Abstract
The location of the primary tumor or lymph node metastases dictates the inclusion of the oral cavity, salivary glands, and jaws in the radiation treatment portals for patients who have head and neck cancer. The clinical sequelae of the radiation treatment include mucositis, hyposalivation, loss of taste, osteoradionecrosis, radiation caries, and trismus. These sequelae may be dose-limiting and have a tremendous effect on the patient’s quality of life. Most treatment protocols to prevent these sequelae are still based on clinical experience, but alternatives based on fundamental basic and clinical research are becoming more and more available. Many of these alternatives either need further study before they can be incorporated into the protocols commonly used to prevent and treat the radiation-related oral sequelae or await implementation of these protocols. In this review, the various possibilities for prevention and/or treatment of radiation-induced changes in healthy oral tissues and their consequences are discussed.
Introduction
Radiation therapy plays an important role in the treatment of patients with head and neck cancer. Depending on the location of the malignancy (primary tumor, lymph node metastases), inevitably, the salivary glands, oral mucosa, and jaws have to be included in the radiation treatment portals. As a result, changes induced by exposure to radiation occur in these tissues. The resulting oral sequelae may cause substantial problems during and after radiation therapy and are major factors in determining the patient’s quality of life (Vissink et al., 2003). Acute exacerbation of focal infection, e.g., periapical and periodontal infection, and severe mucositis occasionally may necessitate an adjustment or an interruption of the radiation treatment schedule. For all of these reasons, oral complications should be prevented or reduced to a minimum (Consensus statement, 1990; Jansma et al., 1992; Epstein and Stevenson-Moore, 2001). Most preventive procedures described in the literature are based on clinical experience, since there is a rather small number of sound clinical trials reported in the literature, and there is a great diversity in supportive care treatment policies and preventive approach policies in daily practice (Jansma et al., 1992; Scully and Epstein, 1996; Epstein and Stevenson-Moore, 2001; Schiødt and Hermund, 2002). In this review, the various possibilities to prevent or treat the radiation-induced changes in healthy oral tissues and their consequences are discussed.
Mucositis
Radiation mucositis is considered to be an inevitable but transient side-effect of therapeutic head and neck irradiation (Scully and Epstein, 1996; Karthaus et al., 1999; Plevovà, 1999; Sonis et al., 1999). Its occurrence and severity are strongly related to dose, fraction size, radiation portals, fractionation, and type of ionizing irradiation (Denham et al., 1999). The use of various radiation treatment modalities and schedules of fractionation can play an important role in the prevention of mucositis. The use of high-energy photonbeams, with linear accelerators, provides a more homogenous dose distribution in and outside the target area compared with the orthovoltage technique. This is due to the higher penetration of high-energy beams. Consequently, the number of hot spots in the normal tissues is reduced. This has resulted in some decrease in the incidence and severity of mucositis. More recently, it has been claimed that new irradiation techniques like hyperfractionation and accelerated treatment improve local control in head and neck cancer (Horiot et al., 1994; Russell, 2000; Vissink et al., 2003). Trials, however, have shown that the median time to onset of pseudomembranous mucositis was more rapid for patients treated on, e.g., an accelerated schedule, viz. 21 days for an accelerated schedule vs. 33.5 days for those treated with conventional fractionation (Denham et al., 1999). Some clinicians even apply a split-course accelerated schedule to keep mucositis within a tolerable range (Maciejewski et al., 1991). The increase in early toxicity caused by these new techniques remains a matter of clinical concern. Thus, effective control of mucositis has gained importance with implementation of these new radiation schedules. Currently, chemoradiotherapy is also applied more frequently for advanced head and neck cancer and in organ-sparing strategies (Bensadoun et al., 2001); consequently, the significance of effective mucositis prevention and treatment will further increase, since chemotherapy may induce an exacerbated local tissue reaction.
