in the pre-formative and differentiation phases are more radiosensitive than cells in the secretory or mature stage. If exposure to irradiation occurs before calcification, the tooth bud may be destroyed. Radiation at a later stage of development may arrest further growth and result in irregularities in enamel and dentin together with shortened roots, tooth eruption is mostly delayed but not hindered, but this phenomenon still needs further study.

Prevention And Management 2,3

Radiation caries is mainly an indirect effect of irradiation induced changes in salivary gland tissue that result in hyposalivation, altered salivary composition, a shift in oral flora toward cariogenic bacteria (S. mutans, Lactobacillus species), and dietary changes. For this reason, prevention of hyposalivation will invariably contribute to the prevention of radiation caries.

In the early days of radiotherapy, extraction of the teeth prior to irradiation was proposed. Comprehensive preventive measures have been recommended for head and neck cancer patients before, during, and after radiotherapy. Some of the recommended measures have included rigorous oral hygiene, daily self-application of topical fluoride, and limitation of cariogenic foods, remineralizing mouth rinse solutions, and artificial saliva preparations. Mainly based on clinical experience and empirical evidence, it is now generally accepted that almost complete caries prevention can be achieved in irradiated patients by the daily use of fluoride in conjunction with strict oral hygiene.

Interdental techniques such as flossing assisted, if necessary, with plaque-disclosing agents, can be beneficial. Caries lesions have to be restored before radiotherapy is started. Dietary instructions about non-cariogenic foods should be given. Finally, the patient's ability and willingness to co-operate in the dental therapy and preventive regimen should be assessed, since the level of compliance in this group of patients is often rather poor.

Periodontium 1

Decreased vascularity and acellularity of the periodontal membrane with rupturing, thickening, and disorientation of Sharpey's fibers and widening of the periodontal space have been reported after irradiation. The cementum appears completely acellular, and its capacity for repair and regeneration is severely compromised. Early changes include radiographic widening of the periodontal ligament spaces and destruction of bony trabecules. The changes in cementum and periodontal ligament may predispose individuals to infection .

The risk of periodontal infection is also increased due to radiation-induced hyposalivation, the concomitant increased plaque accumulation and shift in oral microflora. The direct and indirect effects of high-dose radiotherapy on the periodontium result in an increased risk of periodontal attachment loss and tooth loss, and even in an increased risk for the development of osteoradionecrosis. This underscores the need for proper pre- and post-irradiation treatment planning.

Prevention And Management2,3 As early as 1965, Silverman and Chierici stated that meticulous care must be taken in evaluating the periodontal status before, during, and after radiation treatment. Mechanical oral hygiene procedures (calculus removal, root planing, soft tissue curettage, tooth surface polishing, and daily plaque removal) must be used to remove the local etiologic factors of inflammatory diseases of the periodontium.

Bone1

The gross changes in the bone matrix after irradiation develop relatively slowly. The initial changes in bone result from injury to the remodeling system (osteocytes, osteoblasts, and osteoclasts). Osteoblasts tend to be more radiosensitive than osteoclasts; thus a relative increase in the lytic activity may occur. Whether the altered bone remodeling activity is the result of direct irradiation injury to the cells of the remodeling system or the indirect result of irradiation-induced vascular injury, or a combination of both phenomena, is still a matter of debate.

Radiation injury to the fine vasculature of bone and its surrounding tissues first leads to hyperemia, followed by endarteritis, thrombosis, and a progressive occlusion and obliteration of small vessels. Within bone, this results in a further reduction of the number of cells and progressive fibrosis. With time, the marrow exhibits marked acellularity and hypo- or avascularity, with significant fibrosis and fatty degeneration. Some lacunae may become devoid of osteocytes. The endosteum atrophies, with significant loss of active osteoblasts and osteoclasts. The periosteum demonstrates significant fibrosis, with a similar loss of remodeling elements found hypovascularity and fibrosis to be the common end-stage irradiation-induced tissue injury.

The most severe potential complication of bone irradiation is osteoradionecrosis. The incidence of osteoradionecrosis of the mandible varies from 2.6% to 22%; the range is most commonly from 5% to 15% in recent reports. The incidence of osteoradionecrosis of the maxilla is much lower. The definition of osteoradionecrosis is "bone death secondary to radiotherapy .

Some authors have advocated using the more general term "osteonecrosis", since necrosis of bone and soft tissue can also occur in other conditions, including cancer patients receiving chemotherapy and in diabetics. The latter authors have stressed that in radiotherapy, the exposure of soft and hard tissues—with subsequent hypoxia, hypovascularity, and hypocellularity—markedly increases the risk of necrosis. For those cases, they proposed the term "post-radiation osteonecrosis".
 
