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 Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 8  |  Issue : 6  |  Page : 72-84

Toxicity with radiotherapy for oral cancers and its management: A practical approach


Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai - 400012, India

Date of Web Publication24-Jan-2012

Correspondence Address:
Sarbani G Laskar
Department of Radiation Oncology, Room No. 128, Ground Floor, Main Building, Tata Memorial Hospital, Parel, Mumbai- 400 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.92219

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 > Abstract 

Radiotherapy-induced damage in the oral mucosa is the result of the deleterious effects of radiation, not only on the oral mucosa itself but also on the skin, adjacent salivary glands, bone, dentition, and masticatory apparatus. From basic skin care to dental and oral health maintenance, several ointments and lotions, oral and parenteral medications, biological response modifiers, cytoprotective drugs, newer radiation techniques and surgery have been introduced to combat and more importantly to prevent the development of these complications. Radiotherapy-induced oral complications involve complex and dynamic pathobiological processes. This in the immediate- and long-term course lowers the quality of life and predisposes patients to serious clinical disorders. Here, we focus on these oral complications of radiotherapy, highlight preventive and therapeutic developments, and review the current treatment options available for these disorders.

Keywords: Future directions, management, pathobiology, QOL, radiation toxicity


How to cite this article:
Basu T, Laskar SG, Gupta T, Budrukkar A, Murthy V, Agarwal JP. Toxicity with radiotherapy for oral cancers and its management: A practical approach. J Can Res Ther 2012;8, Suppl S2:72-84

How to cite this URL:
Basu T, Laskar SG, Gupta T, Budrukkar A, Murthy V, Agarwal JP. Toxicity with radiotherapy for oral cancers and its management: A practical approach. J Can Res Ther [serial online] 2012 [cited 2019 Sep 18];8:72-84. Available from: http://www.cancerjournal.net/text.asp?2012/8/6/72/92219


 > Introduction Top


Radiation therapy is an integral component in the management of cancers of the oral cavity. As a result, various normal, uninvolved structures like the salivary glands, oral mucosa, masticatory apparatus, dentition and jaws inadvertently receive significant doses of radiation. The resulting oral sequelae may cause substantial problems during and after radiation therapy and are major factors in determining the patient's quality of life in the long term. Here, we focus on the clinical and pathological aspects of these complications along with approaches for prevention and management.


 > Radiation-Induced Skin Toxicity Top


Acute skin reaction is one of the most common side effects of radiation therapy, contributing to discomfort, irritation, itching, burning and pain. Skin changes of varying grades can be experienced in up to 95% of patients of head and neck cancer on radiotherapy. [1]

Pathogenesis

Following an initial dose of radiation, a fixed percentage of basal cells are destroyed. The remaining cells become cornified, shed more quickly, disrupting the balance between normal production of cells at the basal layer and destruction of cells at the skin surface. [2] Erythema begins as a result of capillary dilatation in the dermis accompanied by edema because of increased vascularity and obstruction. [3] Changes in pigmentation are caused by the migration of melanin to the more superficial layers of the epidermis. Hair growth is interrupted as hair follicles revert to a resting phase of their cell cycle. Epilation is due to high susceptibility of anagen follicles (anagen effluvium) to radiation. A dose of 3Gy produces complete, reversible anagen alopecia; permanent alopecia begins to occur at 30Gy. [4],[5]

Normal tissue repair results from a homeostatic stimulus or feedback mechanism with re-epithelialization with the proliferation and differentiation of cells from the basal membrane and the migration of epithelial cells from outside the treatment field in about 10 days. [1],[6]

Clinical features

Early radiation skin reactions occur within one to four weeks of treatment and may persist for two to four weeks following treatment. They are graded by severity along a continuum ranging from erythema and dry desquamation to moist desquamation and in more severe cases, ulceration. [1],[7]

During the first two weeks of treatment, the patient generally does not experience any discomfort. Transient erythema may occur within 24 h and localized to the treatment field after two to three weeks of radiation. The skin appears red, warm, and may have a rashy appearance. Hyperpigmentation occurs after two to four weeks with the cumulative dose reaching 20 Gy. [8] Sweat and sebaceous glands can be permanently destroyed after approximately 30 Gy causing reduced skin lubrication, dryness and pruritus. At doses of 30-40 Gy hyperemia and edema occur and if severe, there is epilation leading to moist desquamation that can occur at doses of 45-60 Gy. Complete hair loss can occur at doses ≥ 55 Gy, with regrowth occurring approximately two months after the last dose of radiation.