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 (Scully and Epstein, 1996; Zimmermann et al., 1998; Karthaus et al., 1999; Plevovà,1999; Sonis et al., 1999; Sutherland and Browman, 2001). 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.
Currently, 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 (Miaskowski, 1990; Scully and Epstein, 1996; Zimmermann et al., 1998). Although it has been suggested that good oral hygiene may reduce the development and severity of mucositis, no controlled studies of large numbers of patients have yet been undertaken. This is also the case for the other recommendations mentioned in this paragraph, which are all predominantly based on clinical experience rather than on controlled studies. Nevertheless, these recommendations still are a part of most protocols aimed to reduce the oral sequelae of head and neck radiotherapy. To prevent iatrogenic mucosal damage, irritating factors such as sharp or rough fillings should be smoothened or polished prior to radiotherapy, and prosthetic appliances should be closely evaluated (Engelmeier and King, 1983). Plaque control and oral hygiene should be maintained (Borowski et al., 1994; Scully and Epstein, 1996). Some authors recommend discouraging the wearing of dentures during radiotherapy (Curtis et al., 1976; Beumer and Brady, 1978). 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 (Lockhart, 1986; Epstein, 1990). In keeping with the aim of eliminating irritating factors, the use of tobacco, alcohol, and spicy and acidic foods should also be discouraged (Scully and Epstein, 1996).
For relief of pain and discomfort due to mucositis, several anaesthetics, analgesics, and mucosal-coating agents have been recommended (Scully and Epstein, 1996). In their meta-analysis of randomized controlled trials on the prophylaxis of radiation mucositis, Sutherland and Browman (2001) rated these agents as indirect (e.g., benzydamine) or direct (e.g., sucralfate) cytoprotectants. It has to be stressed, however, that these agents exert no therapeutic effect. Periodic rinses with topical anaesthetics such as viscous xylocaine (lidocaine) and benzydamine have been proposed (Dreizen et al., 1977b; Lockhart, 1986; Scully and Epstein, 1996; Meredith et al., 1997). For relief of pain and resolution of mucositis, encouraging results have also been reported with the use of sucralfate suspensions, which are believed to form a barrier on the oral mucosa (Makkonen et al., 1994; Franzén et al., 1995). However, this finding could not be reproduced (Meredith et al., 1997; Lievens et al., 1998), and therefore its clinical value is still questionable (Sutherland and Browman, 2001). (In)direct cytoprotectants, antibacterials have been used to prevent or reduce radiation mucositis (Sutherland and Browman, 2001). The potential beneficial effects of aqueous chlorhexidine rinses to control chemotherapy-associated oral mucositis have been reported (Scully and Epstein, 1996), but they are unable to control radiation mucositis (Spijkervet et al., 1989b; Epstein et al., 1992; Foote et al., 1994; Scully and Epstein, 1996; Adamietz et al., 1998). 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 (Rice and Gill, 1979; Spijkervet et al., 1989a; Martin and van Saene, 1992; Martin, 1993), 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 (Spijkervet et al., 1990). Several authors have studied the radiation-mucositis-reducing effect of polymyxin E/tobramycin/ amphotericin B (PTA)-containing lozenges, pastilles, or paste (Spijkervet et al., 1990, 1991; Symonds et al., 1996; Okuno et al., 1997; Wijers et al., 2001; El-Sayed et al., 2002). 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. This was also the conclusion of the Sutherland and Browman (2001) meta-analysis, which showed that only narrow-spectrum antibiotic lozenges have some benefit in the prophylaxis of radiation mucositis.
