INTRODUCTION: mucosa, diverse and complex diversity of

INTRODUCTION: Cancer is the most popular term used to refer to a malignant neoplasm which is defined as “an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimulus which evoked the change” as given by Sir Rupert Willis. The high rate of proliferative potential of the malignant cells and ability to surpass the defence mechanisms of the body has made it a life threatening condition. Head and neck cancer is a broad term used to describe diverse malignant neoplasms involving the upper aero-digestive tract. Head and neck cancers (HANC) contribute to 6% of the all the cancers that are diagnosed in the world 1. The progress in the field of technology has resulted in introduction of more successful treatment options to eradicate oral cancer increase the survival rate. Contemporary treatment modalities include surgical intervention, chemotherapy, radiotherapy and hematopoietic stem cell transplantation (HSCT). However, these are associated with collateral damage that occurs to the surrounding head and neck structures. The increased susceptibility of oral cavity to the direct and indirect toxic effects of radiotherapy is due to the higher turnover rate of cells in the oral mucosa, diverse and complex diversity of the oral microflora and higher chances of trauma occurring in the oral cavity 2. Radiation therapy can be used as a primary treatment modality depending upon the stage and extent of the disease or in combination with the adjuvant therapies as mentioned above. The factors which play a significant role in eliciting these undesirable consequences are the region of irradiation, the radiation dosage and the individual’s biological response to irradiation 3. The toxicities are classified as early (acute) or delayed (chronic) effects based on the time and course of their development relative to the radiotherapy. Early effects are seen within 2-3 weeks whereas the late effects manifest in months or years. The most commonly seen delayed effects in the oral cavity include xerostomia, soft tissue injury, mucositis, trismus, dysphagia, oesophageal toxicity and osteoradionecrosis. Early literature reviews have shown that oral health is a reflection of the general health of the individual. As a result, poorly restored dentition, periodontal disease, pathologies, neglecting oral care are aggravating factors of post radiation complications 4. There is a stark necessity of dental clearance before starting any kind of treatment for head and neck cancer patients. By maintaining oral hygiene and health, one can preserve daily functions such as mastication, verbal and non verbal communication and prevention of further infections. The aim of this literature review is to elaborate the various complications associated with radiation therapy and the pre- and post treatment management of such conditions.  PRINCIPLE OF RADIOTHERAPY: Being one of the most effective forms of treatment, radiotherapy plays an indispensable role in treating head and neck cancers. Radiotherapy works predominantly on the principle of ionising radiation. This component of the electromagnetic spectrum has the ability to induce cell damage by direct damage of the DNA of the malignant cells or by indirect damage carried out by free radical released as a reactionary product of water and radiation 5. The cell loses its ability to sustain continuous cell division after irreplaceable damage has been caused to the genetic material of the cell. The most important property of malignant cells is the uncontrolled cell division. As a result, when this proliferative potential is altered, complete sterilisation of the tumour cells occurs. Partial sterilisation takes place when the cells enter a phase of stasis or regression. The dose of ionising radiation depends upon a list of factors such as type of malignancy, location of the malignancy and sensitivity of surrounding anatomical structures 6. Fractionation of dose for head and neck cancer patients is done by administering 2Gy per fraction is delivered once per day, 5 days a week, over a 5-7 week period, making the total dosage 64-70 Gy 7. The main aim of this treatment is to deliver a concentrated and lethal radiation dose to the tumour site and at the same time minimise damage to the surrounding structures. However, significant changes do occur in the integrity and functioning of healthy cells. The dose-response relationship in the healthy tissues depends upon the survival of the stem cells and the time of response depends upon the turnover of the mature cells. Epithelial cells exhibit acute effects within days as they have rapid cell turnover rate. Bone has a slower turnover rate producing late effects which take months to years to manifest 8. The various complications and their management will be described in the following sections.  