Potentially malignant oral disease and oral cancer
Potentially malignant oral disease is morphologically altered tissue that is present on clinical examination in which cancer is more likely to occur than in normal tissue. Examples include leukoplakia or erythroplakias. These lesions could be premalignant and exhibit dysplasia on histopathological exam. The overall risk for malignant transformation in oral dysplastic lesions is approximately 20% (Silverman et al, 1984). Approximately, 90% of oral cancers are squamous cell carcinomas.
Current treatment. Treatment of oral dysplastic lesions includes surgical management and the use of chemopreventive agents (Lodi et al, 2006). The treatment for oral squamous cell carcinomas may include single or combination modality surgery, radiotherapy, or chemotherapy [described in detail elsewhere (Haddad and Shin, 2008)]. As understanding of oral carcinogenesis has improved, it is now possible to target various operational mutations and aberrant molecular pathways. One targeted agent has been approved for the treatment of squamous cell carcinomas (cetuximab, an epidermal growth factor receptor antagonist), and several other agents are under development (Gold et al, 2009). Preventive activities, such as risk factor cessation coupled with close surveillance following treatment, are of paramount importance given the high rate of recurrent or new disease.
Problems with the current treatment. Aggressive treatment regimens associated with significant morbidity are used for treatment of later stage oral cancers. In the future, it is conceivable that targeted chemotherapies will become customized to an individual’s malignant disease, thus limiting morbidity. Improvements are needed in preventive activities including risk factor avoidance or reduction, early stage disease detection, and identification of individuals (or lesions) at higher risk for developing oral cancer. Currently, there are no reliable treatments to prevent malignant transformation of dysplastic lesions or the development of recurrent/new disease in patients with a history of oral cancer (Kelloff et al, 2006; Lodi et al, 2006). The difficulty in developing such a reliable treatment is that each individual cancer (or premalignant oral lesion) is unique, carrying its own blend of mutations and thus not all patients will benefit from the same therapy.
Novel formulations and research into improved topical drug delivery for oral cancer. Opportunities for the topical treatment of oral cancer are limited by the ability for a putative agent to reach the tumour effectively. As such, topical treatments are generally indicated for local (early stage) cancers, premalignant oral lesions, or in patients with field carcinogenesis who are at a high risk for new or recurrent disease. Topical agents such as tolonium chloride (toluidine blue) might be used to identify subclinical or low-risk disease that is predictive of malignant transformation (Zhang et al, 2005). There is paucity of literature on topical therapies, and most studies have explored their efficacy in the treatment of oral premalignant lesions.
Topical retinoids have shown variable efficacy in oral premalignant lesions over the short term (Tradati et al, 1994; Epstein and Gorsky, 1999; Piattelli et al, 1999; Gaeta et al, 2000). There have been two RCTs; one used a mucoadhesive disc to provide an extended release of acitretin into the oral cavity (Gaeta et al, 2000) and the other used an isotretinoin gel (Piattelli et al, 1999). An RCT exploring the efficacy of a topical ketorolac oral rinse demonstrated no efficacy (Mulshine et al, 2004), although some investigators suggest that the differential permeation of topically delivered NSAIDS or COX-2 inhibitors may impact efficacy (Sood et al, 2005), or that novel mucoadhesive delivery systems, such as a polymer film, may be feasible (Wang et al, 2007). Two studies demonstrated variable efficacy of topical bleomycin (Epstein et al, 1994, 1998), one was an RCT (Epstein et al, 1994). One novel study explored the efficacy of a topical rinse containing an attenuated adenovirus engineered to destroy p53-mutant cells in three cohorts of patients with oral epithelial dysplastic lesions (Rudin et al, 2003). There were some complete responses, although most were transient. The delivery of black raspberry anthocyanins in a bioadhesive gel showed limited efficacy in reversing or down-grading oral dysplastic lesions (Mallery et al, 2008; Shumway et al, 2008). A study exploring the pharmacokinetics and distribution/uptake of this gel to target tissues in oral lesion-free subjects demonstrated variability suggesting that these local factors could influence efficacy (Ugalde et al, 2009).
