Investigations into the effects of head and neck radiotherapy and the potential anticariogenicity of casein phosphopeptide-amorphous calcium phosphate and stannous fluoride
AuthorSim, Christina Poh Choo
AffiliationMelbourne Dental School
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2020-06-06. This item is currently available to University of Melbourne staff and students only, login required.
© 2018 Dr. Christina Poh Choo Sim
Radiotherapy is the primary treatment modality for most head and neck cancers, in particular, nasopharyngeal carcinoma (NPC). The use of advanced radiotherapy techniques such as intensity modulated radiotherapy (IMRT) improves tumour targeting whilst minimising radiation dose to normal non-target tissues. However, salivary gland dysfunction still persists as the salivary glands remain in the treatment portal. The major post-irradiation oral complication is dry mouth resulting from hyposalivation with subsequent development of radiation caries, a highly destructive form of dental caries which has a rapid onset and progression. The use of high strength fluoride products, 5,000 ppm fluoride as 1.1% sodium fluoride (NaF) has been recommended in the United States and Europe as the standard of care for the control of radiation caries. These products are not available in Singapore and the recommended radiation caries control is via the use of 1,000 ppm fluoride as 0.4% stannous fluoride (SnF2). Fluoride-driven remineralisation is limited by the bioavailability of calcium and phosphate and the use of the saliva biomimetic, casein phosphopeptide amorphous calcium phosphate (CPP-ACP), has been reported to be effective as an adjunctive treatment to fluoride therapy in the management of early carious lesions in healthy individuals. The use of CPP-ACP to augment fluoride remineralisation in patients with hyposalivation has not yet been explored, in particular, as an adjunct to SnF2 therapy. In an in vitro six species polymicrobial biofilm model representative of supragingival plaque cultured on sound human enamel substrata and subjected to a high acid challenge, the rate of demineralisation produced by the individual CPP-ACP and SnF2 treatments was similar at 112.1 vol%min.µm/day, a significant 50.2% reduction compared with the control. For the same period, the combined CPP-ACP/SnF2 treatment resulted in a significant 72% reduction in demineralisation rate to 64.1 vol%min.µm/day. Significant biofilm compositional changes were produced by the CPP-ACP-based treatments, indicating a CPP-ACP prebiotic effect on the biofilm development favouring the growth of commensal species. The combined CPP-ACP/SnF2 treatment also produced the highest net remineralisation (30.6%) of enamel subsurface lesions in an in situ study. This in situ study is the first to show that the extent of remineralisation of CPP-ACP/F is dependent on the form of fluoride added; fluoride added as CPP-ACP/SnF2 exhibited significantly greater net remineralisation of enamel subsurface lesions compared with fluoride added as CPP-ACP/NaF at the same fluoride concentration. The CPP-ACP/SnF2 treatment produced the highest mean weight percent fluoride deposition throughout the depths of the lesions with the mineral deposited consistent with the formation of fluorapatite. The CPP-binding kinetics showed that the presence of stannous ions in the CPP-ACFP nanocomplexes enhanced the stability of the complexes even at low pH, delivering greater amounts of calcium, phosphate and fluoride ions to the tooth surface and promoting greater remineralisation of enamel subsurface lesions. This study is the first to show that the delivery of stable nanocomplexes to the tooth surface is critical to maximise remineralisation, providing better subsurface remineralisation in vivo. The adjunctive use of CPP-ACP with a SnF2/NaF regime was efficacious in a placebo-controlled randomised clinical study in NPC patients undergoing IMRT. The CPP-ACP group exhibited a significant reduction in coronal caries progression for total surfaces (47%); smooth surfaces (38%) and occlusal surfaces (79%) compared with the placebo group three months post-radiotherapy. This is of great benefit as these patients were at risk of caries even at the early stage of the cancer treatment as reflected by the significantly low salivary flow rates, pH and buffering capacity. Access to critical calcium, phosphate and fluoride ions required for remineralisation was restricted as evidenced by the significant decline in ion velocity of these ions and the mineral saturation indices. In summary, the superior pre-clinical in vitro and in situ results of CPP-ACP/SnF2 treatment in significantly reducing the rate of enamel demineralisation and promoting remineralisation were confirmed in vivo by the first placebo-controlled randomised clinical study in NPC patients undergoing IMRT. This novel study suggests that CPP-ACP/SnF2 has beneficial application for caries control in high risk individuals.
Keywordshead-and-neck radiotherapy; xerostomia; dental caries; remineralisation; casein phosphopeptide-amorphous calcium phosphate; stannous fluoride
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