In oral mucosa, radiation effects appear early in the course of therapy.  The severity of the local tissue reactions depends on the radiation dose, the size of each radiation fraction, the volume of tissue irradiated, the fractionation scheme, and the type of ionizing radiation used.  Recent research efforts have shed some light on the pathophysiology of these acute and late changes.  This program describes the changes, and the efforts that have bee made in recent years to minimize the acute effects (radiation mucositis).  In addition the program discusses the recent significant rise in radiation trismus observed in patients undergoing chemoRT and the comments on the effect of dynamic bite openers used for prevention.

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Maxillofacial Prosthetics – Radiation Effects Mucosa, Taste, Jaw Opening — Course Transcript

  • 1. 3. Radiation Effects – Mucosa, Taste, Jaw Opening John Beumer III, DDS, MS Eric Sung, DDS Division of Advanced Prosthodontics, Biomaterials and Hospital Dentistry and UCLA School of Dentistry All rights reserved. This program of instruction is covered by copyright ©. No part of this program of instruction may be reproduced, recorded, or transmitted, by any means, electronic, digital, photographic, mechanical, etc., or by any information storage or retrieval system, without prior permission of the authors.
  • 2. Radiation Effects – Mucosa, Taste, Jaw Opening
 Treatment and Preventionv  Mucosa v  Acute effects v  Mucositis v  Fungal infections v  Management of mucositis v  Taste apparatus v  Late effects v  Mucous membranes v  Muscle v  Skin v  Edemav  Jaw opening v  Dynamic bite openers
  • 3. Radiation Effects – Oral Mucous MembranesEarly changes in oral mucous membranes v  Pathophysiology of oral mucositis (Sonis, 1998, 2004)
  • 4. Pathophysiology- Radiation MucositisSonis model (1998, 2004) Initiation l  Reactive oxygen species results in breaks in DNA strands Primary damage response l  NF-kB l  Upregulation of genes producing proinflammatory cytokines Signal amplification l  Colonization of oral bacteria leads to production of additional cytokines which lead to more tissue damage Ulceration Healing
  • 5. Radiation Mucositis Key – FactsPresents initially as an erythematous reaction which soondevelops into oral ulcerations covered with pseudomembranes.Severity dependent upon:v  Clinical treatment volume, dose and fractionation.v  Sites: The less keratinized the mucosa the more severe the mucosal reactionsv  More severe in patients presenting with chronic alcoholism and liver cirrhosisv  More severe in patients with insulin dependent diabetesv  Severity may be lessened by a reduction of oral bacterial loadsMucositis is more severe in patients.receiving concomitant chemotherapy.
  • 6. Radiation Mucositis – Key Facts v  It is one of the most clinically significant side effects of treatment. v  Its frequency and severity limit the aggressiveness of therapy and may interrupt or preclude completion of therapy. v  It has a significant impact on the cost of care (Peterson et al, 2001). v  There is no effective treatment. v  Palliation of symptoms is the only possible approach at present..
  • 7. Radiation Mucositis – Key Facts v  Incidence – 80% per cent or more depending upon the dose per fraction (Vinssink et al, 2003) v  Secondary to radiation induced mitotic death of the cells composing the basal layer of the epithelium (Scully and Epstein, 1996; Dumbrique et al, 2000). v  Rarely seen when the dose per fraction is below 180 cGy per fraction (Silverman, 2003).
  • 8. MucositisOral mucositis begins as an erythematous reaction associatedwith the tumor site generally after about 7-10 days of thetherapy. This erythema is accompanied by soreness and aburning sensation.
  • 9. Mucositisv The erythematous reaction is followed by ulceration. With conservativetreatment approaches the ulcerations remain confined to the tissues associatedwith the tumor volume.v With more aggressive treatment (ie. Chemoradiation) the mucositis is moreextensive involving normal tissues adjacent to the gross tumor volume.v With conservative treatment approaches the mucosa re-epithelializes 2-4weeks following completion of therapy. If concomitant chemotherapy is employed, twice or longer the usual time is required for re-epithelization.