Risk for skin reactions increase with prior surgery, burns, or skin lesions. [9],[10] Patient risk factors also include use of concurrent chemotherapy/targeted therapies, diabetes or renal failure, compromised nutritional status, smoking, auto-immune disorders and environmental conditions. [11],[12]

Treatment-related risk factors include a larger treatment volume, higher dose per fraction, longer duration of treatment, use of lower energy photons and electrons depositing a higher skin dose, and use of any bolus material. [13] It has been observed that 52% of radiation therapy centers encounter dry desquamation as a frequent occurrence and 85% moist desquamation as an occasional event. [9]

Management

Routine skin care, ointments and dressings are the cornerstone of management of radiation skin reaction. There continues to be a paucity of evidence to recommend many of the interventions and are often recommended in practice based on clinical experience. [1]

Traditional belief of restrictive skin care practices has been outdated by megavoltage radiation and the advice is to have regular bath with lukewarm water taking care not to rub over the area. [10] The two trials assessing skin washing both detected less severe skin reactions in the washing groups. [14] Patients should avoid swimming in chlorinated swimming pools. [1] Advice is to wear loose cotton clothing or soft fabrics to prevent mechanical injury. Cosmetic products should also be avoided to prevent sensitivity reactions and irritation. Electric razors should be used for any shaving in the treatment field.

The primary aim for managing dry desquamation is to alleviate patient discomfort, prevent skin breakdown and minimize potential for infection. Initial use of a plain, non-scented, lanolin-free hydrophilic cream traps moisture at the skin surface and maintains skin pliability. Emollient creams/ointments containing trolamine, hyaluronic acid, almond, sucralfate, chamomile all have been tried.

Biafine (trolamine), an oil-in-water emulsion with nonsteroidal anti-inflammatory properties, is commonly used for radiation-induced dermatitis. Two randomized non-blinded trials assessed the effectiveness of topical Biafine cream and one randomized single-blind trial compared calendula ointment to Biafine cream, there was no significant difference in occurrence of skin reactions. [15] The extent of acute skin reaction, pain, and itching were reported in the only trial that assessed chamomile cream vs. almond ointment. No statistically significant difference in the frequency of skin reaction was detected between treatment groups, although ≥Grade 2 reactions seemed to appear later and less frequently in the chamomile cream-treated areas. [16]

A number of steroid ointments have also being tried. Bostrom detected a significant benefit in favor of 0.1% mometasone furoate cream in terms of lower maximal erythema scores and grade 3 or greater skin reaction. [17] Schmuth randomized 0.1% methylprednisolone aceponate (MPA) cream vs. 0.5% dexpanthenol cream and found no significant difference in the degree of skin reaction between patients. [18] Low dose (1%) corticosteroid cream may be beneficial in the reduction of itching and irritation. [18] Only three trials have assessed patients' experience of the sensation of burning of the skin. [19] The more specific Skindex scale favored corticosteroid (MPA) cream over dexpanthenol. [20] Potential allergic reaction to topical corticosteroids should be kept in mind.

Hyaluronic acid, a polymer, accelerates the granulation phase of healing. Only one human study has been conducted assessing the prophylactic use of hyaluronic acid (HA) 0.2% cream in patients receiving radiotherapy for head and neck cancer, applied to the skin twice daily at the start of radiation, indicated a statistically significant improvement in delaying the onset of skin reaction by the third week as well as reduction in intensity and duration of reaction. [21]

During moist desquamation, the skin becomes open and susceptible to infection. Randomized trials compared topical sucralfate against a placebo reported no difference in erythema by using sodium sucrose octasulfate. [16],[22] Oral use of sucralfate reported by Lievens et al. found no significant reduction in dermatitis compared with a placebo similarly for oral enzymes. [23] Antimicrobial ointments like silver sulfadiazine should not be used as prophylactic management because of concerns about sensitivity or resistance.

The use of dressings in the management of radiation skin reactions is based on the understanding that a moist wound-healing environment promotes the rate of re-epithelialization faster. [24] Few studies have evaluated the effects of hydrocolloids, semi permeable dressings, or hydrogels in the management of radiation skin reactions. Moisture vapor permeable (MVP) dressings have been assessed by the rate of healing and patient comfort in comparison to hydrous lanolin gauze dressing. It was found that healing time and reduction of severity were both better with MVP dressing. When compared with Gentian violet, dressing comfort and esthetics were statistically significant for the hydrocolloid dressing. [25]

Human amniotic membrane (AM) [26] has been used successfully as a temporary biologic dressing to prevent wound infection in burn patients. AM is the innermost of the layers forming the fetal membranes and has a thin epithelial layer, a thick basement membrane and an avascular stroma consisting mainly of collagen. [27] Experimental and clinical studies have demonstrated that AM has antibacterial properties, low immunogenicity, promotes re-epithelialization, decreases inflammatory process and modulates angiogenesis. [28] It is cost effective in radiation-induced ulcer in view of rapid healing, less frequent changes and reduction in analgesic requirements. The problem is the restricted availability. [29]


 > Oral Mucositis Top


Mucositis is a common toxicity of radiation therapy characterized by ulceration of oral mucosa causing pain, dysphagia and dysfunction. [30],[31] Oral mucositis remains an undesirable, painful, and expensive side effect of cytotoxic cancer therapy, and is disheartening for patients and frustrating for caregivers. [32] According to various available literature, incidence of oral mucositis ranges between 80 and 97% [33],[34],[35] while grade 3 and 4 mucositis being 40-55% depending upon type of radiotherapy and concomitant use of chemotherapy. [36],[37]