There is also a significant amount of preliminary research indicating that the administration of growth factors (granulocyte-macrophage colony-stimulating factor, keratinocyte growth factor) has a potential to reduce the development of radiation mucositis and can significantly promote healing (Nicolatou et al., 1998; Farrell et al., 1999; Mascarin et al., 1999; Wagner et al., 1999; Makkonen et al., 2000). The reduction of mucositis and promotion of healing by growth factors are most likely due to the stimulation of surviving stem cells (Dörr et al., 2001), but this needs further study, because these therapies may affect tumor response. This consideration is also applicable to the administration of the radioprotective agent amifostine during radiation treatment (Antonadou et al., 2002; Buntzel et al., 2002). A major flaw of most of the preliminary growth factor and radioprotector studies is that their trial design is at least questionable and the outcomes subject to debate (Sutherland and Browman, 2001). Nevertheless, the results of these preliminary studies are promising and may finally lead to modification of current oral care programs that are of limited efficacy in preventing and treating radiation mucositis. Clearly, high-quality randomized, placebo-controlled clinical trials are needed.
In summary, although there are major similarities in the etiopathogenesis of radiation mucositis and mucosal toxicity resulting from chemotherapy, radiation mucositis is more difficult to prevent and/or treat. Various agents have been shown to be potentially effective in the prevention and/or treatment of mucositis induced by chemotherapy, but not radiation mucositis (Worthington et al., 2002). Only the administration of antibiotic lozenges has been shown to be of some use in the reduction of the severity of radiation mucositis. Results with the administration of growth factors and radical scavengers are promising and need further study, focused not only on the prevention of mucositis but also on the potential effects of these therapies on tumor response.
Taste Loss
Alteration of taste sensation occurs as a result of the direct effect of radiation on the taste buds and due to changes in the saliva (Mossman, 1986; Spielman, 1998). In most instances, taste gradually returns to normal or near-normal levels within one year after radiotherapy (Tomita and Osaki, 1990). 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 radiochemotherapy (Buntzel et al., 2002). 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 (Lees, 1999; Erkurt et al., 2000). 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 (Vissink et al., 2003). 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 (Epstein et al., 1999a).
Some patients may be left with residual hypogeusia after radiotherapy. Zinc supplements are reported to be helpful in increasing taste acuity in such patients (Ripamonti et al., 1998; Matsuo, 2000). 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.
Hyposalivation
The most effective intervention for reduced salivary gland function is its prevention (Cooper et al., 1995), because once chronic hyposalivation occurs, treatment essentially relies upon stimulation of the residual secretory capacity of the salivary glands (Johnson et al., 1993; LeVeque et al., 1993; Blom et al., 1996; Johnstone et al., 2001), the use of saliva replacements if the result of stimulation of the residual salivary flow is insufficient (Vissink et al., 1987; Sreebny et al., 1995; Van der Reijden et al., 1996; Epstein et al., 1999b; Momm et al., 2001), or possibly, in future, by gene transfer to repair hypofunctional gland parenchyma or to produce secretory transgene products (Delporte et al., 1997; Baum and O’Connell, 1999; Atkinson and Baum, 2001; Vitolo and Baum, 2002). Surgical transposition of the submandibular salivary glands outside the treatment portals has also been described as a successful method for the prevention of hyposalivation (Jha et al., 2000), 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 (Hazuka et al., 1993; Cooper et al., 1995; Jones et al., 1996; Nishioka et al., 1997; Wu et al., 2000; Eisbruch et al., 1999, 2001; Henson et al., 2001; Roesink et al., 2001). Changing a conventional schedule of fractionated radiotherapy into a schedule of continuous, hyperfractionated, accelerated radiotherapy (CHART) results in some sparing of salivary gland function (Leslie and Dishe, 1991, 1994), 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 (Henson et al., 2001).
Second to meticulous treatment planning and beam arrangement, the greatest potential to prevent salivary glands from post-radiotherapy functional loss comes from sialogogue studies (Greenspan and Daniels, 1987; Joensuu et al., 1993; Johnson et al., 1993; LeVeque et al., 1993; Epstein et al., 1994; Rieke et al., 1995; Niedermeier et al., 1998; Horiot et al., 2000). 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 (Niedermeier et al., 1998).
