Oncology patients present particular challenges in management from the perspective of the general dental practitioner, and this is equally true even when the malignancy involves tissues beyond the head and neck region. When patients who have already been given a diagnosis present for a dental workup prior to surgery, chemotherapy or radiotherapy for their malignancy, the focus moves to careful screening for orodental diseases and conditions which may generate acute problems during the period of the patient’s in- and out-patient care, and compromise their medical care.
General dental practitioners may be asked by their patients for advice regarding optimal use of dental care products during periods of hospitalization, to reduce mucositis and other complications of care. This is an area which is outside the sphere of knowledge of most dental clinicians.
Finally, following treatment of their malignancy, the patient will return for care from their general dental practitioner, and now the emphasis is on continuous assessment, maintenance of oral health, and the prevention of long-term complications of cancer treatment.
This paper will address these issues in turn, using the most recent and highest level published evidence, and provide information on a range of strategies which are currently being explored to reduce the complications of cancer treatment. Active participation of the general dental practitioner in the patient’s overall care is essential so that appropriate preventive and therapeutic strategies are followed prior to medical treatments. The dental practitioner plays a critical role in the ongoing education of patients and in the maintenance of oral health for the remainder of the patient’s life, and through this makes a significant contribution to the patient’s quality of life.
Ideally, this phase should commence well before the patient’s medical treatment begins so that optimal oral health can be achieved, and wounds from extractions will have healed completely before chemotherapy and radiotherapy commence. The primary focus of the dental practitioner is to identify and remove sources of infection in the oral cavity before the patient commences their chemotherapy or radiation.
Screening for oral disease
A thorough clinical examination should be supplemented with a panoramic (OPG) radiograph. The value of an OPG rests mostly in screening for teeth with chronic endodontic pathology not previously disclosed, assessing third molars, and gauging the overall severity of periodontal bone loss across the dentition. Individual periapical radiographs can then be taken, with maximal diagnostic value.
Identification of oral foci of infection is critical in patients about to undergo chemotherapy since there will be some degree of suppression of host immune responses and particularly neutrophil levels from approximately 7 days after the commencement of chemotherapy. Endodontic foci of infection are a common problem during periods of neutropenia and are a recognized source of fevers of unknown origin1 (Fig 1). Panoramic radiographs have value both in child and adult patients for screening purposes prior to cancer treatment, and have been shown to be more useful than full mouth periapical films for assessing impacted third molars, detecting neoplasms, and identifying lesions of multiple myeloma.2,3 The patient is likely to undergo additional imaging studies, such as CT scans, MRI, and, occasionally, a nuclear medicine scan of bones, to detect metastatic disease. However, these investigations will normally be organized through their oncologist rather than by their dentist.
Gingival and periodontal therapy
Oral hygiene instruction should be given, emphasizing correct methods for toothbrushing and interdental cleaning. Scaling and prophylaxis, polishing of restorations, removal of overhanging margins and sharp edges, and correction of coronal anatomy should all be undertaken to maximize periodontal health.
There is a strong evidence base from which to recommend at this stage the use of an anti-plaque anti-inflammatory dentifrice to reduce gingival inflammation as rapidly as possible, and to establish as low levels of plaque as possible. There is an extensive literature which indicates that a triclosan/copolymer dentifrice (Colgate Total®) used twice daily will result in a significant reduction in both plaque and gingival inflammation, and that the reduction will be greatest in those sites that harbour the most plaque and have the most severe gingivitis. This same dentifrice has been shown to exert anti-inflammatory effects which slow the progression of periodontitis. These three issues are explored in depth in recent reviews.5–7
The initial assessment of patients with malignancies of the haemopoietic system may reveal oral lesions, particularly gingival infiltration in patients with leukaemias of myeloid, and less commonly, of lymphoid origin (Fig 2). The typical forms of leukaemia are acute lymphocytic leukaemia (ALL) in children, acute myelocytic leukaemia (AML) in teenagers and younger adults, chronic myelocytic leukaemia (CML) in adults, and chronic lymphocytic leukaemia (CLL) in patients aged above 40 years and in the elderly. However, leukaemias of different types can occur in patients of any age. Leukaemic enlargements occur because gingival tissue supports continuous trafficking of lymphocytes and macrophages, and contains specialized post-capillary venules for egress of these cells from the circulation into the tissues at sites of gingivitis or periodontitis.4
At the initial dental appointment, it is essential to discuss other aspects of oral self care, such as effective interdental cleaning and appropriate remineralizing treatments, so that the risks of dental caries and periodontitis are reduced to as low a level as possible before the patient’s medical treatment commences.