Figure 4: Post Radiation induce Osteoradionecrosis


The diagnosis of osteoradionecrosis is based mainly on patient history and clinical signs such as severe pain, non-healing (exposed) bone within the treatment area after completion of radiotherapy, and repeated infections. This process may progress to fistula or sequester formation and eventual spontaneous fracture. The presenting lesion (e.g., superficial involvement vs. localized or diffuse involvement of the mandible) dictates the treatment protocol to be followed and stresses the need for an effective clinical staging system.

In the early literature, the pathogenesis of osteoradionecrosis of the jaws was regarded as the inevitable triad sequelae of radiation, trauma, and infection. In this concept, trauma serves as a portal of entry for oral bacteria into the underlying bone. Osteoradionecrosis is thus considered to be an infectious process, which progresses rapidly and spreads throughout the bone that cannot wall off the infection because of compromised vascularity and minimal regenerative capabilities. The source of trauma may be anything, including denture irritation, sharp or hard food particles, and sharp bony ridges. Tooth removal is said to be the most common cause of trauma.

Later, Marx suggested that the underlying problem in osteoradionecrosis is a compromised wound-healing rather than an infection. Furthermore, osteoradionecrosis is as much a disease process of the covering soft tissues as that of the underlying bone. According to Marx, the sequence in the development of osteoradionecrosis is:
  1. Radiation;
  2. Hypoxic-hypovascular-hypocellular tissue: the ability of bone to replace normal collagen loss or normal cellular loss is severely compromised or non-existent;
  3. Tissue breakdown: unrelated to micro-organisms but related to the degree of radiation damage and the rate of normal or induced cellular death (Collagen lysis and cell death exceed synthesis and cellular replication.); and
  4. Chronic non-healing wounds: energy, oxygen, and metabolic demands exceed the supply.

Conceptually, spontaneous and trauma-induced osteoradionecrosis are different entities. Spontaneous osteoradionecrosis, which has been reported to occur in almost 35% of all cases of osteoradionecrosis, is related to increased age, high radiation dose (> 65 Gy), field of radiation (volume of the mandible included in the field and proximity of maximal dosing to bone), hyperfractionation, use of implant sources too close to the bone, and combined interstitial and external beam irradiation.

Trauma-induced osteoradionecrosis represents a mixture of cell death and cell injury. As the years pass after irradiation, the tissue becomes more fibrotic and more hypovascular. If the tissue is traumatized by surgical procedures (e.g., extractions) or by persistent infection, it is suddenly required to meet the demands of wound healing. The reduced healing capacity may result in osteoradionecrosis—a risk which increases with time.

Several pre- and post-irradiation factors may increase the risk of osteoradionecrosis. Pre-irradiation extraction followed by inadequate healing time is known to predispose to osteoradionecrosis. In dentulous patients, the osteoradionecrosis risk is increased after radiotherapy if there is a trauma in the radiation field, such as tooth removal or other surgical procedures (periodontal procedures, biopsies), poor oral hygiene and inadequate home care, and ongoing periodontal or periapical infection. In edentulous patients, trauma induced by prosthetic appliances is regarded as a predisposing factor, especially when related to certain mastication and Para functional habits.

However, the use of implants can minimize the trauma induced by prosthetic appliances. To date, no cases of osteoradionecrosis related to dental implants have been reported. In both the irradiated mandible and the maxilla, the placement of implants seems to be a reliable procedure, at least in the short term.

Prevention And Management 2,3,4

In addition to improved radiotherapy and shielding, the first step toward prevention of osteoradionecrosis is a thorough, early pre-irradiation dental assessment. This pre-treatment oral examination should attempt to identify the main factors that will likely increase the risk for osteoradionecrosis so that steps may be taken to control or eliminate as many factors as are practical before radiotherapy begins. The primary goal should be to optimize the condition of the patient's dentition, so that high-risk procedures, such as extraction of teeth, apicoectomies, etc., will not have to be performed in the post-irradiation period.

The value of this oral screening is limited if it is performed very close to the initiation of radiotherapy so as to preclude dental intervention. For maximum impact of screening, adequate time for treatment and healing must be allowed. Whether or not to extract teeth prior to radiotherapy to eliminate this potential source of infection has been a controversial issue for a long time. The timing of dental extractions in relation to the beginning or completion of radiotherapy has been studied by many investigators, and their findings have varied widely.