  • 10. MucositisIn most patients the ulcerations remains confined to the tumorsite. After radiation the ulcerations re-epithelialize and becomecovered with “normal” appearing oral mucosa. However, if concomitant chemotherapy is employed these ulcerations may take several months to heal.
  • 11. MucositisBackscatter – Mucositis is particularly localized in thispatient. This results when a metallic crown rests against oralmucous membrane and is in the path of the radiation beam.Prevention is easily accomplished by displacing the buccalmucosa or tongue away from the crown with a stent.
  • 12. BackscatterTitanium reconstruction plates, implants, traysand mesh (Schwartz et al, 1979; Mian et al, 1987) Dose enhancement at the bone implant interface is about 15-18%.
  • 13. Backscatter Irradiation of existing implantsBackscatter- This patient received 6000 cGy postoperatively.Previously, a fibula free flap had been used to reconstruct amandibular continuity defect. Implants were placed at thesame time the fibula was placed.
  • 14. Backscatter Irradiation of existing implantsFollowing radiation, the patient developed a dehiscence over theleft implant which eventually lead to exposure of bone. The two leftimplants were eventually lost. A piece of bone was sequestratedand eventually this area became covered with mucosa.
  • 15. BackscatterIrradiation of existing implantsHowever, the flap was not lost andmandibular continuity was maintained.
  • 16. Acute Effects – Oral Mucous Membranes Patients with compromised oral mucous membranes secondary to chronic alcoholism with liver cirrhosis or insulin dependent diabetes and those treated with chemoradiation may develop more severe mucositis. A BIn patient “A” virtually all of the epithelium on the soft palate waslost and therapy had to be interrupted to allow the mucosa to re-epithelialize. In patient “B” the tongue became depapillated buttherapy was completed without interruption.
  • 17. Acute Effects – Oral Mucous Membranes Candida albicans infectionDuring the administration of radiation therapy acute candidiasis can occur(Ramirez-Amador, etal, 1997).Topical therapy: It is best managed by nystatin suppositories used as an orallozenge (100,000 units per suppository) or by the use of nystatin oral rinse(100,000 units per cc). If the patient is wearing dentures, they should besoaked in a nystatin solution daily. If the patient has difficulty dissolving the lozenges intraorally because of xerostomia, a nystatin oral suspension is a useful alternative.
  • 18. Acute Effects – Oral Mucous Membranes Candida albicans infectionSystemic therapy: *Prolonged use of antifungalv  Ketoconazole (200 mg daily agents is discouraged with food) because of the risk ofv  Fluorconozole ( 100 mg daily) developing fungal resistance. (Silverman, 2003) Systemic therapy is preferred in the potentially noncompliant patient.
  • 19. Acute Effects – Oral Mucous Membranesv Changes in the oral flora during therapy are thoughtto intensify radiation mucositis (Ramirez-Amador etal, 1997).v Colonization by gram negative bacilli (Spijkervet,1991) appear to induce more severe mucosalreactions such as the reaction in this patient.
  • 20. Acute Effects – Oral Mucous MembranesManagement of mucositis during therapy v At present there is no effective approved means of reducing the severity of oral mucositis v During the past 15 years 1his field has been the subject of intense study
  • 21. TreatmentManagement of mucositis during therapy Continues to be supportive and symptomatic v Saline and soda rinses v Viscous xylocaine v Systemic analgesics v Antifungal medications
  • 22. Treatment of Mucositis Research Approachesv  Radioprotective agentsv  Anti-inflammatory agentsv  Mucosal decontaminationv  Growth factors
  • 23. Treatment of Mucositis Research ApproachesRadioprotective agents – Free radical andreactive oxygen inhibitorsv  Amifostinev  Benzydaminev  N-acetylcysteine
  • 24. Treatment of Mucositis Research Approaches Radioprotective agents – Free radical and reactive oxygen inhibitors (Antonadou et al, 2002; Buntzel et al, 2002; Sonis, 2004; Law et al, 2007) v  Amifostine v  Benzydamine v  N-acetylcysteine”   These agents act as free radical and ROS scavengers and theoretically minimize much of the deleterious effects of irradiation on normal cells.”   These drugs are also potent anti-inflammatory agents.