For effective remineralization, there is now extensive evidence from critical reviews to support the use of products which contain casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) for gaining the most effective caries prevention and remineralization, as the preferred option.8–10 Products such as GC Tooth Mousse™ can prevent tooth demineralization, improve enamel remineralization and enhance fluoride activity. The CPP-ACP complexes readily incorporate fluoride ions, forming casein phosphopeptide-amorphous calcium fluoride phosphate (CPP-ACFP), and this has led to the emergence of products such as GC Tooth Mousse Plus™,11 which would be preferred for patients to use from their initial workup through to their post-treatment maintenance. It is well known that the use of fluorides alone will not be effective in preventing dental caries in these high-risk patients.12
Teeth with small carious lesions can be treated conventionally, whereas teeth with irreversible pulpitis or periapical pathosis may require an alteration from the conventional treatment regimen. Ideally, a delay of at least 7 days should be sought between endodontic treatment and the onset of chemotherapy. Thorough biomechanical preparation of the root canal, placement of a calcium hydroxide paste, and a thick multi-layered restoration with strong sealing properties (such as glass ionomer cements used in a sandwich) are recommended because of the foreseeable problems of coronal leakage. Calcium hydroxide is the optimal material for inhibiting growth of bacteria in the root canal environment as an inter-visit dressing.13
Removal of teeth
One of the more difficult aspects of the pre-treatment phase is the management of severe caries and teeth with endodontic pathology. Provided that the patient’s haematological profile (particularly the level of platelets) is acceptable, and sufficient time exists for healing of the extraction sites, removal of chronically infected or exfoliating deciduous teeth, and endodontically compromised non-restorable permanent teeth can be contemplated. Ideally, extractions should take place 7–10 days prior to the commencement of chemotherapy or radiotherapy. Support with prophylactic antibiotics is normally considered mandatory when the granulocyte count is less than 2000/mm3, and a platelet transfusion if the platelet count is below 40 000/mm3.
A minimally traumatic surgical approach is essential for tooth removal in this case. Alveolectomy is often undertaken so that complete closure is achieved using multiple interrupted sutures, to allow healing by primary intention. Because of these particular requirements, such extractions are normally undertaken as part of a wider plan of care developed by the oncology team members as a group, rather than as an isolated procedure undertaken by the general dental practitioner.
Decisions regarding tooth removal are particularly important in patients who are to undergo radiotherapy of the head and neck region. Patients must be evaluated carefully before commencing radiation therapy so that any broken down and unrestorable teeth, and teeth with significant periodontal bone loss can be identified for extraction prior to radiotherapy. A range of guidelines exist for this decision-making process,14–17 but in essence the key issue is preventing the need for post-radiotherapy tooth removal that contributes to osteoradionecrosis (ORN), arguably the most severe sequel of radiotherapy to the head and neck region.
ORN develops frequently following dental extractions in irradiated sites because of the reduced vascular aspects of healing, causing vascular insufficiency, combined with altered cellular events including complex fibro-atrophic mechanisms.18 The incidence of mandibular ORN in head and neck cancer patients managed with radical or postoperative irradiation varies in the literature from 0.4% to 56%.19 Factors which influence the risk of ORN are listed in Table 1.
|Total radiotherapy dose||Tumour size and stage|
|Biologically effective dose||Anatomical location|
|Photon energy||Oral hygiene|
|Brachytherapy dose rate||Tobacco and alcohol use|
|Field size||Other illnesses|
|Fraction size||Pre-radiation bone surgery|
|Volume of bone irradiated with a high dose||Periodontal status|
The management of ORN is difficult and can involve significant time and cost. Treatments for ORN may cause significant bone and soft tissue loss, as well as pain and morbidity, which reduce quality of life. The treatments for ORN may range from saline irrigations, antibiotics, topically applied biocides, gentle removal of visibly loosened bone elements, through to surgical treatment augmented with hyperbaric oxygen, and radical resection of the lesion with subsequent reconstruction.17
ORN can occur from extractions undertaken before radiotherapy, and can occur in all areas of the jaws, not only in the posterior mandible, as is often believed. Although ORN occurs typically in the first 3 years after radiotherapy, patients remain at indefinite risk for the remainder of their lives. It is also clear that radiation-induced hyposalivation is irreversible and that the risks of developing caries, and ORN following tooth removal are life-long threats.20,21 It is for these reasons that prevention of ORN in the head and neck patient involves different and more radical decision-making processes than would normally be the case in routine dental practice.