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 (Valdez et al., 1993; Zimmerman et al., 1997). 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. Other studies could not repeat the potential protective effect of pilocarpine on post-radiation xerostomia (Lajtman et al., 2000; Mateos et al., 2001; Sangthawan et al., 2001), but this may be due to the large doses given and volumes irradiated. Valdez et al.(1993) and Lajtman et al.(2000) posed that the ’protective effect’ may be due to stimulation of salivary gland tissue outside the radiation portal. Rat studies, however, showed that pilocarpine has a protective effect on the irradiated tissue as well (Coppes et al., 1997a,b, 2001; Roesink et al., 1999) without influencing tumor response to treatment (Licht et al., 2002). Analysis of all of these data suggests that the administration of pilocarpine, as a prophylactic agent, is effective only when the radiation delivered to the salivary glands is limited in both dose and volume. Thus, a randomized double-blind dose-volume/salivary-gland-function study has to be performed to assess the sub-population of head and neck cancer patients in whom it is worthwhile to use pilocarpine as a protective agent. A clinically significant ‘sparing’ effect of the administration of pilocarpine can be expected only in those patients in whom a sufficient volume of salivary gland is treated with a dose on the steep part of the dose-response curve.
Direct radioprotection in a classic way may be achieved by the use of amifostine, a radical scavenger, when systemically administered during radiation treatment. Subjectively, it has been shown that amifostine has a potential to reduce xerostomia during and after radiation treatment (Antonadou et al., 2002; Buntzel et al., 2002). Unfortunately, this drug has also been shown to have the undesirable effect of tumor protection (McChesney et al., 1986). Thus, caution must be exercised, since most clinical studies do not have the power to evaluate the influence of amifostine on the therapeutic index. Also, the trial design of most amifostine studies is at least questionable and the outcomes subject to debate.
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 (Vissink et al., 1988a,b).
Sialogogues can be used to treat hyposalivation. Although a significant proportion of the salivary glands may be included in the radiation fields in patients with malignancies in the head and neck, it is rare that all the minor and major glands will be totally compromised by the radiation therapy (Greenspan, 1990). The unaffected or untreated parts of the salivary glands are the target for these sialogogues. 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 (Senahayake et al., 1998). 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 1 presents some frequently used gustatory and tactile sialogogues. With regard to the pharmacological substances, the potential beneficial effects of pilocarpine have already been discussed. Other drugs that have been reported to be of significance in the treatment of hyposalivation include anetholtrithione (Hassenstein et al., 1978; Epstein and Schubert, 1987) and cevimeline (Petrone et al., 2002). Common pharmacological sialogogues are listed in Table 2. Stimulation of the residual capacity by acupuncture has led to some promising results (Blom et al., 1996; Johnstone et al., 2001) 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 symptomatic approach. For such patients, the stored autologous saliva collected before irradiation or the saliva from other patients (saliva bank) might be a worthwhile solution (Sreebny et al., 1995), 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, saline, solutions containing sodium (bi)carbonate and sodium chloride, Emser salt, or diluted milk of magnesia (Vissink et al., 1988a,b). 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 (Levine, 1993). For this reason, many clinicians treat xerostomia with more viscous glycerine-containing mouthwashes, which require less frequent application (Klestov et al., 1981; Wiesenfeld et al., 1983). 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) (Matzker and Schreiber, 1972; Shannon et al., 1977) or mucin (’s-Gravenmade et al., 1974). The addition of fluoride to saliva substitutes increases the potentially enamel-remineralizing properties of the saliva substitute (Shannon et al., 1978; Vissink et al., 1985). Mucin-containing saliva substitutes are usually preferred over CMC-containing substitutes, by patients with both Sjögren’s syndrome and radiation-induced xerostomia (Vissink et al., 1983; Visch et al., 1986). In addition, it has been suggested that mucin-based artificial saliva is also more effective in restoring normal oral flora (Weerkamp et al., 1987), an effect that has not been observed with other types of saliva substitutes (Epstein et al., 1999b; Johansson et al., 2000). When compared with the CMC substitutes, mucin-containing substitutes have superior rheological and wetting properties (Vissink et al., 1984, 1986). More recently, a promising substitute which contains xanthan gum as a base has been developed (Van der Reijden et al., 1996; Jellema et al., 2001). It mimics natural saliva better than the CMC-based substitutes (Van der Reijden et al., 1994). 