Observational studies using topical application of the photosensitizing agent 5-aminolevulinic acid applied to oral premalignant lesions followed by photodynamic therapy using a red light (630 nm) have reported a high response rate up to 6 months (Kubler et al, 1998; Sieron et al, 2003). The use of such topical photosensitizers may also facilitate early detection of potentially malignant oral lesions (Chang and Wilder-Smith, 2005). Further studies using this novel technique are needed.
Mucositis is an inflammatory condition of the oral mucosa, which results from cancer chemotherapy, particularly marrow conditioning regimens for bone marrow transplantation and head and neck radiotherapy, particularly for treatment of oral cancer. Dose-related mucosal damage results in painful ulceration and problems associated with eating, speaking and swallowing and an increased risk of infections. This can lead to significant morbidity and even delays or abandonment of anti-cancer treatment.
Current treatment. Current strategies for prevention and treatment of oral mucositis have been extensively reviewed in two recent Cochrane reviews (Worthington et al, 2007; Clarkson et al, 2010).
Problems with current treatment. Current treatments do not prevent patients developing mucositis; they are of low efficacy and mucositis still limits the use of chemotherapy and radiotherapy.
Novel formulations/research into improved topical drug delivery for mucositis. Intraepithelial delivery of transforming growth factor beta-3 (TGF-β3) to inhibit epithelial cell proliferation could have potential for the prevention of mucositis (Sonis et al, 1997; Squier et al, 1999). TGF-β3 temporarily arrests the cell division, protecting the cells from chemotherapy damage, but permits rapid proliferation and repopulation post-treatment. Topically delivered TGF-β3 was able to penetrate the epithelium and could be detected in the basal cell layer at therapeutically effective concentrations (Squier et al, 1999). Fifty per cent of TGF-β3 was found in the original homodimer state indicating that sufficient amounts of TGF-β3 remained stable in the epithelium and the saliva (Squier et al, 1999). Senel et al encapsulated TGF-β3 in a chitosan gel (a bioadhesive, biocompatible and biodegradable polymer commonly used as a permeability enhancer for medical applications) and demonstrated improved drug retention at the application site, six- to sevenfold increased permeability and protection against Candida infection (Senel et al, 2000). It is speculated that the chitosan could also provide a protective and lubricating barrier to reduce the discomfort experienced by patients suffering from the inflammatory and ulcerative condition of mucositis (Senel et al, 2000). There is also interest in the topical delivery of keratinocyte growth factor (KGF) for the prevention and treatment of mucositis. Currently, this drug is administered systemically (Spielberger et al, 2004).
Other treatment strategies include the use of mucoadhesive covering agents in the form of viscous mouthwashes and gels that provide physical coating and protection for thinned or ulcerated oral mucosa e.g. Gengigel®, Gelclair® and MuGard®. These agents do appear to provide some symptomatic relief for patients with mucositis. There is also some encouraging data on the potential beneficial effects of using a supersaturated calcium phosphate mouthwash to prevent oral mucositis (Papas et al, 2003).
Immunologically mediated diseases
Immunologically mediated diseases constitute one of the most common groups of disorders to affect the oral mucosa and thus form one of the main therapeutic challenges of contemporary oral medicine practice. These disorders usually centre upon T-cell [e.g. oral lichen planus (Sugerman et al, 2002; Lodi et al, 2005)] and/or B-cell [e.g. pemphigus (Mignogna et al, 2009) and mucous membrane pemphigoid (MMP) (Al-Johani et al, 2007)] dysfunction, although the precise immunological drivers of disorders such as recurrent aphthous stomatitis remain unclear (Jurge et al, 2006).