ORAL COMPLICATIONS 1. XEROSTOMIARadiation damage to the major and minor salivary glands such as parotid, submandibular and sublingual glands can lead to dry mouth or xerostomia. Glands with serous salivary secretion, such as parotid are more sensitive to ionising radiation. Although salivary gland tumours constitute only 5% of all head and neck cancers, most destruction to salivary structures occurs during radiation dose to other surrounding structures. At low radiation dose (less than 30 Gy) the damage is reversible and takes 2 years to recover post cessation of radiation 9. Loss of acinar cells, alterations in the ductal epithelium, fibrosis and fatty degeneration which occurs at doses above 75 Gy produces the various manifestations of radiation induced salivary gland damage 10. A study conducted showed 5% loss of function per 1 Gy of mean dose to the parotid gland 11. The early effects begin within 1-2 weeks into the radiation treatment due to decrease in the salivary flow rate. Submandibular gland is seen to be more radioresistant than parotid gland. The symptoms which are most commonly reported are dryness, burning sensation, discomfort, cracked lips, alterations in tongue surface, difficulty in wearing dentures and other functional movements. Saliva also has an antimicrobial effect which causes rapid progression of dental caries and oral diseases during salivary hypofunction 12. The management of salivary hypofunction is as follows.   Management of Xerostomia: Patients are advised to take frequent sips of water (every 10 minutes) or melt ice chips in the mouth for comfort. Patients are advised not to have coffee, tea, soft drinks with caffeine and commercial mouth rinses containing alcohol as these can dehydrate the mouth. Food items rich in ascorbic, malic and citric acid stimulate the glands but acidic content can irritate the other tissues. Salivary substitutes have been able to only mimic the texture of natural saliva but cannot restore the biochemical properties. Artificial saliva sprays  (eg. Xerotin, Salivart) and mouth moisturising gel (eg. Biotene Oral Balance) can also be used. Cracked lips can be treated by applying petroleum jelly or lanolin containing preparation. Alcohol free mouth rinses  (eg. BioXtra alcohol free mouth rinse) are used to maintain adequate oral hygiene4. Systemic sialogogues have the potential to stimulate natural saliva from the functional glands. Saliva stimulating tablets (SST) and medication like pilocarpine (Salagen, 5mg, thrice a day) can also be used as a means of pharmacological intervention for glands which have residual function 13. Cevilmeline, a sialogogue used for treatment of Sjogrens syndrome can also be used. Xylitol or sorbitol based chewing gums are used to increase salivary flow rate 4. For prevention of demineralisation and dental caries, 1.1% neutral sodium fluoride gel daily with the aid of a vinyl tray can be done 14. Changes in the radiotherapy techniques by reducing dosage of ionising radiation to atleast one gland also reduces incidence of these complications. Oil pulling therapy is also used to reduce xerostomia 15. 2. DYSGEUSIA90% of the patients report alterations in taste disturbance as an early sequelae of radiotherapy. Damage to the specialised mucosa i.e. the taste buds that are seen on the lips, tongue, oral cavity, pharynx, upper oesophagus and nasal cavity. Biochemical alteration in the concentrations of sodium, potassium and calcium in the taste bud cell receptors is also seen 16.Reduction in the quantity and quality of the saliva also contributes to the altered taste sensation. The peak of dysgeusia is seen at 4-8 weeks. The following three phenomena are majorly observed: • Hypogeusia- characterised by reduction in overall taste• Ageusia- Total absence of taste• Dysgeusia- alteration in the normal taste. Most commonly affected tastes are salt and bitter. Mild dygeusia is tolerable and affects appetite, reduces calorie intake, induces further weight loss, hampers nutritional status and exerts a great impact on the individuals quality of life 4.  