Pre-irradiation extractions, when performed and timed correctly, do not significantly increase the overall risk of osteoradionecrosis. It is now generally accepted that all teeth with a questionable prognosis must be extracted before radiotherapy
 

TABLE 4

Teeth with Questionable Prognosis to be removed before the start of Radiotherapy

  1. Advanced caries lesions with questionable pulpal status or pulpal involvement
  1. Extensive periapical lesions
  1. Moderate to advanced periodontal disease (pocket depth in excess of 5 mm), especially with advanced bone loss and mobility or Furcation involvement
  1. Residual root tips not fully covered by alveolar bone or showing radiolucency
  1. Impacted or incompletely erupted teeth, particularly third molars, that are not fully covered by alveolar bone or that are in contact  with the oral environment
  1. Teeth close to tumor


The less motivated the patient, the more aggressive one should be in extracting teeth prior to radiotherapy. The extractions should be performed as atraumatically (careful tissue handling) as possible and with primary closure. Frequently suggested healing intervals ranged from 10 to 14 days. An interval of 14 days still poses a minor risk for the development of osteoradionecrosis. The risk was reduced to zero if there was a 21-day or greater interval between extraction and initiation of radiation therapy. However, the time between the diagnosis of the tumor and the start of the radiotherapy should be kept as short as possible if the highest probability of cure is to be attained.

Extraction of teeth or wounding during radiation therapy will create an extremely high risk for osteoradionecrosis and is strongly discouraged, because surgical wounding and radiation wounding result in an additive problem for the patient Also, antibiotic coverage is strongly recommended. There is some evidence that hyperbaric oxygen (HBO) treatment is more beneficial than conventional antibiotic prophylaxis in preventing osteoradionecrosis (5% incidence of osteoradionecrosis vs. 30%, respectively. HBO therapy stimulates angiogenesis, increases neovascularization, optimizes cellular levels of oxygen for osteoblasts and fibroblast proliferation, stimulates collagen formation, and supports in growing blood vessels, all of which enhances the healing potential in irradiated compromised tissues. If extensive wounding or extraction in radiation portals is necessary, then HBO treatment should be used both prior to surgery and after wounding occurs.

Furthermore, after completion of the course of radiotherapy, there is a five- to six-month window of tissue repair and healing prior to the irradiation induced onset of progressive fibrosis and loss of vascularity. This healing phase is a much safer time to undertake necessary extractions, and HBO is usually not needed. There are two goals in the treatment of osteoradionecrosis, viz. Elimination of the necrotic bone and improvement in the vascularity of the remaining radiation-damaged tissues The presenting lesion dictates the treatment protocol to be followed, and this requires an effective clinical staging system, particularly for lesions in the mandible

The most widely used systems are the system developed by Marx (1983, 1984) and the clinical staging system of Epstein et al. (1997). The system of Marx (1983, 1984) focuses chiefly on the use of and response to HBO, and thus on the treatment of osteoradionecrosis; while the clinical staging system proposed by Epstein et al. (1997) is more concerned with its pathogenesis. The latter system classifies osteoradionecrosis as resolved, chronic persistent or active progressive, either with or without pathologic fracture.

Recently, Schwartz and Kagan (2002) modified the clinical staging system of Epstein et al. (1997) by focusing on the extent and nature of soft-tissue necrosis rather than on the presence or absence of a fracture.

They proposed three stages, subdivided into stages with and without soft-tissue necrosis. The first step in the treatment of osteoradionecrosis is débridement of all bone that is no longer vascularized. The removal of this dead bone eliminates any nidus for continued infection and inflammation, but does nothing to improve the vascularity of the adjacent tissue bed and the remaining vascularized bone.

These tissues remain compromised by the previous radiation and are at continued risk for the development of osteoradionecrosis in the future. Therefore, based on clinical experience and empirical evidence, a protocol has been developed aimed not only to improve the healing of radiation injured tissue, but also to increase their vascularity permanently. In this so-called Marx protocol, antibiotic therapy, hyperbaric oxygen therapy, and debridement are combined.

According to the Marx protocol, bone exposures of the mandible are initially treated by local debridement and HBO (stage I treatment). Smaller defects frequently close with this management. Defects that do not fully respond are treated by marginal mandibulectomy of the involved region, followed by additional HBO treatment exposures (stage II).

In case of failure of stage II management, initial defects that involve the inferior border of the mandible, defects having an oro cutaneous fistula, or pathologic fractures are managed by resection of the involved portion of the mandible down to a margin of healthy bone and stabilization of the defect by extra-oral fixation (stage III). Since osteoradionecrosis is a result of hypovascularity and not necessarily an infection, antibiotic therapy is considered adjunctive, the mainstay of treatment is surgical.

In summary, osteoradionecrosis is a lifelong threat to patients radiated in the head and neck region. Therefore, these patients need a proper dental check-up before treatment and close monitoring afterward. Since compliance is often a problem in these patients, one should be rather aggressive in extracting teeth prior to radiotherapy.

Muscles And Joints 1

Trismus, or limited jaw opening, may develop due to tumor invasion of the masticatory muscles and/or the Temporomandibular joint (TMJ), or be the result of radiotherapy if masticatory muscles and/or the TMJ is included in the field of radiation, or a combination of both. The limited jaw opening interferes with oral hygiene, speech, nutritional intake, examination of the oropharynx, and dental treatment, and can be particularly discomforting to the patient. Trismus occurs with unpredictable frequency and severity. Generally, trismus develops three to six months after radiation treatment is completed and frequently becomes a lifelong problem.

