Radiation Effects – Salivary Glands, Bone and Teeth Table of Contentsv Salivary glands v Damage - Mechanism of action v Oral flora changes and radiation caries fungal infections v Xerostomia v Managementv Bone v Mechanism of damage v Late effects v Cellularity v Remodeling apparatus v Osteolytic activityv Periodontal ligamentv Teeth v Pulpal changes v Dental development
Salivary Damage-Mechanism of Actionv Salivary gland parenchyma Normal salivary gland consists of acinar cells, myoepithelial cells, and a ductal system consisting of striated ducts and intercalated ducts.v Primitive glandular stem cells, found in the ductal elements are responsible for regeneration of Irradiated salivary gland these cell populations.v Reduced production of saliva is ultimately secondary to the sterilization of these cell populations by irradiation (Konings et al, 2005).
Salivary Damage-Mechanism of Actionv Reduction in flow observable the first Normal salivary Gland Normal Salivary gland week of therapy.v Changes occur in volume, viscosity, pH and buffering capacity, inorganic and organic constituents after therapy (Driezen et al, 1977; Brown et al, 1976; Marks et al, 1981; Malkkonen et al, 1986; Valdez et al, 1993; Almstahl et al, 2001). Irradiated salivary glandv Mean output can be reduced by from 86-93% (Curtis et al, 1976; Driezen et al, 1977; Marunick et al, 1991)v These changes predispose to caries, fungal infections, periodontal diseasev Swallowing and speech are also Irradiated Salivary Gland impaired.
Salivary Damage-Mechanism of Actionv Early on apoptosis is limited Normal salivary gland to 2-3% of all cell types (Paardekoper et al, 1998)v Howeverfunction of secretory cells compromised v Secretory responses are reduced by 50% by the first few treatments (Coppes et al, Irradiated salivary gland 2000). v Probably secondary to impairment of signal transduction by the plasma membrane of the secretory Normal Salivary Gland cells (Paardekoper et al, 1998; Coppes et al, 2001)
Salivary damage-Mechanism of Actionv During therapy and for a few Normal salivary gland months thereafter some evidence of recovery of acinar cells is observedv However above 3000 cGy there is a dramatic reduction of secretory cells accompanied by progressive fibrosis and compromise of the vasculature Irradiated salivary gland v Function returns to pretreatment levels if dose is less than 2600 cGy (Eisbruch et al, 1999; Eisbruch et al, 2003) v In young patients receiving doses of 35-4500 cGy, damage is reversible Irradiated v At doses above 55 cGy there is no salivary gland recovery of function (Franzen et al, 1992; Eisbruch et al, 1999; Roesink et al, 1999)
Salivary damage-Mechanism of Actionv Reduced function is Normal salivary gland probably due to the inability of stem cells to replace aging and dying parenchymal cells (Konings et al, Irradiated salivary gland 2005). Irradiated salivary gland
Salivary Damage - Mechanism of Action Mean Dose Concept vs the Volume Effect Irradiated Salivary Gland Normal Salivary Glandv Mean dose may not be the ultimate predictor of damage to the salivary glandsv Late damage to salivary gland parenchyma may be precipitated by secondary events v Damage can be caused by damage to blood vessels of irradiated portions of the gland supplying the nonirradiated portions (Konings et al, 2005; Konings et al, 2006)
Radiation Induced XerostomiaEffects on oral health and function and quality of lifev Increasedrisk of caries and periodontal disease and fungal infections v Oral flora changesv Difficulty in swallowingv Impaired speech articulationv Difficulty in sleepingv Impaired tolerance of complete dentures (loss of peripheral seal and lubrication)v Compromise of taste acuity
Radiation cariesThis patient received 6800 cGy for asquamous carcinoma of the tonsil.Several years prior to radiation she hadseveral porcelain veneers placed.Closer exam reveals that several had becomedetached and all had become severelyundermined with caries. These teeth are beyond restoration and the clinician should direct his/her efforts toward preventing the infection from developing into an osteoradionecrosis.