Pathogenesis

Radiation and/or chemotherapy induce cellular damage causing death of the basal epithelial cells generating free radicals. [31] This up-regulates pro-inflammatory cytokines specially TNF-α causing inflammation and ulceration. Finally healing occurs by epithelial proliferation, as well as, cellular and tissue differentiation, restoring the integrity of the epithelium. However, cell regeneration often cannot keep up with the rate of cell death, resulting in some or complete denudation of the mucosa. [38],[39]

A previous study assessing the sequence of gene expression in irradiated oral mucosa showed an intricate functional interaction in succession of affected genes. [36] Furthermore, the biological endpoint of cell death leading to tissue injury could occur through routes mediated by NF-κB, P53, and ceramide pathway. [40]

Oral microbial flora also contributes probably through endotoxins produced by Gram-negative bacilli. Mucosal barrier injury associated with mucositis promotes an increase in pathogens such as α-hemolytic streptococci. [41] Roles for fungi (candida) and viruses (herpes simplex 1) in the etiology of mucositis have been the subject of speculation since 1980s and remain marginally controversial. [42]

Clinical feature

Radiation-induced mucositis is a function of cumulative dose and typically begins at doses of about 15-20 Gy. Ulcerative mucositis is usually noted at doses of 30 Gy. Advanced mucositis is seen as ulceration, with or without a pseudomembrane, on a bed of erythema. [43]

Symptoms of radiation-induced mucositis include intense pain, dysphagia, odynophagia with anorexia and difficulty in speaking. The pain from mucositis is often so intense that it can prevent oral intake necessitating use of parenteral opioid analgesics, affect quality of life, and result in interruption of cancer therapy. [44]

Both therapy and patient-related factors are important in the development of mucositis. To a large extent, treatment type and dose can be overwhelming risk factors. Age, body mass, and gender have been identified as possible patient- associated risk factors. Genetic factors may play a dominant role in determining mucositis risk, specially TNF-α. [40],[45] Studies evaluating saliva and micro-organisms have concluded no role of them in primary etiology of mucositis. [40]

Grading of the severity of mucositis has no universally accepted system. Most commonly, mucositis score is used to measure and convey the toxicity of a particular therapy serves as a nursing management tool and used to determine the efficacy of new treatments for the condition. The commonly used scoring tools are the WHO, RTOG, and the NCI-CTC. [46],[47]

Management

Jaroneski identified assessment as the most significant clinical intervention in prevention of mucositis. [43] Regimens for the prevention of radiation-induced mucositis include anti-inflammatory drugs, antimicrobial substances, biological response modifiers, and cytoprotective compounds. [47],[48]

In 1990, The "National Institute of Health Consensus Conference on Oral Complications of Cancer Therapies" recommended that all patients with cancer should have an oral examination before treatment, and, if needed, treatment of oral disease in an effort to reduce the risk of complications during treatment. This forms the basis of basic oral care. [49],[50] Actions such as brushing teeth using foam 'toothbrushes' or swabs, flossing, or using topical fluoride is important in maintaining mucosal health, integrity, and function, but its preventive role is doubtful. [51],[52]

Some general measures are used to prevent trauma and infection. Trauma can be reduced by adjusting sharp edges on teeth or restorations. The wearing of dentures should be discouraged, at least during the night. Spicy, hard or hot food, irritants like alcohol and tobacco should be avoided, and the oral tissues including the lips should be kept moist. [53] With respect to prevention of infection, first important step is to diagnose oral foci prior to cancer therapy. Removal of dental plaque and calculus, to reduce the bacterial load and gingival inflammation, is essential. [47],[48] Psycho education, a process that prepares individuals for medical procedures including what to expect and how to cope, is a useful adjunct to other measures. [49]

Several gargles have been tried in mucositis prevention; none of them have shown a significant benefit in reducing oral mucositis. Chlorhexidine, a broad-spectrum, topical antiseptic, may be used for its antiplaque and antifungal properties. [49],[54] The evidence from three studies was consistent in showing that it had no impact in preventing oral mucositis. [55],[56],[57] The routine and cost-effective approach being to rinse with a solution of 1/2 tsp baking soda (and/or ¼ or ½ teaspoon of table salt) in 1 cup lukewarm water several times a day to clean and lubricate the oral tissues and to buffer the oral environment. [58],[59]

The treatment for radiation-induced mucositis includes avoidance, mucosal-coating drugs, lubricants, emollients, and pain management strategies. [31] Systemically delivered treatments of mucositis like antioxidants (β carotene, azelastine), immunomodulatory drugs (indomethacin), anticholinergic drugs, pentoxifylline, cytokines, antiviral drugs, and glutamic acid are being used with varying success. [60]

Topical application of Benzydamine hydrochloride, a nonsteroidal drug having anti-inflammatory, analgesic, anesthetic, and antimicrobial capabilities, also inhibits the production and effects of pro-inflammatory cytokines, particularly TNF. [49] Clinical trials of topical benzydamine has been found to reduce frequency and severity of ulcerative oral lesions and pain in radiation-induced oral mucositis. [61] Randomized trial with benzydamine showed improved ulcer-free rate and reduced incidence of erythema. The conclusion was based on cumulative radiation doses of 50 Gy and the efficacy of the drug with higher doses or in combination with chemotherapy was not established. [62],[63]