Trismus is attributed to muscle fibrosis and scarring in response to radiation injury as well as to fibrosis of the ligaments around the TMJ and scarring of the pterygo-mandibular raphes. Besides tumor growth and surgical procedures, the severity of trismus is dependent on the configuration of the radiation field (unilateral or bilateral), the radiation source, and the radiation dose. It has been reported that trismus develops after high radiation doses to the TMJ only, while other authors reported that trismus may already develop after low doses and increases with increasing doses. The most decisive factor which determines whether Trismus will develop is probably the inclusion of the pterygoid muscles in the treatment portals.

Prevention and Management 2,3

Prevention of trismus, rather than its treatment, is the most desirable objective. The maximum mouth opening (inter-arch or inter-incisal distance) should be measured before radiotherapy is started, and the patient and/or clinician should measure this distance frequently thereafter to ensure its maintenance. Patients at risk of trismus should be put on home exercises to maintain maximum opening and jaw mobility as soon as radiotherapy begins.

Use of tongue blades or rubber stops in these exercises to increase the size of mandibular opening is also recommended. In patients in whom trismus has developed, the exercise program should be intensified and, if necessary, combined with physiotherapy to regain the lost inter-arch distance. Prosthetic appliances (dynamic bite openers) containing springs and bands designed to re-stretch the muscles have been helpful in some patients. Whatever the approach to this problem, patient compliance and perseverance are critical for success, because dramatic results are not achieved immediately.

Nutritional Status 1

Several studies have shown that up to 60% of head and neck cancer patients were nutritionally compromised at initial diagnosis. A pre-operative weight loss of 10% of body weight has been reported as a predictive risk factor for major post-operative complications. During radiotherapy, oral intake of food may be impeded due to mucositis, loss of taste acuity, hyposalivation, and changes in viscosity of saliva.

Pain during chewing and swallowing due to mucositis or stomatitis which predisposes the patient to lose appetite, nausea, and malaise may further decrease the nutritional status and result in significant weight loss. The more frequent use of intensive chemo radiotherapy in head and neck cancer exacerbates this problem, since swallowing dysfunction is prevalent after such therapy. In general, it can be stated that a 10% loss of body weight is not uncommon following head and neck radiotherapy.

In severe cases of weight loss, nutrition either by a nasogastric tube or a percutaneous endoscopic gastrostomy (PEG) may become necessary. Patients often prefer a PEG rather than a nasogastric tube, but it has been reported that a PEG is often required for longer periods of time and is associated with more persistent dysphagia and an increased need for pharyngo-esophageal dilatation. These observations need further study. Weight loss leads to weakness, inactivity, discouragement, anorexia, and susceptibility to infection. It has been postulated that patients with a good nutritional and emotional status have improved tumor response to both radiotherapy and chemotherapy, but this hypothesis still needs to be validated.

In addition, the early and late morbidity of radiation treatment is less in patients who are in good health. It is therefore of utmost importance that a good nutritional and positive emotional status be maintained in the head and neck cancer patients receiving radiotherapy.

Conclusion

Radiotherapy should be the treatment of choice in all patients with early head and neck cancer where the use of surgery may result in significant alteration of anatomy and/or function. Radiotherapy can give nearly 100% tumor control in early-stage lesions (T1 NO).Advanced tumors (T4 N3)will have lowtumor control so for this reason, combined therapy may be indicated. Combined therapy is usually irradiation and surgery, but definitive radiotherapy reserving surgery for salvage of failures can be a valid alternative.

The latter is particularly so in terms of oral cavity and the oropharynx and for the neck metastatic lymph node problem. Improved cancer control activities aimed at prevention and early diagnosis should present a better future for these patients.Dental health care providers are a necessary part of the team and must be involved in the care of the head and neck cancer patient. Continuing research is needed in the field of radiotherapy.

REFRENCES
  1. Vissink A, Jansma J, Spijkervet FKL, Burlage FR, Coppes RP.Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 2003; 14(3):199-212.
  2. Vissink A, Jansma J, Spijkervet FKL, Burlage FR, Coppes RP.Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med 2003; 14(3):213-225.
  3. Sharma K, Mohanti BK, Rath GK, Bhatnagar S. Pattern of palliative care, pain management and referral trends in patients recovering radiotherapy at a tertiary cancer centre. Indian J Palliat Care 2009;15(2):148-54.
  4. Braam PM, Roesink JM, Raaikmakers CP, Busschers WB, Terhaard CH. Quality of life and salivary output in patients with head and neck cancer five years after radiotherapy. Rad Oncol 2007;2(3):1-8.

More References Are Available On Request

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