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Authors:Dr. Milanjeet Kaur.

Radiation therapy is a significant treatment modality in the management of Head and Neck Cancers. Imaging is an important aspect in planning radiotherapy. Along with that high dose of radiation is also associated with side effects. Oral health management plays an important role in preventing these complications. Therefore, it is mandatory to initiate prompt oral health care that can prevent the associated orodental complications. This article is a review on role of an Oral physician & Radiologist in oral complications associated with radiation therapy,their prevention and management. It also mentions about the role of oral Radiologist in Radiotherapy

Introduction
The term ‘Radiotherapy’ refers to treatment using ionizing radiation, which interacts with fluids to produce free ions. The use of radiotherapy in head and neck cancer was established between 1920 and 1940 by the pioneering work of Coutard in Paris and Paterson in Manchester UK, among others.1 In the late 1980s, three-dimensional radio-therapy became available to the research com¬munity and has been widely used clinically since the 1990s.2 The most important mechanism of the observed effects of radiotherapy on tumors and normal tissues is mitotic death, whereby an irradiated cell survives functionally intact until such time as it subsequently attempts to divide, when the DNA damage renders it unable to go through normal mitosis and death ensues. The chance of a given dose of radiation sterilizing all tumour cells depends on four factors: Radiosensitivity, Oxygenation, Growth rate and Tumor size.1

Intention Of Radiation Therapy
For cure.
For palliation.
Combined with surgery.
Various mechanisms by which radiotherapy is delivered include
External Beam Or Teletherapy usually employs two or more beams of supervoltage radiation converging on the tumour volume.3
Various Modalities to improve teletherapy include
Fractionation
A course of external beam radiotherapy is fractionated, that is the total dose is divided into a number of smaller doses delivered over a period of several weeks. The larger the number of fractions, the greater the total dose required to produce the same effect. The aim of fractionation is to increase the differential effect of the radiation on the tumor compared with the normal tissues.
Altered Fractionation
There is some evidence that the effect of radiotherapy on late reacting normal tissues can be reduced relative to tumor effect by the use of small fraction sizes. This increase in number and reduction in size of fractions is known as hyperfractionation. But Hyperfractionation have shown to increase acute radiation mucositis.1,2

Conformal Radiotherapy is accurate shaping of the beam to conform to the precise volume of tumor, with a small margin, achieved using multiple ‘leaves’ known as multi-leaf collimators.

Conventional3 Dimensional Conformal Radiotherapy (3DCRT) delivery was implemented by conforming the incident-beam portal outlines to the target volume projections for a user-specified set of beam directions or during rotational beam delivery. The radiation beams had uniform intensity, or where appropriate, the intensity was varied by beam modifiers such as compensating filters or wedges. This treatment method was referred to as conventional 3DCRT.4,5

Intensity Modulated Radiation Therapy which uses radiation beams of varying intensity and allows for a greater sparing of normal structures. It optimizes the delivery of irradiation to irregularly-shaped volumes and has the ability to produce concavities in radiation treatment volumes. IMRT can be delivered using linear accelerators with static multi-leaf collimators (MLC, step and shoot IMRT) or dynamic leaf MLCs, tomotherapy machines or volumetric arc modulated therapy(VMAT).IMRT also spares pharyngeal constrictor muscles, which are important for a normal swallow. The sharp dose gradients that exist with IMRT plans could result in a geographical miss of the tumors. Optimal IMRT delivery therefore relies on accurate image guidance.4,5
Image Guided Radiation Therapy (IGRT) in which integrated CT guides changes in radiation throughout the course of treatment is a useful tool that can detect and correct random and systematic errors that occur during treatment delivery. Image guidance can be used for improved tumor delineation and/or to correct for intra and/or inter-fraction motion during radiotherapy.