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 (Regelink et al., 1998; Epstein et al., 1999b), 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 (Van der Reijden et al., 1996), and return to the use of water. Klestov et al.(1981), Visch et al.(1986), and Vissink et al.(1987) believe that the most useful indices of the effectiveness of artificial saliva are the degree of night-time discomfort and difficulty in talking. Furthermore, the success of artificial saliva usage is strictly dependent on adequate instructions (Vissink et al., 1988a). In addition, there is also a great variation in the toleration to artificial salivas among patients (Van der Reijden et al., 1996). Because of this variability, it is worthwhile to use different types of saliva substitutes in a particular patient, to select the most effective substitute in that patient (Van der Reijden et al., 1996; Samarawickrama, 2002). A comparison of the effects of saliva substitutes and saliva stimulants (Anderson et al., 1995; Stewart et al., 1998; Rhodus and Bereuter, 2000) indicates that the effect of a treatment also depends on the remaining secretory potential of the salivary glands. Based on the literature, the following recommendations for the treatment of hyposalivation have been proposed (Regelink et al., 1998):
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.
In summary, other than by meticulous treatment planning and beam arrangement, radiation-induced hyposalivation is difficult to prevent. Radioprotective (pre)treatments, although promising, need further research with respect to dose-volume dependency (pilocarpine) and tumor protection (amifostine). Gene transfer technology may have to be considered, but much basic research has to be done before these techniques can be applied in the clinic. Possibly, the adenoretroviral vector, AdLTR, which infects dividing and non-dividing cells and mediates long-term transgene expression (Zheng et al., 2000) containing, e.g., one or more aquaporin genes, could be effective. The same applies to stem cell transplantation. Since most patients treated for head and neck cancer are elderly, and embryonic stem cells have their ethical problems, such studies may focus on multipotent adult progenitor cells (Jiang et al., 2002). The latter approach is currently under investigation at our institute, and the preliminary results are very promising. Although much research has been performed, a saliva substitute that is effective and can be applied in all patients is not yet available. When such a substitute is developed, it should ideally contain agents that not only lubricate and hydrate the oral tissues, but also other saliva constituents (Nieuw Amerongen and Veerman, 2002; Tenovuo, 2002) that are involved in the maintenance of oral health. Finally, we still do not know how much saliva or how much of a saliva substitute is needed to moisten the oral tissues in xerostomia patients adequately. There are quite a few patients who complain of oral dryness even though they exhibit a moist appearance of the oral mucosa and vice versa. This makes the choice of the cut-off point to decide whether a particular curative or symptomatic treatment is effective in xerostomia patients a hard one.
Radiation Caries
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 (Del Regato, 1939). Advocates for oral hygiene regimens (Martin and Sugarbaker, 1940) and restorative procedures (Frisch and Sproull, 1962) met with limited success in caries prevention in those days. Since then, comprehensive preventive measures have been recommended for head and neck cancer patients before, during, and after radiotherapy (Daly et al., 1972; Regezi et al., 1976). Some of the recommended measures have included rigorous oral hygiene, daily self-application of topical fluoride, limitation of cariogenic foods, remineralizing mouthrinse 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 (Dreizen et al., 1977a; Horiot et al., 1983; Jansma et al., 1989, 1992; Joyston-Bechal et al., 1992; Spak et al., 1994; Epstein et al., 1995). Interdental techniques such as flossing, assisted, if necessary, with plaque-disclosing agents, can be beneficial (Horiot et al., 1981; Jansma et al., 1992; Spak et al., 1994; Toljanic et al., 2002). 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 (Horiot et al., 1981; Jansma et al., 1992; Joyston-Bechal et al., 1992; Spak et al., 1994; Epstein et al., 1996; Toljanic et al., 2002).