Oral changes during radiotherapy for head and neck cancer
Fractionated megavoltage radiotherapy is a common treatment modalilty in this patient group, and it exerts profound effects on the oral and perioral tissues (Table 2). These treatments are usually given once or twice per day, 5 days per week, for up to 6 weeks. Each radiation treatment takes only a few minutes, although the sessions are much longer because of the need for precise positioning of the irradiating beam. Current methods of radiotherapy are designed to deliver less bystander injury and less scatter of radiation onto adjacent healthy tissues.
|Short term||Long term|
|Impaired nutrition||Aggressive dental caries|
|Taste loss||Impaired healing|
|Reduced quality of life|
Radiation induces inflammatory changes in the oral epithelium and its submucosa. Erythema develops after several days. The mucosa becomes deep red in colour, and becomes thin and friable. Ulcerations develop, and slough may be present where epithelial cells have not been removed by muscle activity or fluid flow. Epithelial structures which are specialized (such as papillae on the tongue) may disappear during this stage, and then regenerate to variable levels.
Direct effects of radiation on the blood vascular network (endarteritis obliterans) may reduce the blood supply to the oral cavity. This, together with impaired collagen synthesis, causes delayed healing of oral wounds such as ulcerations.
Both local radiotherapy and total body irradiation induce malformations of developing teeth, ranging from enamel hypoplasia through to growth arrest, with stunting of crown or root development. Radiation partially breaks collagen cross-links in dentine and causes physical changes at the dentino-enamel junction. However, the accompanying radiation-induced changes in salivary flow and in the properties of saliva are the major factors responsible for an environment which is highly conducive to rapidly progressive demineralization and cavitation which proceeds very rapidly at the cervical aspect, undermining the enamel and allowing brittle fracture of the labial enamel or the entire crown to occur (Fig 3).
Radiation for head and neck cancer causes a rapid and profound reduction in salivary output, as secretory acinar cells are damaged and are replaced by ductal elements and inflammatory cells. Radiation doses above 40 Gy result in irreversible damage to salivary glands. As salivary output reduces, the saliva becomes more viscous and more tenacious, and its lubricating properties decline dramatically. This is a permanent and irreversible change which will impact upon quality of life for the remainder of the patient’s life. In fact, during the early days of a patient’s radiation therapy, a painful transient enlargement of the salivary glands may occur because of the acute nature of the injury sustained.
The properties of saliva are affected negatively by irradiation of the salivary glands. The pH and buffering capacity of the saliva decline in synchrony, and the inhibitory effects of saliva on the oral flora (mediated by immunoglobulins, lactoferrin, and peroxidase) are greatly reduced. Accordingly, there is an increase in plaque accumulation as well as a change in the composition of the oral flora, with a predominance of aciduric bacteria, and thus increased caries risk. The same physicochemical changes are favourable to aciduric fungi such as Candida albicans, which can then cause overt disease.
A range of factors other than radiation may contribute to salivary dysfunction in the head and neck cancer patient, including chemotherapy, dehydration, and medications.
Total body irradiation
Total body irradiation, as is used in the treatment of lymphoblastic leukaemias or as part of pre-marrow transplant conditioning, can cause stunting of dental development in children, however the photon density is too low in the head and neck region to cause permanent injury to salivary glands or to the dentine of erupted teeth. Transient reductions occur in salivary output, which are reversible over the ensuing months, providing no secondary conditions develop which damage the glandular elements.
Cytotoxic chemotherapy is widely used in oncology, the principle being that malignant cells with their uncontrolled high turnover will be affected in a semi-selective fashion. Chemotherapy also kills rapidly growing healthy cells, accounting for its well-known side effects of oral mucosal ulceration (mucositis), hair loss (alopecia), bone marrow suppression, and gastrointestinal problems.
Modern chemotherapy typically uses a number of agents in combination, particularly for treatment of haemopoietic malignancies such as leukaemias and lymphomas. A broad range of agents are available, including hypomethylating or demethylating agents, tyrosine kinase inhibitors, histone deacetylase inhibitors, and proteasome inhibitors. Added to these may be immunomodulators, retinoids, monoclonal antibodies, dendritic cell and other cancer vaccines, and donor lymphocytes. The side effect profile varies dramatically from one class of agent to another, as well as within the one group.