Image Guidance For Delineation
Computed tomography (CT) scans are the standard imaging modality used in radiation treatment planning as they provide a three-dimensional view of the tumours and normal anatomy, along with the electron density data which enables dose calculations. CT-MRI fusion should be considered for radiotherapy planning wherever possible, especially in central nervous system and skull base tumours. Positron emission tomography enables biological imaging of tumours.5
IGRT For Planning Tumor Volume Margin Reduction
Reduction in the size of the tumour and change in the local anatomy lead to an inter-fraction change. Regular in-room images can be obtained using 'CT on rails', kilovoltage cone beam CT (kVCBCT), megavoltage cone beam CT (MVCBCT) or using a tomotherapy machine. The images obtained from these in-room modalities are fused with the CT used for planning, using bony and soft tissue contrast and changes in the treatment plan or patient position, can be made to account for the inter-fraction motion. In addition, tumors can be tracked using infra-red markers placed on the patient's skin and aligning these to bony landmarks or fiducial markers in order to make changes to the treatment plan based on the changes in the internal anatomy. The four dimensional CT can also be used.5
Image Guidance For Treatment Verification
In addition to the conventional two-dimensional verification, modern devices also enable three-dimensional volumetric verification (using kVCBCT) and in vivo dosimetry. The CT- detector array systems on tomotherapy machines can also be used for verification and in vivo dosimetry.
Stereotactic Radiotherapy also enables the delivery of exquisitely conformed radiation in large fraction sizes, whic h also enables improved tumor control while limiting the normal tissue toxicity. Due to the exquisite dose sculpting, robust image-guided technologies (gating or chasing) have to be coupled with the radiation delivery systems. Stereotactic radiotherapy can be delivered using linear accelerator systems or Cyberknife® (Accuray Inc, CA, USA). This technique is currently widely used for treating intra-cranial oligometastases.4,5
Most recent modality include CYBERKNIFE system which is a method of delivering radiotherapy, with the intention of targeting treatment. The system comprises of a linear particle accelerator and a robotic arm. This method is referred to as 6D because corrections are made for the 3 translational motions (X, Y and Z axis) and three rotational motions but this is not widely available. Cyberknife can greatly raise the fractional dose of stereotactic radiosurgery, thus improving its clinical efficacy. Cyberknife (CK) had obvious technical advantage in fixation, real-time authentication and dynamic tracing. So its treatment precision was higher than that of other radiotherapy methods. The CK is a new radiotherapy method that can give higher therapeutic doses directly to the tumor. From Aug. 2001, it was approved by FDA and had treated over 25, 000 cases.6
Brachytherapy – Brachytherapy (literally: short-distance treatment) is a general term applied to radiotherapy delivered from a source of radiation placed very close to the tumor. There are two methods: interstitial implants and surface/intracavitary moulds. In interstitial treatment, solid sources of radiation are implanted directly into the tumor, producing a high intensity of radiation in the immediate vicinity of the sources. The treatment times are short, usually 3–8 days, so repopulation is not a problem. The most popular radioactive material for interstitial and intracavitary irradiation of head and neck cancer is now iridium-192. Interstitial or intracavitary implants are used mainly for the anterior two thirds of the oral cavity like tongue, floor of the mouth and buccal mucosa where the introducers can be inserted intraorally.1,3

Radiosensitisors & Radioprotectors
Solid tumors can outgrow their blood supply, causing a low-oxygen state known as hypoxia. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Use of Radiosensitisors like cisplatin7,5-flourouracil, Rituximab8, misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine etc. sensitizes tumor cells to radiation. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Hyperbaric oxygen improves results of teletherapy, but is too time-consuming and hazardous for routine use.1 Nitric oxide, fluoropyrimidines, Pyrimidines, nicotinamide is showing clinical promise. Drugs under evaluation include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide, Drugs involved in DNA repair pathways like potent poly(ADP ribose)polymerase inhibitor, AG14,361. Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6,474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib).9

Radioprotectors are agents which make normal tissue radioresistant.
Radioprotecting agents can be classified into three groups:
1) radioprotectors,
2) adaptogens and
3) absorbents
Radioprotectors are generally sulfhydryl compounds and other antioxidants. These include several myelo-, entero- and cerebro- protectors.
Adaptogens act as stimulators of radioresistance. These are natural protectors, which offer chemical protection under low levels of ionizing radiation. Absorbants protect organisms from internal radiation and chemicals. These include drugs which prevent the incorporation of radioiodine by the thyroid gland and the absorption of radionuclides 137Cs, 90Sr, 239Pu, etc.
Considering the results of investigating great number of radioprotective compounds, it can be stated that those containing sulphur have the most protective effect. That are aminothiols like Amifostine, aminodisulphides, tiourei derivatives, thiosulphur and thiophosphoric acid, dithiocarbamates, thiazole, some biogen amines and their derivatives.10
Palliative radiotherapy
The aim is to relieve the symptoms of the disease for patients with incurable disease, without attempting to cure the patient. A moderate dose of radiation is administered over a short time, for example, 20 Gy over 5 days.1
High doses of radiation to oral cavity and salivary glands can have dramatic effects on patient’s oral health. Therefore, the oral health care of irradiated patient demands particular attention during and after the radiation therapy and initiate dental care programme that can greatly aid in reducing orodental complications.