Patients with oro-pharyngeal pain often need adjuvant drugs, physical therapy and psychological therapy in addition to systemic analgesics. No guideline is possible for the use of topical morphine sulfate or topical fentanyl, for radiation-induced OM. Sucralfate, a non-absorbable aluminum salt of sucrose and octasulfate, adheres to ulcer base creating a surface barrier. The drug also has some antibacterial and direct cytoprotectant activity. However, reduced overall oropharyngeal pain was recorded in one study. [58] A double-blind randomized trial assessed the protective effect of alpha-tocopherol in radiation-induced mucositis, showed significant benefit in symptomatic radiation mucositis. [30]

In patients undergoing postoperative radiotherapy, use of amifostine is associated with a reduction in mucositis, but complicated by its acute toxicity (nausea, emesis, hypotension, allergic reactions, and taste disturbances) necessitating interruption or discontinuation. Furthermore, there are theoretic concerns that amifostine may protect not only normal tissue but also tumor cells from the effects of radiotherapy. [64]

The role of antibacterial therapy in the control of radiation-induced mucositis has not been established and phase II study of Polymyxin B, Tobramycin and Clotrimazole did not find significant differences in the rate of confluent mucositis. [65],[66]

Oral mucosal injury, secondary to radiotherapy, may be reduced significantly by the use of appropriate radiation blocks and conformal treatment reducing the volume of mucosa exposed to radiation. [67],[68] Careful radiotherapy planning with constraints on the uninvolved mucosa is a useful and effective step to reduce the volume of mucositis.

Palifermin, a newer drug binding specifically to fibroblast growth factor (FGFR2b), expressed uniquely in epithelial cells of epidermis and oral mucosa, enhances the regenerative capacity of epithelial tissues by cytoprotective effects, modulation of cytokine profile and trophic/regenerative effects. [69],[70],[71] Animal studies have shown that it prevents oral mucositis induced by chemotherapy and irradiation. The timing of palifermin administration is critical, as pre-exposure administration induces a number of cellular responses that appear to collectively reinforce the epithelial barrier and increase tolerance to subsequent chemo/radiotherapy. Palifermin has been evaluated for oral mucositis prevention in Phase-II concurrent setting with ten once-weekly doses of 60 μg /kg but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. [72] Further, in a placebo controlled trial, Palifermin reduced the occurrence of severe oral mucositis in patients undergoing postoperative radio chemotherapy. [73] There are ongoing trials of Palifermin to evaluate the reduction of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. [74] Though it is available in India, the cost and lack of widely accepted clinical benefit need to be resolved.

The colony-stimulating factors molgramostim and filgrastim have also been investigated. Molgramostim used concurrently with radiotherapy was assessed in a consecutive series of patients and was associated with reduced mucositis suggesting mucosal protective effect. [75]

Multiple studies have indicated that low-level laser therapy can reduce the severity of chemotherapy and radiation-induced oral mucositis. It has been speculated that it may reduce levels of reactive oxygen species and/or pro-inflammatory cytokines that contribute to the pathogenesis of mucositis. [76],[77]


 > Xerostomia and Related Problems Top


Xerostomia is the most prominent complication in patients of head and neck radiotherapy. Radiation-induced damage to the salivary gland alters the volume, consistency, and pH of saliva. Saliva changes from thin secretions with a neutral pH to thick, acidic tenacious secretion. [78] Patients suffer from oral discomfort, pain, difficulty in speaking and swallowing with increased risk of dental caries or oral infection. [79] Ultimately, this leads to decreased nutritional intake and weight loss, with a significant impact on patient's quality of life. [80]

Pathogenesis

Saliva is important for lubrication of the mouth and oropharynx modulating the oral microbial flora, remineralizing teeth, maintaining the mucosal immune system, and prepare the food bolus during mastication. [81],[82] The major salivary glands produce up to 90% of salivary secretions. The average output of saliva in healthy individuals ranges between 620 and 1000 ml per day. [78],[83]

The granulation hypothesis described radiation-induced lipid peroxidation, and, consequently, leakage of proteolytic enzymes with immediate lysis of the cells. Apparently, saliva-producing cells lose their function few days after irradiation. [84] Konings et al, proposed two separate mechanisms to explain this. First, there is a defect in cellular functioning and late damage is explained by classical cell killing of progenitor cells and stem cells. Salivary function continues to decline for up to several months after RT. Thereafter, some recovery is possible until 12-18 months after RT, depending on the dose received by the salivary glands and the volume of the gland included in the irradiation fields. [85] Radiation-induced xerostomia starts early during treatment: in the first week, a 50-60% decrease in salivary flow occurs; and, after seven weeks salivary flow diminishes to approximately 20%. [86]