Management of Dysgeusia: Several modalities are available for the treatment of altered taste sensation. Zinc supplementation has been clinically observed to alleviate the symptoms of dysgeusia. The mode of action of zinc is that it acts as a structurally important element in the proteins responsible for regulating the taste bud pores 17. Other method used is vitamin D supplementation in the diet. Long term improvement is done by giving dietary counselling to the patient prior, during and after cessation of radiotherapy treatment. The nutritionist generally advises the patient to drink more quantity of fluids during meals which will enable dissolution of taste components in the food and further facilitate their movement to the taste buds, eventually improving the taste perception 18. Slower chewing of food results in thorough release of more flavours and stimulates increased salivary production. Patients should also make sure they switch the food items during meals to avoid adaptation of taste receptors to a particular taste and ensure that they have a balanced diet 19.  3. ORAL MUCOSITISOral mucositis has been defined as the inflammation and ulceration of the oral mucosa with pseudomembrane formation with a potential source of infection which may eventually lead to death. 90-97% of head and neck cancer patients receiving radiation therapy have been reported to develop some degree of oral mucositis as a common complication 20. The sequence of presentation of clinical symptoms is as follows. In the first five to seven days after radiation therapy, erythema followed by white plaques are seen on the mucosal surface which are tender on palpation. Epithelial crusting and fibrin exudate is also seen due to the inflammation and pseudomembrane formation. Exposure of the underlying connective tissue due to loss of surface epithelial cells is seen in severe cases. Systemic infections may also occur through the passage of pathogenic organisms through the denuded epithelium 21. World Health Organisation classified oral mucositis into the following five grades 22: I. Grade 0: No mucositisII. Grade 1: Painless ulcer, erythema or mild sensitivity is presentationIII. Grade 2: Painful erythema or ulcers that do not interfere with the patients ability to have food are presentIIII. Grade 3: Confluent ulcers that interfere with the patient’s ability to take food are presentV. Grade 4: Enteral or parenteral support is needed. The most common sites of occurrence are buccal mucosa, floor of mouth, soft palate or mucosa of the upper digestive tract. The frequency and severity of mucositis depends on factors such as type of tumour, age of the patients (most common in younger patients), oral and dental health, nutritional condition of the patient and the radiation dosage 23. 10 Gy cumulative dose of ionising radiation produces the early signs of oral mucositis.  Management of oral mucositis:The main objective of the treatment modalities is to provide palliative support, alleviate discomfort and improve the quality of the patient’s life. One of the strategy for pain relief is the use of oral solution mixture popularly known as “Magic Mouthwash” which is composed of diphenhydramine, viscous lidocaine, subsalicylate, bismuth and corticosteroids. It reduces acute pain and inflammation thus making consumption of food much easier 24. Various pharmacological interventions are also available. Opioids are the primary drug of choice as an analgesic. Efficacy of growth factors and cytokines has been clinically proven to reduce the development of high grade mucositis and reduce the duration of the lesion. An example of such a drug is Palifermin (Kepivance, Thousand Oaks, CA, USA), a recombinant human keratinocyte growth factor shows promise in reducing the severity of mucositis 25. Palifermin is associated with decreased use of parenteral nutrition and improved well being but also causes taste alteration as a significant adverse effect. Oral rinses such as isotonic saline or sodium bicarbonate are also used but their efficacy is not certified. Simple mouthwash is prepared comprising of 10ml of salt and 10ml of sodium bicarbonate in 250ml of water 26. Chlorhexidine containing rinses reduce the chances of microbial infections and reduce risk of caries but there has been no effect on reducing pain of mucositis. The discomfort can be reduced by using coating agents such as aluminium/magnesium hydroxide 27. Oral cryotherapy, by placing ice chips in the mouth every 30 minutes, works on the principle of vasoconstriction. Short term anaesthesia is produced by the topical anaesthetics used in rinses. The side effects of these agents is the increased risk of aspiration and cardiac effects produced. Benzydamine hydrochloride and antihistamines such as diphenhydramine are used to reduce oral mucosal pain 28. 