Current treatment and future treatment directions by disorder. Oral lichen planus (OLP): To date, the mainstay of therapy of OLP has been topical corticosteroids, but there have been few randomized controlled trials to definitively prove effectiveness (Zakrzewska et al, 2005). There is evidence that topical application of corticosteroids such as betamethasone mouthwash, fluticasone spray, fluocinolone cream, fluocinolone acetonide gel or in adhesive paste, dexamethasone mouthwash, clobetasol propionate (as cream, aqueous solution, ointment or in an oral adhesive paste) and mometasone furoate can each cause a lessening of the symptoms of OLP [reviewed by (Thongprasom and Dhanuthai, 2008)]. In recent years, there have been several studies of the potential efficacy of topical calcineurin inhibitors, notably tacrolimus and pimecrolimus for the treatment of OLP, but as yet there remain no well-powered studies that truly demonstrate clinical efficacy – although they may have a therapeutic role in the management of OLP that is recalcitrant to topical corticosteroids [reviewed by (Al Johani et al, 2009; Lopez-Jornet et al, 2010)].
Oral lichen planus has been suggested to be a TNF-α-driven disorder (Thornhill, 2001, 2010; Sugerman et al, 2002) and of relevance topical thalidomide (1% in paste) may be as effective as topical 0.043% dexamethasone in paste for the short-term treatment of OLP. Similarly, there are reports of systemic thalidomide being effective for mucocutaneous LP (Maender et al, 2005; Petropoulou et al, 2006). However, the use of thalidomide, even topically, is of concern because of its known adverse side effect profile (Porter and Jorge, 2002); however, the advent of thalidomide analogues with fewer side effects may provide the opportunity for local application of such anti-TNF-α agents. The human anti-TNF-α monoclonal adalimumab has been reported to cause resolution of cutaneous and vulval LP (Chao, 2009); however, LP-like disease has been reported as an adverse side effect of infliximab and adalimumab (Asarch et al, 2009), indeed OLP secondary to thalidomide has previously been reported (Bez et al, 1999). There are no open or randomized controlled studies of the efficacy of infliximab, adalimumab or etanercept for the treatment of LP. Similarly, the role of TNF-α in the pathogenesis of LP remains unclear. These, together with the challenge of the known adverse side effects of TNF-α agents, and the possible risk of reactivation of TB, would suggest that their systemic use for OLP may be questionable. Delivery systems that facilitate topical delivery of these to affected areas of mucosa could, however, revolutionize the treatment of OLP.
Similar to the TNF-α biological agents, there are almost no data on the potential efficacy of rituximab [an anti-CD 20 (B-cell) monoclonal antibody], although there is one report of clinical efficacy in a patient with oral, cutaneous and oesophageal disease (Parmentier et al, 2008). In view of the likely central role of T-cells in the pathogenesis of OLP (Thornhill, 2001, 2010; Carrozzo and Thorpe, 2009) it would be challenging, if not unjustifiable, to develop a therapeutic strategy based around rituximab.
Pemphigus. The clinical spectrum of pemphigus vulgaris (PV) (the most common form of oral mucosal pemphigus) (Black et al, 2005) suggests that topical agents are likely to have a role in the management of oral disease, although this will depend upon the severity of disease. As with OLP, the topical agents that have previously been employed have largely comprised different corticosteroids, and there have been some reports of efficacy with topical ciclosporin or tacrolimus for corticosteroid-recalcitrant oral disease [reviewed by (Al Johani et al, 2009)]. Systemic corticosteroids are the first-line therapy for severe oral and/or cutaneous PV (Knudson et al, 2010) and a spectrum of corticosteroid sparing agents have been proposed as adjuvant therapies. The latter include azathioprine, methotrexate, mycophenolate mofetil (Beissert et al, 2010; Koga et al, 2010), cyclophosphamide, ciclosporin (Knudson et al, 2010) and perhaps systemic tacrolimus (Busing et al, 2010). Intravenous immunoglobulin (IVIG) is suggested by some authorities to be effective for rapidly progressing, severe and/or treatment-resistant PV (Mignogna et al, 2010). There is some evidence that the anti-TNF-α biological agents or rituximab are of benefit in the treatment of PV that involves the oral mucosa [reviewed by (Mignogna et al, 2009)]. Again, topical delivery systems that could efficiently deliver antibody based biological agents to oral lesions could avoid the necessity for systemic administration with its attendant side effects. Of relevance to local application of drugs, adjuvant perilesional or intralesional triamcinolone acetonide injections may lessen or cause resolution of signs and symptoms of oral PV (Mignogna et al, 2010).