Post-irradiation gustatory dysfunction has been reported to occur two to three days after the onset of radiation therapy, with doses as small as 200-400cGy. Taste bud degeneration typically occurs six to seven days after irradiation. This can be associated with damage to either the intragemmal nerve cells or taste cells, or both. However, damage to taste cells, which replenish approximately every 10 days, would likely to recover at least partially, unless the proliferative capacity of the receptor cells is disrupted. [80],[87]

Clinical feature

Clinically, xerostomia has been reported in association with as little as 4-6 Gy. Doses > 30 Gy generally lead to permanent or semipermanent xerostomia. Both resting and stimulated salivary flow are inhibited. However, a compensatory hypertrophy of the unirradiated salivary-gland tissue occurs after a few months and up to one year, which lessens the sensation of xerostomia; however, little further improvement can be expected after this period. [88],[89]

If all major salivary glands are included in the radiation field, salivary function often falls by 50-60% in the first week, with basal salivary flow reaching a measurable minimum 2-3 weeks after use of 23 Gy of fractionated radiotherapy. [90] QOL in patients who are treated for HNC is influenced strongly by xerostomia and all of its ramifications. A survey of 65 patients who survived for longer than 6 months after RT revealed 91.8% had dry mouth, 43% chewing difficulty, 63.1% dysphagia, 75.4% taste loss and 50.8% had altered speech. [91]

Most patients with xerostomia experience difficulty in eating dry or hard food. Mastication and oral manipulation of food becomes painful with need for frequent sips of water. [92] Taste discrimination become increasingly compromised. Decreased saliva output affects taste, contributing to the slow return after RT. This is most pronounced after two months, when bitter and salt qualities generally are impaired. Gradual recovery is observed during the first year, partial loss still persists from 1 to 2 years after treatment. [80]

Speech difficulty is another common complain of radiation-induced xerostomia. Even after five years, patients still report self perceived speech problems related to understanding and comprehension. [93] Dryness of the oral mucosa predisposes to mucosal fissures and ulcerations contributing to xerostomia syndrome. At the end, this can result in decreased nutritional intake and weight loss, posing a major health problem for some patients. [94]

Management

Aggressive pre-radiation oral care coupled with assessment, ideally two to three weeks before treatment is essential for determining oral health status, necessary dental interventions and healing from any invasive procedures. Good oral hygiene, detection of oral abnormalities, treatment of salivary dysfunction and appropriate nutritional intake are important pretreatment strategies. [40]

Antioxidants and free-radical scavengers have long been used to lessen some of the toxic effects of radiation in healthy cells. [95] Amifostine (WR-2721, Ethyol1), a potential radioprotector while entering bloodstream, is rapidly hydrolyzed by alkaline phosphatases of the endothelium and converted to its active form, WR-1065 which enters cells and nuclei and acts as a potent scavenger against free radicals, preventing radiation damage to DNA. [96],[97] Amifostine significantly reduced the incidence of grade 2 acute xerostomia. But, the important issue is toxicity and grade 3 xerostomia, upon which amifostine has no effect, the need for daily injections and cost concerns. [98]

The extent of the damage caused by RT depends both on the volume of tissue irradiated and dose of radiation delivered. It is possible to spare a portion of the parotid gland by the implementation of 3DCRT and IMRT. [99],[100] There is evidence that reduction of xerostomia results in improved QOL. A mean gland dose of 26 Gy was initially proposed as a planning objective for substantial sparing of the gland function by Eisbruch et al. Mean parotid dose of >25.8 Gy was likely to reduce salivary flow to 25% of its pretreatment value, and the incidence of xerostomia was decreased significantly when the mean parotid dose of at least one gland was kept <25.8 Gy. [88],[101]

Saliva substitutes and sialogogues have been tried after development of xerostomia. [40] Artificial saliva substitutes (oral rinses containing hyetellose, hyprolose, or carmellose) developed to supplement the reduced saliva production are purely palliative substances, which act by temporarily wetting the oral mucosa. [40],[102]

Sialogogues target untreated or unaffected residual salivary tissue. Gustatory stimuli, especially acidic substances, are used as hard boiled sucking sweets to increase salivary secretion. Bitter substances also stimulate salivary secretion, whereas sweet substances stimulate salivary flow. A combination of tactile and gustatory stimuli can be found in sugarless chewing gum. [103],[104]

Pilocarpine (non-selective cholinergic agonists) is currently the sole sialogogic agent approved by the FDA for radiation-induced xerostomia. But, patients with a history of asthma, severe COPD, congestive heart disease, and narrow angle glaucoma should avoid these drugs. However, certain issues such as duration of use etc remain unaddressed. [105],[106],[107],[108]

Cevimeline (quinuclidine analogue of acetylcholine) has been found safe and effective in treating xerostomia in patients with Sjogren disease and may have merit for the treatment of radiation-induced xerostomia. [107],[108] Less wide-spread approaches being surgical transfer of one submandibular gland to the submental space, outside the radiation field in postoperative RT [109],[110] and investigational method like intra oral aquaporin gene transfer. [111],[112]