  • 25. Treatment of Mucositis Research Approaches Radioprotective agents – Free radical and reactive oxygen inhibitors (Antonadou et al, 2002; Buntzel et al, 2002; Sonis, 2004; Law et al, 2007 v  Amifostine v  Benzydamine v  N-acetylcysteine”   The data is has been contradictory and study designs have been questioned (Sutherland and Bowman, 2001).”   Concern voiced regarding tumor uptake and impact on tumor response (Vissink et al, 2003).
  • 26. Treatment of Mucositis Research ApproachesMucosal decontamination v  Chlorhexidine – Has not shown to be effective in reducing the severity of mucositis (Spijkervet et al, 1989; Epstein et al, 1992; Foote et al, 1994; Dodd et al, 1996; Adamietz et al, 1998). v  Antibacterial lozenges targeting gram negative bacillus (combination of amphotericin B, polymyxin, and tobramycin) have shown some promise in reducing the severity of mucositis (Spijkervet et al, 1990, 1991; Symonds et al, 1996; Wijers et al, 2001; Mellroy, 2007)
  • 27. Treatment of Mucositis Research ApproachesGrowth factors l  Keratin growth factor (KGF) l  Granulocyte-macrophage stimulating factor May promote more rapid healing by stimulating surviving stem cells but have the potential of affecting the tumor response
  • 28. Chemoradiationv  Used as an adjunct or concomitantlyv  Oral side effects are more severe •  Acute effects §  Oral mucositis is more severe and generally takes 3 to 8 months to resolve as opposed to the 2-4 weeks when radiation alone is given. Some patients are unable to complete therapy because of the side effects. §  About one half of the patients need “G” tubes placed in order to make it through radiation.
  • 29. . Chemoradiation Late effects v Incidence of scarring and fibrosis, osteoradionecrosis and soft tissue necrosis appears much higher when used in conjunction with CRT. Little data available when used with IMRT v Asubstantial number of patients are unable to swallow after therapy secondary to atrophy and fibrosis associated with the muscles of the pharynx. These patients must be fitted with permanent “G” tubes. v Increasing number of patients suffer from velopharyngeal incompetence, velopharyngeal sufficiency and trismus after chemoradiation secondary to fibrosis and atrophy of the muscles associated with mastication and velopharyngeal function.
  • 30. Acute Effects – Taste Apparatusv  Taste acuity is readily affected by tumoricidal doses of radiation (Sandow et al, 2006; Mirza et al, 2008).v  Dramatically effects the quality of life (Redda and Allis, 2006v  Changes in taste cells and buds are due to both the direct and indirect effects of irradiation (Yamashita et al, 2006).
  • 31. Acute Effects – Taste Apparatusv  Architecture of the taste buds is almost completely eliminated at 5000 cGy.v  Alterations in taste acuity are first noticed during the second week of therapy (Conger and Wells, 1969; Conger, 1973; Silverman et al, 1983).v  Perception of bitter and acid flavors is more susceptible to impairment than salt and sweet
  • 32. Acute Effects – Taste Apparatusv  Taste generally returns to “near normal” 2-4 following re- epithelialization if salivary flow is reasonable.v  In patients with severe xerostomia following radiation the number of buds is decreased, their morphology is altered and taste may not return to normal.v  Reduction may also be secondary to loss of nerve fibers innervating the taste budsv  Clinical trials with Zinc supplements have shown promise (Silverman et al, 1983; Ripamonte et al, 1998; Matsuo et al, 2000)
  • 33. Acute Effects – Olfactionv  Since the olfactory epithelium is high in the nasal passage and often not within the clinical treatment volume smell is less affectedv  Smell thresholds after radiation exposure are increased dramatically (Ophir et al, 1988).v  Few if any patients experience complete recovery
  • 34. Late Effects – Oral Mucous Membranesv  Scarring and fibrosis of lamina propriav  Telangiectasia – dilation and coalescence of small venules close to the surface of the epitheliumv  Epithelial layer is thinner and less keratinized Clinical significance: The oral mucosa is easily traumatized or perforated. The ulcerations that develop are slow to heal because of the reduced vascularity and fibrosis of the underlying connective tissue.Clinical significance: The denture bearing mucosal surfaces arecompromised making tolerance of complete dentures difficult.