Clinical significance of radiation • Acute and chronicinduced xerstomia fungal infections" Changes in the oral flora predispose to: • Radiation caries Compromised tolerance of complete dentures • Increased friction at the denture-mucosal interface • Difficulty in obtaining and maintaining peripheral seal
Changes in the oral floraSignificant population shifts in oral flora v Cariogenic organisms gain at the expense of noncariogenic organisms v Increasesseen in the relative numbers of Streptococcus mutans, lactobacillus (Llory et al, 1971; Brown et al, 1972; Brown et al, 1975; Keene et al, 1981; Keene and Flemming, 1987; Epstein et al, 1991) v Significant increases in fungal organisms (Brown et al, 1975)
Changes in the oral floraSignificant increases in the populations of: v Streptococcus mutans v Actinomyces v Lactobacillus These changes predispose the patient to radiation caries. The caries progresses rapidly and in most patients becomes so extensive that it is nonrestorable. Eventually, teeth fracture at the gingival margin.
CRT - Radiation fields, xerostomia and and morbidityHigh posterior fields • Risk of caries is high • Risk of osteoradionecrosis is low Opposed mandibular fields • Risk of caries is reduced • Risk of osteoradionecrosis is high
Changes in the oral flora The numbers of fungal organisms increase 100 fold As a result, chronic candidiasis, is very common after therapy. It presents in a variety of forms, as seen here. Nystatin is drug of choice, and it can be dispensed in a number of configurations including lozenges, powder, creams and an oral suspension.
Changes in the oral flora Acute candidiasis is quite rare after the completion of therapy. Note the fungal colonies developing on the mucosal surfaces (arrows).Nystatin remains the least costly and most effective antifungal agent. Foracute forms of candidiasis, vaginal suppositories (100,000 units persuppository, Sig.- tid), used as an oral lozenge are preferred over thenystatin oral lozenges because of the latter’s high glucose content.
Management of Radiation Induced XerostomiaIdeal characteristics of a saliva substitute v Provide a protective coating for the oral mucosa v Capable of remineralization v Maintain normal oral flora patterns v Be long lastingSaliva substitutesv Carboxymethylcellulose based v Mucin based v Water based v Glycerin based Attempts have made to formulate salivary substitutes (Shannon et al, 1977; Shannon et al, 1978; Visch et al, 1986). Patient responses have been mixed and most patients prefer increased water intake.
Management of Radiation Induced Xerostomia Saliva substitutes v Carboxymethylcellulose based v Mucin based v Water based v Glycerin based These agents have been ineffective for the most part, although they have been useful in selected patients in relieving night time discomfort. They also may aid the severe xerostomic patient who experiences difficulty with speech articulation.
Salivary stimulantsAttempts to stimulate salivary activity afterradiation have been disappointingv Most common drugs used: v Pilocarpine v Cevimelinev In most studies, measured flow may be increased but rarely is relief of symptoms noted (Fox et al, 1986; Greenspan and Daniels, 1989; Johnson et al, 1993; Rieke et al, 1995)v Most of the benefit is probably secondary to the stimulation of minor salivary glands since they are more resistant to and recover more effectively from the effects of radiation (Niedemeirer et al, 1998)
Salivary stimulantsPilocarpine v Requires residual salivary gland parenchyma to be effective v Can be dispensed in liquid form used as a mouth rinse (1 mg per cc) or in tablet form (5 mg) v Dosage above 20 mg will induce toxic side effects v Toxic side effects include increased intestinal motility v Marketed as SalagenThis drug may be useful in patients who have been treated with CRT and with radiationtreatment volumes that spare significant amounts of salivary gland parenchyma but has notbeen useful in patients with opposed lateral facial fields that are used to treat tumors of thesoft palate, tonsil, nasopharynx etc. The latter may have little or no residual salivary glandparenchyma.
Salivary stimulants Cevimeline v Requires residual salivary gland parenchyma to be effective v Toxic side effects include increased intestinal motility, excessive sweating, nauseaThis drug has a similar mechanism of action as pilocarpine and like pilocarpinemay be useful in patients who have been treated with radiation treatmentvolumes that spare significant amounts of salivary gland parenchyma (i.e.,opposed mandibular fields). It has been used in Sjogren’s syndrome patientswith some success. Clinical trials are now being conducted in irradiatedpatients.
Salivary gland protective agentsv Amifostine (Antonadou et al, 2002)v Pilocarpine (Roesink et al, 1999, Warde et al, 2002; Burlage et al, 2008)
Salivary gland protective agentsAmifostinev Has been shown to moderately improve subjective symptomsv A free radical scavengerv May limit damage to salivary parenchyma during radiationv Side effects include hypotension, nausea and vomitingv Issues • Questionable rationale • Questionable study designs • Possible protective effect on tumor cells (Vissink et al, 2003) • Cost Clinical results have been disappointing.