Chemotherapy is usually given in a series of cycles, each of which involves intensive treatment over several days, followed by a period for rest and recovery. Cytotoxic chemotherapy is often delivered on an outpatient basis, and patients are monitored for the development of infections and other complications, and if these occur are admitted so that infections, fevers, neutropenia, and other complications can be managed promptly. Patients undergoing high dose chemotherapy, for example as conditioning for haematopoietic cell transplantation, or to treat acute leukaemic disease in blast crisis, are particularly prone to dental side effects (Table 3). These complications will be worse when chemotherapy is combined with radiotherapy.22
|Depressed salivary output (transient)|
|Impaired oral hygiene|
|Bone marrow suppression|
|Accelerated periodontal destruction|
|Acute necrotizing ulcerative gingivitis|
|Reactivated oral viral infections such as HSV|
Oral mucositis, with its accompanying ulceration of the oral mucosa, is perhaps the most important of the complications of chemotherapy and radiotherapy, since it restricts oral intake, and may necessitate nutritional support in the form of total parenteral nutrition (TPN), which then leads to increased length of hospitalization and increased costs of treatment. As well as nausea, dysphagia and alterations in taste sensations further reduce a patient’s desire to eat, and this reduction in oral intake makes nutritional support more likely. While the patient is still able to swallow, they are encouraged to have a bland, soft diet, and avoid acidic, spicy, strongly flavoured, and dry foods. Many patients begin by keeping their oral tissues moist by having frequent sips of water or by using ice chips, however this can cause fluid overload and intense headache, respectively.
The natural course of mucositis can be summarized as follows. Typically, oral mucositis begins 5–10 days following the initiation of chemotherapy. Xerostomia develops and early signs of mucositis appear, including dry glossy smooth areas in the posterior buccal mucosa, areas of epithelial atrophy in the tonsillar region. This progresses to diffuse erythema, with the development of mucosal erosions or ulcerations in the thin and friable epithelium of the buccal mucosa, floor of mouth, tonsillar folds, and lateral tongue. Ulceration of the posterior nasopharyngeal wall may also develop at this stage. Over the ensuing days, the severity of inflammation increases and then stabilizes. Pharyngeal involvement at this stage causes substantial discomfort with speech and swallowing. Healing of the oral ulcerations coincides with recovery of the peripheral blood leukocyte count, and is generally seen when the absolute neutrophil count becomes greater than 500 cells/μL.22 Factors affecting the severity of mucositis are summarized in Table 4.
|Agents used (worse with methotrexate, 5-fluorouracil, and cytarabine)|
|Dosing scheme (worse if continuously infused)|
|Concomitant use of radiotherapy|
|Concurrent use of haemopoietic growth factors|
|Concurrent use of keratinocyte growth factors|
|Age (worse in younger patients because of higher cell turnover)|
|Nature of the underlying malignancy (lower for solid tumours)|
|Re-existing oral health status|
|Pre-existing liver disease|
|Salivary flow rates|
|Chronic irritation from rough restorations or dentures|
|Compliance with mouth care protocols|
|Concomitant oral viral and fungal infections|
|Concomitant graft-versus-host disease|
Oral mucosal ulcerations provide a major portal of entry for infection, both into the perioral tissues and systemically. Gram negative facultative and strictly anaerobic bacteria from the oral cavity can cause septicaemia and thereby fevers of unknown origin. Because of their fastidious growth requirements, blood cultures may be negative. Adding to this process is the pyrogenic action of cytokines such as interleukin–1 beta and tumour necrosis factor alpha which are produced by host cells when exposed to the endotoxins from these Gram negative organisms. This explains why patients with oral mucositis and neutropenia have an elevated risk of septicaemia compared to neutropenic patients who do not have oral mucositis.
A major concern with oral mucositis is that its severity may limit the dose of chemotherapy that can be delivered to the patient, which then compromises the outcome of treatment. Conversely, if mucositis can be prevented or reduced, more aggressive chemotherapy regimens could be used, which may give higher rates of remission and cure. Examples of mucositis are presented in Fig 4. The regions most affected are the mobile parakeratinized mucosal tissues which have a high turnover, particularly the buccal mucosa, labial mucosa, soft palate, lateral tongue and floor of mouth. The orthokeratinized epithelia such as gingival and hard palate have lower rates of cell turnover and so are less affected by agents which target rapidly replicating cells.