4. TRISMUS:Trismus is defined as a tonic contraction of muscles of mastication which results in restricted mouth opening 29. It is estimated that 5- 38% of the patients with head and neck cancer suffer from limited mouth opening or trismus. However, there is a lack of consensus regarding the normal range of mouth opening and when the onset of trismus occurs. Patients with tumours of the palate, nasopharynx and maxillary sinus mostly exhibit trismus. Radiation damage to the temporomandibular joint and muscular structures such as pterygoid and masseter leads to scarring and fibrosis with gradual reduction in mouth opening. It is a late complication which begins approximately six months post treatment due to the slow turnover of cells 30.Functional reduction in mouth opening is interincisor distance of less than 35mm with 20-40mm being indicative of trismus 31. There exists a dose-effect relationship between the mean dose to pterygoid and masseter muscles and probability of acquiring trismus. Dosage greater than 55 Gy results in 47% risk of acquiring trismus. Another study reported a 24% increase in the risk of acquiring trismus for every 10 Gy in pterygoid muscle after a dose of 40 Gy 32. Management of trismus:Exercising of the muscles involved and use of bite openers can be used for improving the mouth opening. Newer techniques such as Intensity Modulated Radiation Therapy (IMRT) minimises the radiation dose to the TMJ. Incidence rate of trismus reduces to 5% by using this modified technique 33. 5. OSTEORADIONECROSISOsteoradionecrosis is defined as the radiographic evidence of bone necrosis due to irreversible progressive devitalisation which occurs within the radiation field where tumour recurrence has been excluded 34. The bone becomes hypovascular, hypocellular and hypoxic. The mandible is more prone to this due to its poor vascularity and high bone density. Osteoradionecrosis is a severe and delayed complication which manifests after 6 months of radiotherapy. The factors which contribute to this are trauma, type of radiation, dosage of radiation, proximity to tumour, volume of tissue involved, presence of teeth, poor oral hygiene and alcohol and tobacco use 35. The variation of prevalence of osteoradionecrosis among different types of radiotherapy techniques is as follows: conventional radiotherapy (7.4%), intensity modulated radiotherapy (5.1%), chemoradiation (6.8%) and brachytherapy (5.3%) 36. The pathophysiology of osteoradionecrosis of the jaws begins with destruction of hard and soft tissues by radiation causing traumatic and spontaneous breakdown of tissue. The metabolic demand of the healing tissue is higher than the supply leading to formation of chronic non-healing wound. Superinfection with oral commensal bacteria occurs and eventually a painless non healing area of exposed bone is seen. The clinical manifestations include pain in the later stages, orofacial fistulas, exposed necrotic bone, pathological fracture and suppuration 37. This condition more commonly occurs in dentate than edentulous patients. A cumulative dosage of  >65 Gy results in necrosis of the mandible. Maxillary osteoradionecrosis is rare and is most often associated with nasopharyngeal cancers 38. Management of osteoradionecrosis:The most commonly used treatment is hyperbaric oxygen therapy in combination with surgical intervention 36. A recent study has shown that pharmacological intervention with drugs like pentoxifylline, tocopherol and clodronate have been used in the treatment of osteoradionecrosis 39. 6. ORAL INFECTIONSRadiation results in suppression of bone marrow made of radiosensitive cells resulting in anemia, thrombocytopenia and leukopenia. The highest risk of infection occurs when the granulocyte count falls below 0.5 G/L. Overall suppression of immunity is associated with increased incidence of bacterial, viral and fungal infections.  6.1 BACTERIAL INFECTIONSThe oral cavity is an ecosystem of microbial flora which have the potential to become pathogenic with immunosuppression. Sepsis due to unknown origin may be a result of  infection by species such as Viridans Streptococcus, Prevotella, Fusobacterium, Actinobacillus actinomycetemcomitans and Actinomyeces 40. These infections can be treated with a combination of penicillin and metronidazole followed by any routine dental procedures 41. Meticulous oral hygiene using proper brushing technique and auxillary aids such as chlorhexidine mouth wash and flossing should also be used. The disadvantages of this mouth wash is its tendency to stain teeth, alcohol content and ability to irritate inflamed tissues. 