Mucous membrane pemphigoid. Strategies for MMP disease that are severe and/or recalcitrant to topical corticosteroids include azathioprine, dapsone (Gurcan and Ahmed, 2009) and other conventional corticosteroid-sparing agents. There are some data suggesting that anti- TNF-α agents or rituximab may be of potential benefit but most information is based upon case reports and small case series of severe disease (Peterson and Chan, 2009). As PV and MMP are antibody-mediated autoimmune diseases, it could be argued that anti-B-cell therapies might be a more logical choice in these conditions than OLP.
Recurrent aphthous stomatitis. Although a wide range of therapeutic strategies have been suggested [reviewed by (Scully et al, 2003; Jurge et al, 2006)], there are few well-designed randomized controlled trials of possible therapies for recurrent aphthous stomatitis (RAS). The mainstays of therapy across the globe remain topical antimicrobials (of which chlorhexidine is the most common and assessed agent) and topical corticosteroids (Porter and Scully, 2005; Jurge et al, 2006; Scully and Porter, 2008). Amlexanox (as cream or Oradisk) has been suggested as an effective therapy for the management of both preventing and resolving the oral ulceration (Khandwala et al, 1997; Murray et al, 2005, 2006), but this agent remains unavailable throughout Europe. There is some evidence that systemic immunosuppressives such as azathioprine and colchicine may lessen the severity or recurrence of RAS but disease may still arise. In contrast, thalidomide (and perhaps pentoxifyline) reduces the frequency and severity of ulceration, suggesting perhaps that TNF-α may be of pathogenic significance. Certainly RAS would seem to reflect a local immunologically driven cytotoxic effect (Jurge et al, 2006); hence, agents that locally target such responses would seem to be key to future therapy. As with OLP, topical drug-delivery systems that cover lesional tissue and deliver anti-TNF-α biological agents, thalidomide or reduced side effect thalidomide analogues could result in more effective treatments for RAS without the need to resort to systemic therapies (such as thalidomide) with their associated side effects.
Future directions for immunologically mediated oral disease. The vast majority of studies of local therapeutic approaches to immunologically mediated oral mucosal disease have centred upon use of commercially available preparations that have principally been designed for cutaneous application. These preparations are highly unlikely to be appropriate for the mouth and as such probably have a suboptimal effect on the target disease. The recent report that mucoadhesive prolonged-release clobetasol tablets may be more effective than clobetasol ointment for the treatment of OLP would suggest that this is indeed true at least with respect to OLP (Cilurzo et al, 2010). There are now several potent systemic drugs and antibody-based biological agents with the potential to interfere more effectively in the disease processes of immunologically mediated oral diseases. Currently, these drugs must be given systemically and they have serious side effects that limit their use to severe and recalcitrant cases. However, the development of effective topical oral mucosal delivery systems for these drugs would simplify their use, target treatment to disease-affected mucosa, thereby reducing the risk of systemic side effects, and raise the prospect of providing more effective treatments to a much wider range of patients affected by these diseases.
Infectious agents targeting the oral mucosa include viral, fungal and bacterial species. The diversity and scope of these infections were recently reviewed (Dahlen, 2009; Sallberg, 2009; Samaranayake et al, 2009; Slots, 2009). Host exposure to infectious agents, changes in the oral environment, interactions with the oral microbiome (Dewhirst et al, 2010) and reduced host defences all potentially contribute to development of opportunistic and non-opportunistic infections of the oral mucosa. Topical and locally delivered antibiotics and antiseptics for the oral and periodontal diseases, such as chlorhexidine, tetracycline, doxicycline, minocycline and metronidazole, have been reviewed elsewhere (Etienne, 2003) and will not be discussed here.
Current treatment. Antifungal drugs are commonly delivered topically to the oral mucosa to treat oral candidiasis (Zhang et al, 2007). The most commonly used formulations include topical nystatin, clotrimazole, miconazole and itraconazole. Currently, there are no effective topical treatments available for intra-oral infections caused by the human herpes viruses or the human papilloma viruses or picornaviruses. Antiviral topical therapies (5% acyclovir cream, 1% penciclovir cream, 10% docosanol cream and 3% foscarnet cream) are available for recurrent labial herpes (Woo and Challacombe, 2007) and some providers have used dermatologic antiviral or sclerosing preparations in the mouth.