As mucositis develops, areas of erythema and atrophy on the mobile mucosal surfaces break down to form ulcers covered by a yellowish white fibrin layer. These ulcers can coalesce to reach large dimensions, but fortunately will heal fully without scar formation when circulating leukocyte counts return to normal. Because of intense pain, patients with oral mucositis have great difficulties in opening their mouths, performing mouth care, and eating even soft foods.
Immune surveillance in the peripheral tissues is dramatically affected by chemotherapy and radiation, with loss of the dendritic cells which perform pivotal roles in presenting new antigens to the immune system. The physical architecture of the system is disrupted and takes some months to regenerate.23,24 It would be expected that this lapse in host defense would provide an opportunity for opportunistic infections, and this proves to be the case. Careful longitudinal studies of patients with periodontal disease show that loss of periodontal attachment can occur during periods of high dose chemotherapy because of the altered host response, even though there are not significant alterations in the prevalence of periodontal pathogens.25
Oral mucositis results from the action of anti-proliferative agents on the oral mucosa, and thus develops independently of oral mucosal infections. Because of bone marrow effects of chemotherapy, namely a corresponding neutropenia, patients become more prone to both bacterial and fungal infections during the neutropenic period which follows the commencement of chemotherapy. Acute necrotizing ulcerative gingivitis, other necrotizing periodontal conditions, and severe oral fungal infections have all been documented to occur at greatly increased prevalence during the period of neutropenia.26–28
These patients are also at elevated risk of oral viral infections, which can further exacerbate the patient’s discomfort. Recurrent oral viral infections encountered during chemotherapy include herpes simplex virus, Epstein Barr virus and cytomegalovirus. Herpes simplex viral lesions will typically present on the hard palate, the attached gingiva, or the dorsum of the tongue, while recurrent Epstein Barr virus can cause ulcerations in the soft palate region or hairy leukoplakia on the lateral margins of the tongue.
Bleeding from the oral tissues can be a significant issue during periods of chemotherapy. Patients who undergo high dose chemotherapy are typically rendered profoundly thrombocytopenic, and can suffer spontaneous gingival bleeding (Fig 5) as well as bleeding from sites of ulcerative oral mucositis, and bleeding into joint spaces (haemarthroses) (Fig 6). In patients with haemopoietic malignancies, oral lesions which may be seen include petechiae (clusters of reddish spots) and purpura (diffuse discolouration), particularly on the palate. Subtle traumatic injuries to the buccal mucosa and other sites may induce the formation of a sizeable haematoma.
In the thrombocytopenic patient, the management of oral bleeding employs several strategies. Gingival bleeding can be controlled by pressure, via the firm application of a gauze pad moistened with sterile saline, combined with an elevated posture. Topical anti-fibrinolytic agents such as tranexamic acid in the form of a mouthrinse is highly effective as an adjunct, while in severe thrombocytopenia, platelet transfusions will be required to prevent further spontaneous bleeding in the oral cavity as well as into the lungs and other sites. Because of the friable nature of the interdental col, patients should not use dental floss or interdental brushes when their platelet counts are below the normal range.
There are a range of methods for evaluating and scoring the severity of oral mucositis, which are used to communicate information between nursing and medical staff and dental professionals. Most scoring systems have both objective components (e.g., erythema and ulceration) and functional components (ability to speak, ability to eat, and self-rated pain). Some systems specifically guide treatment pathways and have been designed with nursing staff in mind as the primary clinical observers, by including mouth scoring as part of standard nursing observations.22 Specific advantages of such systems are that they are simpler to use and more informative than other published scoring systems, and have high reproducibility.
Mouth care during the in-patient period
A comprehensive mouth care protocol will include systemic agents to reduce the likelihood of recurrent infections (e.g., prophylactic fluconazole and acyclovir or valacyclovir for oral fungal and herpetic infections, respectively). Controlled trials have shown that oral and intravenous fluconazole is highly effective at reducing oro-pharyngeal and oesophageal candidosis, whereas compliance with topical antifungal agents is poor and their efficacy is low.27 Fungal infection of the oropharynx and oesophagus results in severe discomfort and pain, impairs nutrition, and in immune compromised patients poses a risk for disseminated fungal infection. In a clinical trial conducted in Brisbane, the combination of the topical antifungal agents nystatin and amphotericin did not prevent candidosis in 56% of bone marrow transplant patients, whereas 3% of patients receiving fluconazole showed clinical candidal infection. The nystatin/amphotericin suspension regimen was in general poorly tolerated. Complaints regarding the taste of the suspensions, or nausea and vomiting were made by two-thirds of patients. There were no side effects noted which could be attributed directly to fluconazole.