Dental Care Before Radiotherapy
Dental evaluation- Dental professionals should document the level of oral hygiene, caries involvement and intended dental treatment plan Extraction of non-salvageable teeth – It is considered hazardous to perform extractions once the radiation therapy begins. The problems encountered in such extractions are oedema, endarteritis, hyalinization of small vessels and gradual diminution of the blood supply. Extractions should be atraumatic and should be limited to 2-3 teeth at a time. Ideally, extraction sites should be allowed at least 10-14 days for proper healing prior to the initiation of radiotherapy. Restoration of teeth with dental caries and fractured teeth. It has been suggested to use a light activated glass ionomer with fluoride – releasing capabilities as the material of choice. If not possible caries excavation and temporary restoration should be done. Maintenance of oral hygiene and preventive care-Initial oral hygiene appointment consists of patient education, oral prophylaxis, fluoride treatment and recall visit. Brushing with a soft tooth brush 2-4 times daily, use of oral rinses like hydrogen peroxide and saline or hydrogen peroxide and water, sodium bicarbonate may be used. Alcohol containing mouth washes may irritate or dry the mucosa and are not recommended. Daily flossing with unwaxed dental floss is advised. Oral prophylaxis is to be performed and instructions given on the use of neutral 1% sodium fluoride gel. Ill fitting dentures are avoided due to tissue fragility. Any sharp cusps of teeth or prosthesis should be smoothened. Use of tobacco and alcohol is strongly discouraged.3,11
During The Therapy Various tissues are affected during head & neck radiotherapy. They include

Bone
Tissue becomes hypocellular, hypovascular and hypoxic. This leads to minimal ability of bone to withstand trauma or to repair. Ultimate end result of these changes is osteoradionecrosis. Osteoradionecrosis can be minimized by oral evaluation and care preoperatively. The use of Hyper baric oxygen is well established and has been employed as an adjuvant in extractions after radiotherapy.12 Best results have been obtained using 2 atmospheres pressure for 2 hours per day for 60 days, that is a total of 120 hours in the chamber. A simpler method, which has been claimed to promote cell growth, is ultrasound. Harris recommends therapeutic ultrasound at a frequency of 3mHz pulsed one in four at an intensity of 1W/cm2 applied to the mandible for 10 minutes daily for 50 days. Spontaneous healing occurs in about 50 per cent of cases using the conservative measures. In cases with persistent symptoms surgical treatment should be considered.1.
Salivary Glands
Effect of radiation on the salivary gland depends on the volume of the gland, dose and functional state of the gland prior to radiotherapy. The serous acinar cells are more sensitive than mucosal cells. A mean dose of 60 Gy is the threshold for producing irreversible damage, in some cases doses as little as 26 Gy have been implicated.11,13
Systemic sialogogues like Pilocarpine (5-10mg tid), Bethanecol (75-200mg/day in divided doses) and Anetholetrithione offer the advantage of stimulating saliva if any residual function is present. Anetholetrithione may stimulate formation of receptor sites and thus may have synergistic effects with Pilocarpine.* A variety of saliva substitutes , sugarless gums or candies may be helpful to stimulate salivary secretion. To reduce increased caries risk chlorhexidine gluconate, an antimicrobial rinse, which has both antifungal and antibacterial properties in addition to antiplaque effects can be used.#
The most effective intervention for xerostomia is its prevention by treatment planning and beam arrangement designed to spare as much of the salivary glands as possible. It is now apparent that spared glands not only retain some measure of salivary output, but also that the output increases over time for at least 2 years af¬ter Radiotherapy.14,15 Use of Amifostine (Ethyol, WR 272a) as the radioprotective agent (which protects normal cells from radiation) is another way to protect the salivary gland.
The ability of its thiol-containing components to protect against normal tissue damage from radiation has been recognized for over 40 years. When Amifostine is administrated intravenously, it rapidly clears from plasma in less than ten minutes. The drug is taken up in the salivary glands and converted into active protective thiol (WR a065) that acts as an oxygen-free radical scavenger. The Amifostine has been approved by the United States’ Food and Drug.9
A Canadian investigators moved one submandibular gland to the submental space, away from the Radiotherapy fields, and reported impressive reduction in xerosto¬mia. However, this technique has yet to gain broad acceptance.16