Salivary gland protective agentsPilocarpine v Administered before and during radiation therapy to limit radiation damage (Roesink et al, 1999; Warde et al, 2002; Burlage et al, 2008) v Animal experiments have shown promise but human data is indeterminate. Some have shown no benefit (Warde et al, 2002) while others have shown some benefit (Burlage et al, 2008) v Others (Valdez et al, 1993) have suggested that the drug affects only the nonirradiated salivary gland parenchyma
Stem cell transplantation and enhancementReduced saliva production is ultimately secondary to the loss of salivary stemcells which preclude replacement of aging acinar and ductal cells. Strategiescurrently being tested in animal models include: v Transplants (Lombaert et al, 2008a) v Secure salivary gland tissue prior to irradiation, retrieve and culture the stem cells and transplant them back into the subject after radiation
Stem cell transplantation and enhancementReduced saliva production is ultimately secondary to the loss of salivary stemcells which preclude replacement of aging acinar and ductal cells. Strategiescurrently being tested in animal models include: v Stimulate surviving salivary gland stem cells with bone marrow cells (Lombaert et al, 2006; Lombaert et al, 2008b) v This option is limited by the number of stem cells surviving radiation
Stem cell transplantation and enhancementReduced saliva production is ultimately secondary to the loss of salivary stemcells which preclude replacement of aging acinar and ductal cells. Strategiescurrently being tested in animal models include: v Increase salivary gland stem cell populations prior to radiation (Lombaert et al, 2008c) v This has been accomplished in an animal model by administering keratinocyte growth factor (N23-KGF) prior to radiation
Maximizing Postradiation Salivary Flowv Best results achieved by sparing salivary glands from high dose radiation (Mira et al, 1981; Roesink et al, 2001; Vissink et al, 2003)v >50% of the parotid glands must be outside the radiation fields in order to prevent severe xerostomia (Mira et al, 1981)
Means of sparing major salivary glands from high dose radiation with IMRT Theoretically possible but the results have been disappointing to date. Source: www.beaumonthospital.comIntensity Modulated Radiation Therapy (IMRT) may reduce thedose to salivary glands. However the dose must be reduced toless than 40 Gy and this may not be possible in many patients .
Radiation Effects – Bone Mechanism of Damage (Delanian and LeFaix, 2004; Lyons and Ghazali, 2008)Damage to bone is the result of dysregulation offibroblastic activity v Initially, endothelial cells damaged that lead increased cytokine production v These cytokines in turn promote the release of inflammatory cytokines v Loss of small vessel network v Fibroblasts transformed into myofibroblasts v Unregulated chronic activation of these myofibroblasts leads to progressive fibrosis
Late Effects – Bone (Silverman and Chierci, 1965; Rohrer et al, 1979)v Reduced vasculature v Loss of osteoprogenitor cells v Fatty and fibrous degeneration v Periosteum- Acellular and loss of vasculature v Occlusion of the inferior alveolar arteryRoot Trabecular bonesurface MarrowSeverity of changes depends on dose
Late Effects – Bone (Silverman and Chierci, 1965; Rohrer et al, 1979)Severity of tissue changes depends on dose. Thehuman specimen shown was exposed to in excessof 70Gy.Root Trabecular bonesurface Marrow
Late Effects – BoneClinical manifestationsv Compromised remodeling and repair, ie healing of extraction sites, osseointegrationv Response to infection, ie risk of Lamellar bone • Loss of central artery in osteoradionecrosis secondary Haversian systems to a dental infection. • Death of osteocytes Root Trabecular bone surface Marrow
Late effects –Lamellar Bonev Loss of central artery in Haversian systems (red arrow)v Loss of osteocytes from their lacunae (yellow arrows) Such bone is essentially nonvital and lacking the capacity for repair and remodeling
Remodeling apparatus -Osteolytic Activity Following high dose radiation some osteoclasts remain as shown in this human specimen. The mandible in Osteoclast this patient received in excess of 70Gy with CRT via opposed lateral mandible fields.Isolated osteoclasts represent either the survivingremnants of the multicellular unit of the remodelingapparatus or find their way into irradiated bone viathe circulation mediated by macrophages.