Oral debridement normally commences with patients using an ultrasoft toothbrush and a fluoride dentifrice combined with interdental cleaning, however once mucositis develops, pain from the oral mucosa makes performing normal mechanical oral hygiene impossible. Adding to this are the significant risks of transient bacteraemia and gingival bleeding, as neutropenia and thrombocytopenia develop.
To remove gross debris, standard mouth care protocols include the use of saline and sodium bicarbonate as ad libitum mouthrinses to hydrate the oral tissues, relieve symptoms of oral dryness and remove food debris. These same rinses can be used on cotton- or sponge-tipped applicators and gauze pads. Use of proprietary or commercial saliva substitutes is commonplace, with a range of products available.29–31 Interest in mucosa-coating agents remains high, and several commercial products appear to have value in this role, including MuGard™, casein derivatives,32 and CPP-ACP crèmes such as Tooth Mousse™.30,31 MuGard is a recently introduced, ready-to-use muco-adhesive oral wound rinse based on a hydrogel, which forms a protective coating over the oral mucosa. It is currently undergoing clinical trials in the United Kingdom for the prevention and treatment of mucositis, and initial results appear promising. The author has used GC Dry Mouth Gel™ in this patient group with good effect, and its buffered neutral pH is an advantage in terms of maintaining an appropriate oral pH.
Alcohol-free preparations of chlorhexidine have traditionally been used in oncology units, although there are several concerns with this, beyond the well-known problems of staining and taste alterations. In the context of mucositis, these issues are the inherently irritant nature of chlorhexidine, and its lack of effect on certain Gram negative bacilli such as Enterobactericiae, Pseudomonadaceae and Acinetobacter spp. which increase in number in the oral microflora during cancer treatment, but which are uncommon in the oropharynx of healthy individuals. Use of chlorhexidine in mouthrinse formulations does not appear capable of preventing these microbiologic changes since these organisms are resistant to it, and as a consequence a progressive change in the oral microflora occurs despite mouthrinse use.
Chlorhexidine does exert some antifungal activity against C. albicans, and mild antiviral activity against human herpes simplex virus, but cannot be relied upon to prevent these opportunistic infections. If alcohol-free chlorhexidine rinses or gels are used, staining problems can be reduced by using preparations with anti-discolouration chemistry,33 or by alternating the product with 1.5% hydrogen peroxide rinses.34 Moreover, to optimize the anti-plaque effect of chlorhexidine, the interval between toothbrushing or using a fluoride product, and rinsing with chlorhexidine should be more than 30 minutes.35
Because pain from mucositis is severe, pain control for mucositis is an integral part of mouth care. Typically this involves using benzocaine lozenges, 2% viscous xylocaine, viscous xylocaine mixed with diphenhydramine hydrochloride and bismuth subsalicylate (Kaopectate), benzydamine rinses, oral analgesics, and eventually progressing to narcotic analgesics such as morphine.22
Many agents have been suggested to have benefits for reducing oral mucositis accompanying chemotherapy and radiotherapy (Table 5). Despite initial interest in selective elimination of the oral flora to reduce head and neck radiotherapy-induced oral mucositis (lozenges containing polymyxin E, tobramycin, and amphotericin B), this concept has become less popular in recent years.36,37
|Oral cooling with ice chips||+++|
|Antibacterial rinses and lozenges (polymyxin E, tobramycine, and amphotericin B)||+++|
|Low level laser therapy||++|
|MuGard hydrogel rinse||+|
|Keratinocyte growth factor||++|
|Leukocyte colony stimulating factors (GM-CSF/G-CSF)||+++|
Several systematic reviews have examined the large literature on mucositis prevention. A subset of this which is gaining prominence is the literature regarding growth factors and cytokines.37,38 Haemopoietic growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF) have been promising when delivered intravenously, but have not shown benefits when used in a mouthrinse.38 There is current interest in fibroblast growth factor-20 as well as other agents.39,40
Recent interest has focused on intravenous administration of recombinant human keratinocyte growth factor (KGF) (Palifermin, Kepivance) for prevention of mucositis in patients with haematologic malignancies. KGF enhances the proliferation, differentiation, and migration of keratinocytes and this has potential to accelerate healing of oral ulcerations. Receptors for KGF are not present on cells of haematopoietic origin, and thus there is no change in the rate of bone marrow recovery. KGF is not indicated in patients with malignancies of epithelial origin because it enhances the growth of such cells. The typical dosing regimen for KGF is 60 μg/kg/day for 3 consecutive days before, and then 3 consecutive days after myelotoxic chemotherapy, for a total of 6 doses.41,42