Postoperative radiation has impact upon swallowing also. Irradiated patients have longer oral transit time, increased pharyngeal residue and reduced cricopharyngeal opening times. Primary goal of swallowing rehabilitation is to prevent malnutrition, dehydration and risk of aspiration. [113],[114] Swallowing maneuvers namely supraglottic swallowing maneuver closing the vocal folds before and during swallowing, effortful swallow improving tongue base retraction and pressure generation, Mendelssohn maneuver improves laryngeal elevation and cricopharyngeal opening and tongue-holding maneuver the contact of tongue base to posterior pharyngeal wall. [115]

Diet alterations and food presentation strategies can also be used therapeutically to improve efficiency and safety of swallowing. A puree diet can be used if surgical resection or trismus prevents chewing. Foods prepared with sauces and gravies may be useful for a xerostomic patient. Alternating solids and liquids can reduce pharyngeal stasis. [116] Range of motion exercises for the jaw, lips, oral tongue, tongue base, upper airway closure, and laryngeal elevation are useful in head and neck cancer patients with structural or tissue damage.

Nutritional changes related to dysphagia are another concern for patients of head and neck cancer who have the highest incidence of protein calorie malnutrition with 1/3 rd being severely malnourished. Pain from mucosal ulcerations can lead to reduced intake and thick, ropey secretions often interfere with adequate intake. [117] although nutritional support does not directly improve survival rates but improve tolerance to cancer treatments, reduce complications with fewer hospitalizations. [118]

Dysphagia also has psychosocial implications. The inability to participate in mealtimes and dining out can be isolating. Increased mealtimes, limited food choices, special food preparation methods, and untidy consumption contribute to avoidance of social food consumption. Psychosocial methods go a long way in combating these issues. [119]


 > Dental Problems Top


In patients of advanced head and neck cancer, preexisting dental disease, tooth extraction, and dental treatment are major risk factors for dental sequelae. [120] Dental demineralization also occurs when the major salivary glands are included in the field of radiation leading to formation of circumferentially progressive dental caries. [121],[122]

Pathogenesis

Several studies have investigated the causes of radiation caries; however, little is known about the structural alterations occurring in the dentin and enamel after irradiation. Rapid demineralization and breakdown of tooth structure following radiotherapy may start as early as 12 weeks after treatment. [123],[124] The effects on teeth depend on the type/ dosage of radiation and the extent of disease. Furthermore, a decrease in the pH and the buffering/ enamel remineralizing properties of the saliva, reduced mastication, and poor oral hygiene contribute to radiation caries. [125],[126]

Clinical features

The initial symptoms are sensitivity of the teeth to external stimuli, primary erosion of the occlusal/incisal surfaces of the teeth, and gingivitis. [120],[127],[128] Dental risk factors (DRFs) are dental disease unrelated to cancer or cancer therapy that directly and/or indirectly increases the risk for oral complications of cancer therapy. [121],[127] DRF includes periodontal disease, pulpal disease and periapical lesions, extensive caries, non functional teeth and oral hygiene, dental awareness and co-operation. This can be eliminated by dental intervention: either tooth extraction or dental treatment, preferably prior to radiotherapy. [129]

Another new assessment is malignancy-related risk factor (MRRF), defined as "nondental risk factor, related to cancer, cancer therapy, and the medical condition, that increases the risk of oral complications." MRRFs are examined and identified at organ (head and neck) and patient level. MRRFs cannot be eliminated by dental intervention. [121]

Management

Orodental care should be completed before the start of radiotherapy to minimize oral disease and possible adverse consequences. [121] Criteria for preradiotherapy extractions are nonrestorable caries, active periapical disease, moderate to severe periodontal disease, partial impaction or incomplete eruption. [118] Maintenance of good oral hygiene, brushing two to four times daily with soft-bristled tooth brush and fluoride toothpaste, flossing prevent plaque and caries teeth. [121],[130] Daily cleaning of dentures, avoidance of hot and spicy food, alcohol and smoking, regular inspection of mouth, lubrication of the lips, topical anesthesia and analgesics, prompt treatment of mucositis and oral infections are of help. [121]

Periodontal prophylactic therapy may be required to reduce oral bacterial load and further infections. [120],[121] Several days before radiation therapy, patients should start a daily 10-min application of a 1.1% neutral pH sodium fluoride or a 0.4% stannous fluoride (non-flavored) gel, but patients with porcelain crowns or resin or glass ionomer restorations should use a neutral pH fluoride. Dietary control and topical fluoride therapy should be started on the first day of radiation therapy, continued for life or the duration of xerostomia. All dental interventions should be completed at least 14 days before the initiation of radiation therapy in order to provide an adequate healing period. [131]

After radiation therapy, close follow up for oral health self-care regimen and dietary counseling sessions are beneficial. It is well accepted that tooth extraction should be avoided even after many years of head and neck radiotherapy and complete or removable dentures should be avoided for one year. [132],[133]


 > Trismus Top


Trismus, defined as tonic contraction of the muscles of mastication, is the result of intra or extra capsular pathology of the temporomandibular joint. In patients with head and neck cancer, the tumor may grow into or near mouth closing muscles, inducing a reflex contraction which results in trismus. Trismus may also occur as morbidity from cancer therapy, like scar induced by surgery or fibrosis as a late radiation effect. [134],[135]