  • 35. Late Effects – Oral Mucous Membranes Scarring and telangiectasia In most patients scarring and telangiectasia are confined to the tumor site ( arrow).
  • 36. Late Effects – Oral Mucous Membranes Scarring and telangiectasiaWhen the telangiectasias extend beyond the localtumor volume as in these two patients, it indicates:v  The patient tolerated the radiation poorly.v  The dose to the normal adjacent tissues was brought to the highest level of tissue tolerance.v  The patient was treated with concomitant chemoradiation
  • 37. Late effects Muscle wasting and fibrosisv In patients treated for pharyngeal, soft palate and base oftongue tumors, fibrosis and muscle wasting of the muscles ofpharyngeal wall and the soft palate responsible forvelopharyngeal closure leads to velopharyngeal insufficiency.v These changes are more common in patients treated withchemo-radiation and many patient are unable to swallow aftercompletion of radiation therapy.
  • 38. Late effects Muscle wasting and fibrosisThis patient was treated with external beam plus brachytherapyfor a squamous carcinoma of the tongue. The volume of tissueencompassed by the implant was larger than normal because oftumor size and infiltration. The tumor dose exceeded 8500 cGy ina large volume of the tongue.
  • 39. Late effects Muscle wasting and fibrosisAfter completion of therapy the tongue mass was reducedand tongue mobility and control impaired. Speech articulationwas dramatically affected and salivary control compromised.
  • 40. Late Effects – Oral Mucous MembranesThis patient received 6800 cGy external beam therapy (CRT) fora squamous cell carcinoma of the anterior floor of the mouth.Note the scarring at the tumor site (arrow). However, there areno signs of radiation effects beyond the tumor site.This patient would be a good candidate for complete dentures. She iscompliant and the scarring and telangiectasia is confined to the tumor site.However, overextension of the lingual flange in this region could result in amucosal perforation and lead to an osteoradionecrosis.
  • 41. Late Effects – Oral Mucous Membranes Patient received 6800 cGy for a squamous cell carcinoma of the anterior floor of the mouth. Note the telangiectasias within the zone of keratinized attached mucosa (ovals)This patient would be a poor candidate fora lower complete denture because thebearing surface mucosa is thin andatrophic and could be easily perforated bya complete denture.
  • 42. Late Effects – Oral Mucous MembranesPatient received 6800 cGy for a squamous cell carcinoma ofthe anterior floor of the mouth. Note the telangiectasias withinthe zone of keratinized attached mucosa (ovals)However, a maxillary complete denture would predispose to little risk.These patients learn to masticate by mashing the bolus against the rugaepattern, incorporated within the denture, with the tongue.
  • 43. Soft Tissue Necrosis A mucosal ulcer in irradiated tissue that has no residual tumorClinical signs: The first priority is to rule outa) Extremely painful recurrent tumor.b) No inflammatory halo Diagnostic methods used:c) No induration Cytology, biopsy and clinical observation
  • 44. Late Effects – Oral Mucous Membranes” Soft Tissue Necrosis – Patient received 5500 cGy via external beam and another 2500 cGy with a radium implant for a squamous cell carcinoma of the lateral border of the tongue.” Nine months after therapy he developed this ulceration at the site of the tumor.” Cytology and biopsy were negative and a diagnosis of radiation soft tissue necrosis was assumed.” The lesion epithelialized 4 months later
  • 45. Acute Effects – Skin ReactionsIn most patients skin reactions are limited toerythema and tanning of the skin.Individuals with light complexions are likely to have the most severe skin reactions.