Low level laser therapy (LLLT) is a further area of current research activity.43 LLLT exerts anti-inflammatory and analgesic actions, and is well tolerated by patients, although it should not be administered to any site where tumour residues may still be present. Animal studies have shown that infrared diode LLLT using parameters of 4 and 8 J/cm2 at a wavelength of 808 nm increase salivary flow rate and pH in rats, and this has been confirmed in other models as well as in humans.44,45 LLLT using the helium-neon laser (wavelength 632.8 nm) has been shown in many studies to improve salivary parameters and reduce mucositis induced by chemotherapy or radiotherapy, although there is ongoing discussion of the optimal dose parameters, while other wavelengths in the visible red region (660 nm) and near infrared region (808 nm) are also effective.46–54 Reported success rates are 81% (95% CI = 61–93%) and 83% (95% CI = 59–96%), when LLLT is used as a preventive treatment, or administered to patients with existing mucositis, respectively.53
Given the significant morbidity and high costs of mucositis, strong interest in its prevention and treatment will continue. A recent study estimated the financial cost of radiation-induced mucositis in a cohort of over 200 consecutive head and neck cancer patients. Oral mucositis occurred in 91% of patients, and in 66% it was rated as severe. The cost (in 2006 US dollars) of oral mucositis on a per patient basis was estimated as between $1700 and $6000, depending on the severity, because of the increased costs of care of these patients, through increased rates of hospitalization, opioid use, and a greater need for fluids and nutritional support. This high cost makes finding effective preventive strategies an attractive proposition.55,56
Any new topical treatment must show greater efficacy than the combination of saline and sodium bicarbonate mouthrinses that form the foundation of all mucositis care protocols.57,58 A recent Cochrane review identified more than 200 studies of mucositis interventions, including trials of agents as diverse as aloe vera, camomile, honey, folinic acid, povidone iodine, and prednisone.59 The review commented that interpretation should consider that benefits may be specific for certain cancer types and treatment, and suggested that future trials should have sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.
Once the patient has returned to outpatient status and can return to the dental office, a number of issues arise regarding their ongoing dental care. The patient will be at increased risk of dental caries and thus a more rigorous preventive programme should be followed, which includes neutral pH saliva substitutes as necessary, salivary pH elevation using sodium bicarbonate mouthrinses, use of a biocide to augment mechanical plaque control, control of acidic and cariogenic dietary inputs, and an effective remineralization strategy to prevent mineral loss from both dental caries and dental erosion.60–65
For post-radiotherapy patients, and those suffering from graft-versus-host disease (GVHD) after haemopoietic transplantation, persisting xerostomia impacts negatively on their quality of life by impairing speech and deglutition; making denture wearing problematic or impossible; increasing the rate at which dental plaque develops; increasing the risk of dental erosion and the rate of tooth wear; increasing the risk of both coronal and root surface caries; and enhancing the carriage of high levels of C. albicans. These patients occasionally experience infections of major salivary glands from staphylococci, as well as salivary gland enlargement and localized hyperthermia.
As well as using neutral pH salivary substitutes, patients can make their own sodium bicarbonate mouthrinse, and use this to elevate both pH and buffer capacity immediately after meals and snacks. Citric acid-flavoured products must be avoided, because of the sequestration of salivary calcium ions which will ensue if these are used with any degree of regularity.
Biocides used in at-home care in these patients can include agents such as a triclosan/copolymer dentifrice, since its inherent anti-inflammatory properties will be of assistance in reducing irritant responses to sodium lauryl sulphate in the dentifrice. Alcohol-free chlorhexidine rinses and gels can continue to be used, on an intermittent (weekly) basis so that staining of dental deposits (plaque and calculus), as well as of the tongue and the margins of restorations does not become problematic.
Patients can apply high concentration (9000 ppm) neutral sodium fluoride gel for 4 minutes each day in a custom applicator tray. This is an effective biocide and does not cause staining. However, it does not provide an appropriate solution for remineralization, thus products which release bio-available calcium, phosphate, and fluoride in the correct ionic ratio for remineralization are critical, such as Tooth Mousse Plus™.