Problems with current treatment. One component of difficulty in effective management of infections is the development of drug resistance. Azole drug resistance is the most common problem encountered in managing oral candidiasis and is related primarily to systemic drug therapy (Yang et al, 2008). Acyclovir and penciclovir resistance is also a growing problem particularly among immune-compromised patients (Woo and Challacombe, 2007). The efficacy of local drug delivery may not be sufficiently high to resolve infections. In addition, yeasts may play a synergistic pathogenic role with opportunistic bacterial pathogens in oral mucosal infections, making multipathogen infections more complex to manage.
Novel formulations/research into improved topical drug delivery for oral infections. Advances in prevention and management of oral mucosal infections will require new agents and improved mechanisms of topical drug delivery. A phase III randomized clinical trial of a diluted 0.00165% topical gentian violet mouthrinse (Traboulsi et al, 2008) compared with nystatin mouthrinse to treat oral candidiasis associated with human immunodeficiency virus is currently being conducted by international investigators in the U.S. AIDS Clinical Trials Network. Use of probiotics delivered by lozenges or in chewing gum has been suggested for altering oral infectious disease susceptibility (primarily to dental caries and periodontitis, but to a lesser extent oral fungal infections) via inter-microbial species interactions and induction of immuno-stimulatory effects (Meurman, 2005; Stamatova and Meurman, 2009).
Antiviral and antifungal pharmacokinetics need to be altered to allow targeted delivery, rapidly followed by sustained release and prolonged retention of high drug concentration localized at the oral infection site. To enhance the bioavailability and therapeutic efficacy of existing azole antifungals, new drug delivery strategies and drug formulations are needed to improve the aqueous wetting and dissolution properties of azole antifungals by increasing their chemical potential, stabilizing the drug-delivery system and targeting high concentration of the azoles to the infection sites (Yang et al, 2008).
A mucoadhesive buccal slow-release tablet formulation containing 50 mg of miconazole applied once daily to treat pseudomembranous candidiasis has shown efficacy and reduces the need for the repeated applications associated with conventional topical antifungal agents (Vazquez et al, 2010). A similar product containing acyclovir has been developed and is in phase III clinical trials for once daily local treatment for recurrent herpes labialis. An occlusive hydrocolloid patch, devoid of any medication has shown similar efficacy to topical acyclovir in the management of herpes labialis (Karlsmark et al, 2008).
Neuropathic pain, defined as a condition that is initiated or caused by a primary lesion or dysfunction in the nervous system, has various aetiologies from local trauma to central nervous system pathologies (Colombo et al, 2006). In the orofacial region, this can be caused by deafferentation pain, traumatic neuroma, or trigeminal or glossopharyngeal neuralgia. Additional orofacial neuropathic conditions include atypical odontalgia and burning mouth syndrome. Neuropathic pain has a severe psychosocial impact on quality of life and mood of affected patients and substantial societal costs.
Current treatment. There are numerous systemic treatments for neuropathic pain (Dworkin et al, 2010). Burning mouth syndrome is a neuropathic pain managed initially with topical clonazepam and then with other neuropathic drugs (Zakrzewska, 2010). Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Topical medication in combination with systemic medications can reduce orofacial neuropathic pain severity (Heir et al, 2008).
Problems with current treatment. Systemic pharmacologic treatment is often accompanied by unpleasant side effects such as sedation, dizziness and drug interactions. In the majority of patients, existing therapies for neuropathic pain are far from effective and are symptomatic rather than disease modifying or curative. Topical medications seem to have increased effectiveness when initial pain levels are mild to moderate (Heir et al, 2008).
Novel formulations and research into improved topical drug delivery for neuropathic pain. Advances in appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation will open doors to novel formulations and local delivery modes (Sawynok, 2005). Emerging therapeutic modalities targeting a variety of mechanisms associated with neuropathic pain disorders should be given priority as should the development of increasingly sophisticated tools for measuring and categorizing neuropathic pain (Backonja and Woolf, 2010).