Despite the magnitude of the problem of radiation caries, there are few reports of basic research on this topic. The preventive caries program consisting of daily oral hygiene and daily topical 1.0% NaF gel application by means of custom-made fluoride carriers, developed by Daly and Drane at the M.D. Anderson Cancer Center at Houston, TX (USA) (Daly and Drane, 1976), has been studied most extensively and forms the basis of the majority of the other studies. This regimen dramatically reduced caries incidence and was also successful in arresting existing lesions, regardless of the cariogenicity of the patients’ diet (Dreizen et al., 1977a,b). On the basis of a more-than-10-year experience with 935 head and neck cancer patients, Horiot et al.(1983) also concluded that this fluoride protocol was a highly reliable method for the prevention of radiation caries, and that the use of a toothpaste with a high fluoride content (3.0% NaF) twice a day was a good alternative, provided its pre-requisites (higher level of compliance) were well-understood by both clinician and patient. Also, fluoride mouthwashes have been used with considerable success (Meyerowitz et al., 1991; Joyston-Bechal et al., 1992), but this requires meticulous oral hygiene. Jansma et al.(1989) showed that the daily use of a 0.05% NaF mouthrinse or a weekly application of a neutral 1% NaF gel was ineffective in the presence of inadequate oral hygiene. The latter study showed that a neutral 1% NaF gel must be applied at least every second day. Good results have also been reported in a preventive program incorporating a chlorhexidine/fluoride regimen (Joyston-Bechal et al., 1992; Newbrun, 1996). Thus, although oral hygiene measures are important in the prevention of radiation caries, they are inadequate as a safeguard against radiation caries without self-applied fluoride applications at least every other day.
There is no consensus about the use of acidulated or neutral forms of topical fluorides, or about the use of sodium fluoride or stannous fluoride preparations. Although acidulated forms have the advantage of increased uptake, the low pH may result in significant mucosal irritation, burning pain, erythema, and ulceration, thereby affecting patient compliance with therapy (Beumer et al., 1979a,b). For this reason, many clinicians advocate the use of neutral or slightly acidic forms of NaF gel, since they are well-tolerated by patients (Dreizen et al., 1977a; Horiot et al., 1983; Jansma et al., 1989; Spak et al., 1994; Epstein et al., 1996). Others have prescribed acidulated phosphate fluoride gel (Carl and Schaaf, 1974) or acidulated forms of SnF2 gel (Fleming, 1983) without experiencing the above-mentioned problems. Less than 2% of the patients using an acidulated 0.4% SnF2 gel (pH 3.2) experienced soft-tissue irritation (Fleming, 1983). It appears, therefore, that the form of topical fluoride used may be dictated by the patient’s tolerance and acceptance, but it is still our experience that neutral fluoride preparations are better tolerated and result in a higher level of patient compliance than acidulated ones.
Because hyposalivation is irreversible in the majority of head and neck irradiation patients, the application of fluoride must be continued indefinitely, regardless of the chemical formulation and application method; otherwise caries will develop within months (Dreizen et al., 1977a; Horiot et al., 1983; Jansma et al., 1989; Epstein et al., 1996). Although no reliable data exist, it has been stated, on the basis of clinical experience, that, in some cases, fluoride use can be reduced following improvement in salivary gland function and continued good oral hygiene (Beumer and Brady, 1978; Beumer et al., 1979a,b; Spak et al., 1994).