Patients who have undergone chemotherapy with or without radiotherapy as conditioning for bone marrow, stem cell or cord blood (haemopoietic) transplantation will be at risk of additional oral disease if their transplant was not autologous (self donated) or syngeneic (from a mono-zygotic twin). These complications include gingival hyperplasia induced by cyclosporin A or other medications such as nifedipine, and GVHD, a condition which is driven by cytotoxic reactions and the release of cytokines, particularly tumour necrosis factor.
There is a strong link between both conditions and immune response genes. Cyclosporin-induced gingival overgrowth has been linked to certain tissue types, which increase susceptibility.66 Synergism occurs with nifedipine and other Ca channel antagonists. The mandibular incisor region is generally the most severely affected, but other areas are also affected, particularly if there is a mouthbreathing habit, or the standard of plaque control is poor. Typical prevalence rates are 12–20% in adults, and greater than 90% in children.
This hyperplasia is reversible and the gingival architecture returns to normal once cyclosporin therapy is discontinued, typically some two years after the transplant. Maintenance of good oral hygiene and regular monitoring of dosage are recognized as critical in reducing untoward effects of cyclosporin on the gingival tissues. Surgical debulking (e.g., by CO2 laser) is rarely needed in such patients, unlike the situation with patients who receive solid organ transplants. The difference between the two groups relates to the dosages used and exposure time. For GVHD prevention and control, typical serum levels are 200 μg/mL, whilst in organ transplants, as an anti-rejection drug, serum levels must be in the range of 300–400 μg/mL. Haemopoietic transplant patients are weaned off the drug at approximately 2 years post-transplant, whilst solid organ transplant recipients will remain on the drug for their lifetime. As a consequence, reported rates of cyclosporin gingival overgrowth in the latter group range from 26 to 90%.66 Switching from cyclosporin to tacrolimus obviates the problem since this alternative drug does not cause gingival overgrowth. It is not, however, used as the first line immunosuppressive agent because of its high cost.
GVHD affects salivary glands and the oral mucosa, as well as the gastrointestinal tract, liver, and the skin. GVHD is an important cause of persisting xerostomia in such patients. A long-term clinical study of post-transplant dental effects of patients from the Royal Brisbane and Women’s Hospital revealed that some 31% of allogeneic recipients experienced persistent xerostomia five years after receiving their transplant.67
The reduced output results from infiltration and destruction of salivary glands (lymphocytic sialadenitis), in a pattern which resembles Sjögren’s syndrome. In parallel, the normal population of IgA producing plasma cells in the major glands, which is critical for the maintenance of mucosal immunity in the oral cavity, is reduced.
It is common to find oral lichenoid lesions as these are the most common oral manifestation of both acute and chronic GVHD. More than 50% of patients who have received allografts will show such lesions. The most frequent site is the buccal mucosa, where the lesions have a reticular appearance and are rarely painful. These classical lesions of intraoral GVHD are composed of whitened plaques interconnected by fine white rings and streaks (Wickham’s striae). These lichenoid eruptions resemble very closely lesions of oral lichen planus from clinical, histopathological and immunohistological standpoints.
Other variants which may also occur include an atrophic form, with smooth red areas and peripheral striae (e.g., gingivae), or an erosive form, with irregular ulcerated areas on the vestibular mucosa, floor of mouth, and lateral tongue. Lesions involving the oral mucosa on the floor of mouth, tongue, and gingiva are less common, but are usually both erosive, and painful. Fortunately, these often respond well to topical steroid treatment.68 Changes in systemic immunosuppressive therapy are indicated for problematic painful oral lesions of GVHD.
Other long-term complications of haemopoietic transplants (defined as those present after day 100) include oral lesions which occur secondarily to the immune compromised state, such as chronic candidosis, reactivated viral infections, oral hairy leukoplakia, and malignancies.
A key aspect of post-treatment care of the oncology patient is regular dental maintenance care. This should initially be scheduled at three-monthly intervals for the first year. Each visit should include removal of deposits (scaling and prophylaxis), oral hygiene instruction, followed by careful inspection of teeth for decalcification and recurrent caries, and fluoride varnish application to risk sites as indicated. Prior to removal of plaque, samples of dental plaque can be taken so that the level of acidogenic bacteria can be assessed. This provides a simple and rapid chairside assessment of caries risk.69 The patient should be instructed in an atraumatic brushing method and provided with a small headed ultrasoft or soft toothbrush. Frequency of brushing should be thrice daily. Interdental cleaning should be undertaken daily. The patient can be provided with self-care products for home application at this stage. The oral and perioral should be examined carefully for anomalies, including evidence of new hard and soft tissue pathology.