Preclinical studies provide evidence that peripheral applications of opioids, alpha-adrenergic agents and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents (Sawynok, 2005). Finding effective topical drug-delivery systems for these agents will be crucial in optimizing their therapeutic potential and efficacy.
Salivary hypofunction and xerostomia
Salivary hypofunction is associated with a reduction in salivary fluid volume and/or a change in salivary composition. It often correlates with xerostomia, the subjective experience of a dry mouth. There are numerous causes including xerogenic medications, systemic diseases such as Sjögren’s syndrome, diabetes, or HIV infection or radiotherapy for head and neck cancer. Salivary hypofunction may be reversible or irreversible and if chronic can have a number of consequences including increased dental caries, oral candidiasis, problems associated with eating, speaking, use of dentures and general mouth comfort.
Current treatment. Treatment is contingent upon the degree of hypofunction and includes the use of systemic sialogogues, electrical stimulation, gustatory agents and saliva substitutes/lubricants. In Sjögren’s syndrome and postradiation patients with some residual function, the systemic use of the muscarinic agents pilocarpine and cevimeline shows benefit (von Bultzingslowen et al, 2007; Jensen et al, 2010; Ramos-Casals et al, 2010). Palliative therapy includes the use of gustatory agents (sugar free chewing gum, mints, lemon drops), saliva substitutes and lubricants in various formulations (gels, rinses, sprays).
Problems with current treatment. Problems with current treatment are that muscarinic agonists have potential cardiorespiratory and other unpleasant side effects and palliative therapies have no sustained effect.
Novel formulations and research into improved topical drug delivery for salivary dysfunction. In Sjögren’s syndrome and postradiation salivary gland dysfunction, evidence from controlled trials suggests benefit of salivary gland stimulation from systemically ingested muscarinic agonists, pilocarpine and cevimeline, for sicca features. Palliative therapy includes replacement of lost fluid with artificial salivary formulations or mucosal lubricants (gels, rinses, sprays) and sugar-free gums and mints.
Problems with current treatment. Problems with current treatment are that muscarinic agonists have unpleasant side effects and palliative therapies have no sustained effect.
Novel formulations/research into improved topical drug delivery for salivary dysfunction. As reviewed in Thelin et al, 2008, preventing fluid absorption from the oral cavity will improve oral hydration and prevent the clinical symptoms and discomfort associated with dry mouth. Therapeutic strategies that prevent fluid absorption and improve oral fluid balance may provide relief for those suffering from dry mouth. Epithelial sodium channel blockers, such as P-552 under phase II study by Parion Sciences, Durham NC, USA, are unique therapeutic agents developed to maintain and stimulate hydration on the body’s mucosal surfaces, including those of the lung, mouth, nose, eye and gastrointestinal tract. Topical delivery is possible by oral rinse or oral spray to provide lasting effect.
In a small double-blind, crossover, randomized controlled trial, locally applied physostigmine (1.8 mg) gel produced long-lasting (120 min) relief in the feeling of dryness among subjects suffering from dry mouth and with hyposalivation (Khosravani et al, 2009). In addition, there is some suggestion that 150 IU interferon-alpha lozenges three times daily may enhance salivary secretion in patients with primary Sjögren’s syndrome (Cummins et al, 2003; von Bultzingslowen et al, 2007). Anhydrous crystalline maltose, a food stabilizer and desiccant for use in foods, cosmetics, and pharmaceuticals, when delivered orally as a 200-mg lozenge three times daily for 24 weeks in patients with primary Sjögren’s syndrome, resulted in improved salivary output and decreased complaints of dry mouth (Fox et al, 2002). Moreover, the presence of a mucoadhesive in the mouth three times a day appears to increase salivary flow and the subjective impression of moisture (Kerr et al, 2010).
Currently clinical investigations are underway using aquaporin gene therapy for restoring function of salivary gland tissues in patients with postradiation therapy salivary hypofunction and there is a potential application for this gene therapy in patients with Sjogren’s syndrome as well (Baum et al, 2010).