Some beneficial effect has been reported with the use of remineralizing solutions and dentifrices, particularly when compared with the caries-preventive effect of conventional fluoride toothpaste in dry mouth patients (Papas et al., 1999). This should be considered as a valuable adjunct to the regular use of fluoride gels. Also, saliva substitutes, especially the ones containing fluoride, have been promoted as potential agents to retard enamel solubility (Shannon et al., 1978; Gelhard et al., 1983; Vissink et al., 1985; Kielbassa et al., 2000). It is questionable, however, whether this is of clinical significance, because of the high caries challenge in and limited use of saliva substitutes by these patients. Furthermore, one must be careful when applying a saliva substitute in a dentate patient, since certain saliva substitutes (e.g., saliva substitutes with a low pH or containing strongly charged polyanion polymers) have been shown to de- rather than remineralize enamel and dentin (Pankhurst et al., 1996; Van der Reijden et al., 1997; Kielbassa et al., 2000; Meyer-Lueckel et al., 2002).
In summary, radiation caries is a lifelong threat to patients who have received radiation treatment for head and neck cancer. Consequently, there is a lifelong need for meticulous oral hygiene and frequent fluoride applications. This preventive regimen, however, is often hampered by poor compliance in this category of patients.
Periodontal Disease
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. The overall effect of the use of mechanical procedures is the reversal or control of inflammation, and there is no controversy that these positive effects on the periodontium are beneficial as pre-treatment interventions (Wright, 1990; Position paper, 1997; Epstein et al., 1998). Optimal oral and periodontal hygiene must be maintained indefinitely, due to the lowered biological potential for healing of the periodontium (alveolar bone, periodontal ligament, cementum) after radiotherapy. The risk for development of periodontal disease and, consequently, osteoradionecrosis is diminished in patients receiving topical fluoride applications and also maintaining good oral hygiene (Yusof and Bakri, 1993; Position paper, 1997; Epstein et al., 1998; Epstein and Stevenson-Moore, 2001; Schiødt and Hermund, 2002).
Osteoradionecrosis
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 (Stevenson-Moore, 1990; Jansma et al., 1992; Constantino et al., 1995; Thorn et al., 2000; Schiødt and Hermund, 2002). 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 (Beumer and Brady, 1978; Beumer et al., 1979a,b; Stevenson-Moore, 1990; Jansma et al., 1992; Curi and Dib, 1997; Tong et al., 1999; Thorn et al., 2000). 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 (Sonis et al., 1990).
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 (Starcke and Shannon, 1977; Murray et al., 1980b; Makkonen et al., 1987). It is now generally accepted that all teeth with a questionable prognosis must be extracted before radiotherapy (Table 3) (Stevenson-Moore, 1990; Jansma et al., 1992; Thorn et al., 2000; Schiødt and Hermund, 2002). The less motivated the patient, the more aggressive one should be in extracting teeth prior to radiotherapy (Beumer et al., 1979a,b; Horiot et al., 1981; Jansma et al., 1992; Toljanic et al., 2002). The extractions should be performed as atraumatically (careful tissue handling) as possible and with primary closure (Jansma et al., 1992). Frequently suggested healing intervals ranged from 10 to 14 days (Beumer et al., 1979a,b; Murray et al., 1980b; Jansma et al., 1992; Tong et al., 1999). An interval of 14 days still poses a minor risk for the development of osteoradionecrosis (Marx and Johnson, 1987). 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 (see Vissink et al., 2003).
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 (Friedman, 1990).