  • 46. Acute Effects – Skin Some patients develop dry and moist desquamation of the skin.
  • 47. Late Effects – Skin Scarring and telangiectasiaThis patient received 5600 cGy for a squamous carcinomaof the right cheek. After therapy he developed scarring andtelangiectasia of the cheek skin.
  • 48. Late Effects – Skin Alopecia, and hyper-pigmentationNote the hair loss within the radiation field. This finding can bevery useful in identifying the fields of radiation when examininga male post radiation (if CRT was used) particularly when theradiation records are not available. Note the hyperpigmentation(oval).
  • 49. Late effects – Edemav  Secondary to obliteration of small lymphatic channels and worsened by scarring and fibrosis (Engerset, 1964; Sherman and O’Brien, 1967).v  Clinically significant when it effects the tongue and buccal mucosav  Generally most prominent in the submental and submandibular areasv  Radical neck dissection potentiates the effects and increases the edema
  • 50. Edema Both patients present with edema of oral cavity structures, one involving the tongue, the other the buccal mucosa. These two patients are susceptible to tongue and cheek biting.Prevention: Accomplished by use of a prosthetic stent designed to displacethe buccal mucosa or tongue away from the interocclusal surfacesIn edentulous patients the enlargement of the tongue has negative effects onthe floor of the mouth contour and adversely affects the lingual extension andthe patients ability to tolerate and control the lower denture.
  • 51. Radiation and Trismusv  Secondary to fibrosis of the muscles of mastication and generally not noticed until 3-6 months after radiation (Goldstein et al, 1999)v  The higher the dose the greater the trismus (Goldstein et al, 1999).v  Occurrence is 10-45% (Kent et al, 2008).v  Mouth opening following radiation is reduced by 18% (Dijkstra, 2004)v  The rate and severity is much higher in patients treated with chemoRTv  Occurs more often when radiation is combined with a surgical procedure (i.e. radical maxillectomy) that effects the TMJ and the muscles of mastication.v  Risk and severity increases with time particularly in patients treated with chemoRTv  IMRT may decrease the risk (Hsiung et al, 2008)
  • 52. Radiation and Trismusv  Dramatically worsened by concomitant chemotherapyv  Maximum opening may be reduced to 5-15 mmv  Treatment consists of exercise and use of dynamic bite openers (Dijkstra et al, 2004).v  Progressively worsens with time.v  Compromises the use of complete dentures, obturator prostheses.*In patients with combined radiation and surgery, early initiation of an exerciseprogram before the fibrosis sets in provides the best results.
  • 53. Radiation and Trismusv  This represents maximum opening for this patientv  13 years ago patient was treated with chemoRT for a nasopharyngeal carcinoma
  • 54. Radiation Trismus -Treatmentv  Dynamic bite openers*# are the most effective form of treatment (Dijkstra, 2004)v  Patient is instructed to stretch with the device for 30 minute sessions three times per day.v  Requires a high level of patient cooperation because of the discomfort associated with the required manipulationv  Tongue blades, taped together and used as a lever have been less effective in increasing mouth opening. *Therabite Corp., West Chester, PA #Dynasplint Systems Inc., Severna Park, MD
  • 55. v  Visitffofr.org for hundreds of additional lectures on Complete Dentures, Implant Dentistry, Removable Partial Dentures, Esthetic Dentistry and Maxillofacial Prosthetics.v  The lectures are free.v  Our objective is to create the best and most comprehensive online programs of instruction in Prosthodontics
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