Teeth
The potential effects of radiation on developing dentition include partial or complete anodontia, tooth dwarfism, incomplete root formation and localized enamel defects. Exposure prior to calcification may destroy the tooth bud, whereas exposure at a late stage of development may arrest growth and result in enamel and dentin irregularities. Dental pulp undergoes fibrosis and atrophy. Radiation caries which involve smooth surfaces cause tooth destruction in a matter of weeks. Caries develop either due to direct influence of radiation or secondary to xerostomia and reduced pH. A shift to cariogenic flora has been documented.3,11,13

Mucous Membranes
Oral mucositis is the most symptomatic problem of patients in cancer Therapy.11 Mucositis is characterized by inflammation and ulceration of the mucosa. With fractionated doses of 2 Gy, mucosal erythema appears within one week. Four weeks after the completion of the treatment, 90-95 % of patients show complete resolution of mucositis.17,18,19
The “updated clinical practice guidelines for the management of mucositis recently in 2007” recommends patient controlled analgesia with morphine as the treatment of choice for pain. Topical morphine or fentanyl can be effective. For prevention sucralfate and antimicrobial lozenges should not be used.20 Midline radiation blocks and three-dimensional radiation therapy to be used.21
Flossing can be discontinued if it causes pain and if the platelet count is less than 40,000/ mm3 (Brown and Wingard, 2004).16 Pain can be reduced with coating agents, topical anaesthetics and analgesics.4,14,22 Acc. to M del Mar Sabater Recolons et al a good gingival status as well as good oral hygiene during radiotherapy is associated with a lower incidence and severity of mucositis.23


Recent Advances For Management Of Oral Mucositis
N-acetyl cysteine - Topical application of this antioxidant was found to reduce the severity of oral mucositis in animal models.14 Studies have indicated that Granulocyte col¬ony-stimulating factor (G-CSF) has generally shown less activity than Granulocyte Macrophage - col¬ony-stimulating factor (GM-CSF) in decreasing the severity of oral mucositis.14,24 Palifermin (Kepivance), or recom¬binant human keratinocyte growth factor-a, is another compound shown to reduce oral muco¬sitis. Mecha¬nisms of action includes down regulation of pro¬inflammatory cytokines; inhibition of epithelial cell DNA damage and apoptosis; and stimulation of epithelial cell growth, differentiation, and mi¬gration. Glutamine supplementation can also re¬verse effect and may help to protect mucosal tissues from damage by radiation therapy or che¬motherapy and thus accelerate recovery.14,25 Gelclair® Bioadherent Oral Gel is a concentrated oral gel that contains the barrier-forming ingredients polyvinylpyrrolidone and sodium hyaluronate that forms a barrier over oral mucosa and provides rapid and durable pain relief in five to seven hours.16,26 Iseganan hydrochloride -Antimicrobial peptide that is associated with a decreased incidence with stomatotoxic chemotherapy Low-level laser therapy -Promotes healing and reduces pain and inflammation.14 Amifostine is under trials for mucositis.5 Interleukin-11 in patients after haematopoietic progenitor cell transplantation led to a decrease in incidence, severity and duration of mucositis. However, there were significant side-effects of treatment, including infection and sepsis.25 Transforming growth factor β3 has shown to reduce mucositis but has not been confirmed in human trials to date. Epithelial growth factor (EGF) have also shown to decrease mucositis in several studies. Dinoprostone is a Prostaglandin E2 (PGE2), which is a naturally occurring cytoprotective agent, has been reported to have shown promising results as preventive treatment to radiation therapy-induced mucositis. Oral Capsaicin in a candy form may produce temporary pain relief. Topical Coating Agents like Sucralfate, magnesium hydroxide, and hydroxypropyl cellulose are some of the film-forming or coating agents which may be beneficial in treating established mucositis.27,5