This limitation in the ability to open the mouth results in impaired mastication, nutritional impairment, difficulty in speaking, and compromised oral hygiene. The prevalence of trismus after head and neck oncology treatment ranges from 5% to 38%. [136]

Pathogenesis

The muscles of mastication (elevator muscles) when damaged stimulate a pain reflex called "muscle guarding". This causes the muscles to contract, resulting in loss of range of motion. [40],[115] No standard quantification exists for trismus, but a measured interincisal opening of <35 mm has been proposed to be predictive of clinical significance for the patients (normal 40-60 mm). [40],[137]

Trismus becomes clinically significant approximately nine weeks post irradiation. Doses of over 50 Gy to the TMJ and pterygoid muscles have been suggested to be required to induce trismus, although controversy exists regarding the dose-dependent effect on trismus. The damage progresses for the next nine months at a rate of 2·4% loss of interincisal opening per month, with a more protracted loss of opening in later years. At four years, the reduction in mean interincisal opening has been measured at 32%. [138]

Trismus will also cause degenerative problems in the temporomandibular joint mimicking arthritic changes accompanied by inflammation and pain. Degenerative changes in the muscle are also highly likely. Disuse atrophy, as seen by reduction in muscle mass, strength and shortening of muscle fibers is observed within days of immobilization. [138],[139]

Clinical feature

Trismus manifests as a slowly evolving inability to open the mouth. Prior to this, musculoskeletal symptoms may develop secondary to radiation therapy and surgery, including soft tissue fibrosis and surgically induced mandibular discontinuity. It is important to recognize them before trismus develops. [40] Patients also present with xerostomia, mucositis, headache, jaw pain, ear ache and deafness. In cases of temporomandibular tightness, the joint itself may become fibrotic or even ankylotic. [140]

Trismus can dramatically affect quality of life in a variety of ways. Limited mouth opening compromises oral hygiene resulting in dental caries (cavities) and infection and occasionally osteoradionecrosis. [137] Limited mouth opening compromises nutrition by reduction in amount of food intake causing significant weight loss and nutritional deficits. It is generally accepted that weight loss of more than 10% of initial body weight indicates inadequate nutritional intake. [141]

Persons with limited mouth opening have difficulty in swallowing and speech. Swallowing is compromised when, due to muscle damage, surgery or radiation, the larynx is unable to elevate properly, or the timing of the elevation does not coincide with the passage of the bolus. Speech is compromised when the mouth is unable to open sufficiently to create normal sounds. [141],[142] Limited mouth opening may also result in compromised airway clearance and improper tongue movement leading to post-swallow excess residue and potential of aspiration. [143]

Management

If possible, trismus related to head and neck cancer should be prevented because once developed it is very difficult to treat. [40] Trismus is often preceded by mandibular dysfunction. Attempts should be made to treat them by stabilization of occlusion, use of trigger-point injection, pain management strategies, muscle relaxants and tricyclic medications. [141]

Physicians should be proactive in identifying early signs of trismus. One simple test is three finger test, in which if the patient can insert three fingers between the central incisors, mouth opening is considered functional. [40] High-energy radiotherapy beams and sophisticated multiple-field techniques should be used whenever possible to reduce the dose to the temporomandibular joint and to the mastication muscles.

Typical first-line strategies for treatment include physical therapy (PT) with manual mouth stretching exercises, tongue depressor therapy, or use of mechanical stretching devices. Usually some tools are used as incentives to enhance exercise compliance or to increase therapeutic effectiveness. These include rubber plugs, wooden tongue blades, TheraBite exercisers and dynamic bite openers. [134],[135] Dynamic opening systems like TheraBite thought to be more efficient in these exercises. [144] To be most effective, PT regimens need to be initiated and maintained early after treatment for malignancy is complete. [144],[145]

For those who do not achieve improvement with these conservative strategies, and especially in patients with interincisal opening<20 mm, surgical therapy in the form of manual stretching under general anesthesia and coronoidectomy are viable options. [146] Forced mouth opening can improve trismus, but is often short-lived, less controlled with risks of alveolus fracture and adjacent soft tissue rupture. Coronoidectomy has been described, to treat refractory trismus. [141],[147]

Pentoxifylline, a methylxanthine derivative used to treat vascular diseases such as intermittent claudication, has been reported to have effects against TNFα, increase erythrocyte flexibility, vasodilate, and inhibit inflammation. [148] In events of established or late evolving trismus, use of pentoxifylline with concomitant use of tocopherol for several months has proven effective. Similarly hyperbaric oxygen (HBO) improves osteogenic capacity and angiogenesis in previously irradiated mandibular bone. HBO might thus also have a beneficial effect on the TMJ after radiotherapy. [149]


 > Osteoradionecrosis Top


Osteoradionecrosis (ORN) is best defined as "bone death secondary to radiotherapy" (Marx and Johnson, 1987; Constantino et al., 1995), [150],[151] or, slow-healing radiation-induced ischemic necrosis of bone with associated soft tissue variable extent occurring in the absence of local primary tumor necrosis, recurrence, or metastatic disease. [40],[115] The incidence of ORN related to radiotherapy was first reported by Regaud. [152] It is about 8.2% in a 30-years retrospective review. [115],[153] Higher incidence in dentate patients is mainly due to injury from extractions and infection from periodontal disease.