6.2 FUNGAL INFECTIONSMost common fungal species which produces an opportunistic infection is Candida albicans, mainly due to reduced immunity, salivary alterations and mucosal lesions. It manifests first as pseudomembranous candidiasis which develops into erythematous and angular chelitis 42. Clinically, this is seen as a white scrappable lesion, commonly known as oral thrush. According to the guidelines provided by the Infectious Disease Society of America (IDSA), the first line of drugs for treatment are clotrimazole troches and nystatin pastilles. However, these are difficult to apply in cases of hyposalivation which made the use of rinses much more beneficial. It is important to note that chlorhexidine and nystatin should not be used concurrently as they render each other ineffective. Systemic fluconazole (100-200 mg/ day) is used in moderate to severe conditions. Patients resistant to fluconazole are treated with voriconazole or amphotericin B. High fever and increased risk of skin cancer due to severe photosensitivity are the side effects of these drugs 43. Many literature reviews have reported that prophylactic use of anti fungal drugs absorbed from the GI tract can be used to prevent fungal infections 44.   6.3 VIRAL INFECTIONSHerpes Simplex Virus infection is the most prevelant viral infection which gets reactivated due to immune suppression following radiation therapy. Other infections which produce symptoms due to reactivation of the latent virus are Varicella Zoster and Epstein Barr virus. The clinical symptoms produced are characteristic ulcers in the mucosa which is not attached to the periosteum. Prodromal symptoms followed by painful vesicular eruptions with burning sensation are seen 45.Oral prophylaxis is done using acyclovir 200-800 mg 3-5 times a day or valacyclovir 500 mg twice a day. Intravenous dose of acyclovir is 5 mg/kg every 8 hours. In case of drug resistance, foscarnet can be used 46. IMPORTANCE OF DENTAL EVALUATION:Pre radiotherapy dental assessment of the patients by the oncologist or the dentist is essential to reduce the morbidity of the patient and also for early diagnosis of diseases. A recent survey conducted among dentists in India shows that only 59% of the dentists are aware about the assessment of patients indicated for radiotherapy 47. Assessment about the caries risk, periodontal status, extractions required and prosthesis fabrication should be done prior to radiotherapy to reduce the risk of complications and improve the quality of life of the patient.  BASIC TREATMENT STRATEGY: The following strategies have to be considered for each patient 48: 1. Pre operative evaluation• Definitive diagnosis• Past medical history• Radiographic examination• Oral examination : Soft tissue examination, periodontal status and caries activity• Whole salivary flow rates• Adjunctive tests• Prognosis• Proposed radiotherapy2. Treatment• Extraction of teeth with poor prognosis• Dental prophylaxis• Restorative dental procedures• Oral hygiene regimen: Tooth brushing technique, fluoride rinse, mouth wash 3. During irradiation therapy:• Weekly prophylaxis• Prescription for analgesic, dietary supplements, antifungal and antimicrobials needed• Daily topical fluoride• Frequent saline rinses• Lip moisturiser• Passive jaw opening exercises4. After radiation therapy:• Oral and neck examination for recurrence• Dental prophylaxis• Restorative procedures if needed• Reinforcing the oral hygiene instructions• Frequent follow up appointments CONCLUSIONThe extensive research in the field of oral cancer has led to the introduction of various treatment modalities, one of which is radiation therapy. This review emphasised on radiotherapy, its complications and management strategies. The complications of radiotherapy have to be considered at every step of treatment so that maximum effort is taken to minimise the oral morbidity of the patient, before, during and after the treatment. It is important for the dentists to be aware of the various assessments that need to be done. Maintaining the quality of life of the patient is of utmost importance which means that the dentist should be aware of the various interventions that need to be done. Management of the complications has also been elaborated in this article to shed light on the pharmacological and non pharmacological methods available. Prevention is better than cure, the same applies to these complications as well.