Tongue And Taste Buds
A reduction in muscle strength of the tongue and difficult oropharyngeal swallow function has been shown with primary chemoradiotherapy.28
Taste deficits as a consequence of head and neck radiation were first described as "taste hallucinations or "blindness of the mouth" (MacCarthy-Leventhal, 1959). Today, this is more correctly referred to as post-irradiation gustatory dysfunction. Post-irradiation gustatory dysfunction has been reported to occur 2 to 3 days after the onset of radiation therapy, with doses as small as 200-400 cGy. Taste bud degeneration typically occurs 6 to 7 days after irradiation.29 Dysgeusia occurs rapidly and exponentially up to 30 Gy and then slows as acuity for all types of taste reaches zero. Taste acuity is partially restored in 20 to 60 days after the completion of radiation and is restored almost completely four months post radiation in most of the patients.4
Bitterness is the basic taste most influenced by cancer and its treatment. Thresholds for other basic taste perceptions (sweet, sour, and salty) are not consistent in how much they are influenced by cancer.
Currently published recommendations for its management include:
• Encouraging patients to maintain a normal, balanced diet to ensure adequate nutrition
• Avoiding the use of metallic silverware to reduce the risk of metallic taste and increasing the consumption of high-protein
• Adding seasonings and spices to enhance flavors and Serving foods at cold temperature

  • Zinc sulfate 22mg BD might be useful
  • These suggestions, though useful, do not resolve the recurring incidence of taste and odor abnormalities.30

    Other Complications
    CANDIDIASIS It is the most common oropharyngeal infection in patients who receive radiation therapy.10,11,12 Acc to Marta C Dahiya et al Non-albicans Candida is also emerging as a relatively common cause of Candidosis in head-and-neck cancer patients.13 Antifungals should be used with denture hygiene implemented when relevant.5 Trismus results because of the fibrosis. A regimen of mouth opening exercises 3-4 times daily can be effective.12 Nutritional deficiency Consultation with a dietician is recommended and hospitalization may be required.3,11

    After Radiation
    During this phase any dental treatment that was deferred during the therapy can be undertaken. After therapy oral hygiene regime and oral exercises are to be continued. It is mandatory to follow up the patient to detect any new or recurrent cancer and to manage chronic oral complications such as xerostomia, mucositis, candidiasis and risk of osteoradionecrosis.

    Conclusion
    Radiotherapy in the region of head and neck is often associated with oral complications. A team approach including the surgeon, radiotherapist and oral physician in managing these patients can prevent or minimize the oral complications and improve quality of the life of patients with cancer.

    References:-
    1. Dunitz M. Principles & practice of head & neck oncology. chapter 4; pg no. 119-140
    2. Eisbruch A. Reducing Radiation-induced Xerostomia With Highly Conformal Radiotherapy Techniques. J Support Oncol 2005;3:201–202
    3. Textbook of Oral Medicine; Burket’s; Eleventh edition; Chapter 7; pg -163-189
    4. Technical basis of Radiation therapy practical clinical applications; S.H. Levitt, J. A. Purdy; 4th edition; 179-234
    5. Recent advances in radiotherapy; SA Bhide and CM Nutting; BMC Medicine 2010, 8:25
    6. Brain metastasis treated with Cyberknife; WANG Zhi-zhen, YUAN Zhi-yong, ZHANG Wen-cheng; Chinese Medical Journal 2009;122(16):1847-1850
    7. Radiosensitizers in cervical cancer. Cisplatin and beyond; Myrna candelaria, alicia garcia-arias, lucely cetina; radiation oncology 2006, 1:15
    8. In Vitro Evaluation of Radioprotective and Radiosensitizing Effects of Rituximab; Nirav S. Kapadia, James M. Engles, and Richard L. Wahl; the journal of nuclear medicine • vol. 49 • no. 4 • april 2008
    9. Chemical radiosensitizers for use in radiotherapy; Clin Oncol (R Coll Radiol), 19(6):397-417.
    10. Radioprotectors in radiotherapy; Cherupally k. K. Nair, dillip k. Parida and taisei nomura; j. Radiat. Res., 42, 21–37 (2001).

More references are available on request

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