Remodeling apparatus – Osteolytic Activity v This patient received 70 Gy to the mandible for an anterior floor of mouth Sq Ca. v Note the dramatic change Preradiation in the prominence of the cortical plates (arrows) and the differences in trabecular patterns between preradiaton and postradiation radiographs. v Osteolytic activity seems Postradiation more prominent in patients treated with chemoRT
Remodeling apparatus – Osteolytic Activity v Spontaneous fractures of the mandible associated with concomitant chemotherapy and CRT. All three patients received approximately 70 Gy a b v All patients received 70 Gy. a and b: Neither was associated with dentition. c: Bilateral fractures through ramus and angle secondary to chemoRT. They were not related to or precipitated by dentition.c
Clinical significance of compromised remodeling apparatusPreradiation extraction of teeth within the clinical treatment volume When extracting teeth in the field prior to radiation radical alveolectomies need to performed in order to avoid the irregular alveolar ridge contours seen below. Even though the alveolar ridge mucosa is covered with healthy mucosa, its irregular boney contour precludes the use of complete dentures when the dose to the mandibular bearing surfaces is high (above 65 Gy).
Clinical significance of compromised remodeling apparatus Osseointegration b c a a: Normal control specimen. Note both contact and distance osteogenesis. b: Specimen exposed to equivalent to 52 Gy. Note dramatic reduction is osteogenesis. c: Specimen exposed to 58 Gy. Note further reduction of osteogenesis (Courtesy of R. Nishimura).
Radiation Effects - Periodontium Changes in the periodontal ligament(Silverman and Chierci, 1965; Rohrer et al, 1979; Fugita et al, 1986; Epstein et al, 1998) v Loss of cellularity v Loss of vasculature v Disorientation of the periodontal ligament fibersResult: The periodontium is a prime pathway for infection. 50 Gy >70 Gy This patient developed an osteoradionecrosis 4 years post radiation secondary to a periodontal abscess
Radiation Effects - Periodontiumv Lacking blood supply, the bone of the lamina dura becomes acellular. Note the empty lacunae.v Cementum likewise, becomes acellular and its capacity for repair is compromised. Given cementum’s compromised capacity of<70 Gy regeneration and repair, periodontal procedures, such as deep scaling and flap surgery, are therefore contraindicated in heavily irradiated dentition.
Radiation Effects – Periodontium (Floral changes?)v Thereappears to an acceleration of attachment loss in patients treated with chemoRT
Teethv Organic component of enamel appears unaffected (Jansma et al, 1990)v Microhardness of dentin is affected at the dentin enamel junction (Keilbassa et al, 1997; Keilbassa et al, 2006) v This phenomenon may be partially responsible for the high rate of cervical caries in dentitions within the clinical target volume
Teeth - Pulp Changes v Atrophy of the odontoblastic layer and an inability to fabricate secondary dentin v Loss of vasculature and fibrosis v Formation of osteodentin and pulp stones
Teeth - Pulp Changesv Atrophy of the odontoblastic layer and an inability to fabricate secondary dentin at levels of exposure as low as 25 Gyv Loss of vasculature and fibrosisv Formation of osteodentin and pulp stones Osteodentin Pulp stones
Clinical Implications of Pulpal Changes v Response to infectious or mechanical injury to the pulp is compromised v Pulp capping is contraindicated. If a pulp exposure is encountered during cavity preparation a root canal should be performed v Pulpal pain mechanisms are altered and patients with advanced caries are generally asymptomatic
Dental development v Levels as low as 2500 cGy effect tooth development (Gorlin and Meskin, 1963; Pietrokovski and Menczel, 1966; Dahllof et al, 1994; Kaste et al, 1994) v Changes reflect a variety of defects that indicate the several stages of development existing during the course of radiotherapy This patient is 16 years of age. He received 3600 cGy of radiation when he was 4 years of age for treatment of a rhabdomyosarcoma.
Systemic sequellae of Radiation of Head and Neck TumorsRadiation induced cancers (Hall, 1995) v SarcomasCarotid atheromas (Zidar, 1997; Freymiller et al, 2000)Progressive fibrosis may lead to (Eisele, 1991; Kang, 2000; Sharabi, 2003; Nguyen et al, 2006, 2008; Nguyen, 2009) v Difficulty swallowing v Vocal cord paralysis v Aspiration pneumoniaHeart (Basavaraju, 2002; Gyennes, 1998; Kahn, 2001) v Valve leaflets may thicken and calcify v Valve orifices narrow v Acellerated form of athersclerosis v Compromise of microvasculature
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