Pathogenesis

Early experimental models of the pathophysiology of ORN showed evidence of bacteria in tissues affected documenting microscopic tissue changes. Meyer proposed his radiation, trauma and infection theory and it became the foundation for the popular use of antibiotics with surgery to treat ORN. [40],[153] Marx examined the traditional concept and concluded that they play a minor role in the pathophysiology of ORN of the jaws, as well as trauma. [150],[151]

A current theory proposes that ORN occurs by radiation-induced fibroatrophic mechanism including free-radical formation and finally bone and tissue necrosis. [154] Micro radiographic analysis of bone suggested four possible mechanisms of bony destruction: progressive resorption of osteoclasts, periosteocytic lysis, extensive demineralization and myofibroblasts apoptosis. Even decades after radiotherapy, the bone remains paucicellular, poorly vascularized, and fibrosed. [155]

Clinical feature

The following points seem to be agreed by majority of the authors when classifying ORN [153]

  1. The affected site should have been previously irradiated.
  2. Absence of recurrent tumor on the affected site.
  3. Mucosal breakdown or failure to heal resulting in bone exposure.
  4. The overlying bone should be 'dead', due to a hypoxic necrosis.
  5. Cellulitis, fistulation, or pathologic fracture need not be present to be considered ORN.
ORN usually develops during the first 6-12 months after radiotherapy; however, the risk remains for life, albeit to a lesser degree. [40],[156]

The higher susceptibility of the mandible has been attributed to its lower blood supply compared with the maxilla and a compact bone structure. [157] Several risk factors associated with development of ORN: age, gender, general health, primary tumor site (tongue and floor of mouth) and stage, dentition status, treatment type (e.g., external beam RT, brachytherapy, surgery, or chemotherapy or combinations), radiation dose, and associated trauma, such as teeth extraction before or after RT or surgery. In recent years, lack of this complication is due to reduced mandibular volumes receiving high doses by conformal RT and IMRT, improved salivary flow rates and improved prophylactic oro-dental care. [158],[159]

Management

ORN can be investigated by many techniques, with orthopantomogram (OPG), being the cheapest and most readily available. Radiological appearance is that of a mixed radio-opaque radiolucent lesion, with the radiolucent areas representing bone destruction. [153]

Some pertinent issues must be taken care of before, during and after radiation therapy in head and neck cancer patients to prevent ORN. Late-onset radiation injuries could result in hypoxia, a major component of delayed wound healing. [115],[160] Hyperbaric oxygen (HBO) stimulates angiogenesis and increases cellular oxygen concentrations. The benefit of hyperbaric oxygen use as a routine treatment in the management of dental extractions in the irradiated jaw is controversial. [154],[161] Careful dental extractions and meticulous follow-up can reduce rates of osteoradionecrosis in the absence of hyperbaric oxygen therapy. [162]

The following points to be kept in mind while managing ORN. Patients at risk for ORN should generally be treated like most other dental patients with pre-radiation dental evaluation. Necessary dental treatment, including the extraction of non restorable teeth, should be completed before radiation commences. Some investigators recommend a 10-21 days delay of radiation therapy after irradiation extractions, which must be weighed against the potential for ORN. Healthy dentition should be maintained in irradiated patients. If ORN occurs, most cases heal, improve, or stabilize without HBO or surgery and extractions in irradiated patients should be performed as atraumatically as possible. [163],[164]


 > Conclusion Top


Head and neck radiotherapy results in several unwanted early (mucositis, loss of taste, hypo salivation) and late (hyposalivation, radiation caries, trismus, osteoradionecrosis) side effects. These sequelae may be dose-limiting and have a tremendous impact on the patient's quality of life. Prevention or reduction to a minimum of these effects should be an integral part of head and neck cancer management.

The problems discussed in this review article highlight the major lacunae of an effective management policy whether related to early recognition, prevention or management. There is tremendous amount of inter institutional variability in managing these patients. The other drawback being unnecessary use of drugs for this condition, which may have no evidence, and are mostly used empirically.

With the implementation of new radiation schedules such as altered fractionation, 3D CRT and IMRT, the late-radiation effects can probably be reduced; but the remaining sequelae are still bothersome to the patients. Adequate prevention and treatment are matters of increasing importance because of the increasing numbers of younger, often dentate, patients. A crucial factor in the success of all preventive and treatment regimens is the compliance of the patient. Since compliance is rather poor in many head and neck cancer patients, much effort has to be made in making the patients aware of the dangers of not complying with the preventive protocols.


 > Acknowledgement Top


We wish to thank all the authors and their articles from which the references being considered in our article. The students, staff members, residents and senior faculty members of the Department of Radiation Oncology, Tata Memorial Hospital were of paramount help in writing this review article. Last but never the least, our patients and their sufferings was the key motivating factor behind writing this practical approach.

 
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