A higher incidence of osteoradionecrosis is observed after cumulative radiation doses to the bone exceed 65 Gy (Murray et al., 1980a; Constantino et al., 1995; Curi and Dib, 1997; Tong et al., 1999; Thorn et al., 2000). Epstein et al. (1987a,b) have reported a two-fold increased risk of necrosis if teeth were extracted after radiotherapy compared with pre-irradiation therapy dental extractions. Also, antibiotic coverage is strongly recommended (Maxymiw et al., 1991; Jansma et al., 1992; Tong et al., 1999). 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; Marx et al., 1985). The real value of HBO in prevention and treatment of osteoradionecrosis still has to be proven in sound randomized controlled clinical trials. HBO therapy stimulates angiogenesis, increases neovascularization, optimizes cellular levels of oxygen for osteoblast and fibroblast proliferation, stimulates collagen formation, and supports ingrowing blood vessels, all of which enhances the healing potential in irradiated compromised tissues (Myers and Marx, 1990). If extensive wounding or extraction in radiation portals is necessary, then HBO treatment should be used both prior to surgery and after wounding occurs (Myers and Marx, 1990). 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 (Marx and Johnson, 1987). 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 (Constantino et al., 1995). The presenting lesion dictates the treatment protocol to be followed, and this requires an effective clinical staging system, particularly for lesions in the mandible (Epstein et al., 1997; Schwartz and Kagan, 2002). 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. Careful clinical research will make the treatment of osteoradionecrosis less empirical.
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 débridement are combined (Marx, 1983; Constantino et al., 1995). This protocol is widely used, but there is some discussion of whether HBO is always necessary, since many clinicians have noted that minor osteoradionecrosis lesions also can be treated without HBO (Schwartz and Kagan, 2002). According to the Marx protocol, bone exposures of the mandible are initially treated by local débridement and HBO (stage I treatment). Smaller defects frequently close with this management. Defects that do not fully respond are treated by marginal mandibuloectomy 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, and in fact HBO is also an adjuvant (Hao et al., 1999).
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.
Trismus
Trismus may be a significant side-effect of radiotherapy, especially in combination with muscular tumor invasion and surgery. The most decisive factor in whether trismus develops or not is probably the inclusion of the medial pterygoid muscles in the treatment portals (Goldstein et al., 1999). Prevention of trismus, rather than its treatment, is the most desirable objective (Goldstein et al., 1999). 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 (Dreizen et al., 1977b; Engelmeier and King, 1983; Lockhart, 1986). Lockhart (1986) recommended the use of tongue blades or rubber stops in these exercises to increase the size of mandibular opening.
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 (Dreizen et al., 1977b). Prosthetic appliances (dynamic bite openers) containing springs and bands designed to re-stretch the muscles have been helpful in some patients (Dreizen et al., 1977b; Engelmeier and King, 1983). Whatever the approach to this problem, patient compliance and perseverance are critical for success, because dramatic results are not achieved immediately (Lockhart, 1986).
Epilogue
As is discussed in this and the preceding review (Vissink et al., 2003), head and neck radiotherapy may result in several unwanted early (mucositis, loss of taste, hyposalivation) and late (hyposalivation, radiation caries, trismus, osteoradionecrosis) side-effects. These sequelae may be dose-limiting and may have a tremendous impact on the patient’s quality of life. Prevention or reduction to a minimum of these effects is possible and should be an integral part of head and neck cancer treatment. With the implementation of new radiation schedules such as hyperfractionation, accelerated fractionation, 3D conformal radiotherapy, and intensity-modulated radiotherapy in head and neck radiotherapy, the late-radiation effects can probably be reduced, but the remaining sequelae are still bothersome to the patients. Adequate prevention and treatment are matters of increasing importance because of the increasing numbers of aged, often dentate, patients. A crucial factor in the success of all preventive and treatment regimens is the compliance of the patient. Since compliance is rather poor in many head and neck cancer patients, much effort has to be made in making the patients aware of the dangers of not complying with the preventive protocols.
Footnotes
Acknowledgements
Support for the studies performed at our institutes was obtained from Praeventiefonds (grant 28-1290), the Dutch Cancer Foundation Koningin Wilhelmina Fonds (grants GUKC 83-20, RRTI 84-08, GUKC 86-03, GUKC 88-01, RUG 93.504, RUG 98.1658, RUG 02.2673), and the fellowship program of the Royal Dutch Academy of Arts and Sciences (1987-1992).