Vous êtes sur la page 1sur 21

Oral mucositis in head and neck cancer

Significant advancements have been made in the management of patients undergoing cancer chemotherapy (CT) and radiotherapy (RT).Mounting evidence indicates that more aggressive regimens improve loco-regional tumour control and survival in patients of head and neck cancer (HNC). The better treatment outcome, however, have come at the expense of increased patient morbidity in the form of many debilitating side effects such as nausea, vomiting, diarrhoea, and mucositis. Such critical issues often delay or restrict the therapy and impede recovery. Mucositis is the inflammation of the mucous membrane lining of the digestive tract from the mouth on down to the anus and when such inflammation involves the mucous membrane of oral and oropharyngeal region, termed as oral mucositis (OM). Oral mucositis is a major problem for cancer patients receiving head and neck radiotherapy, stem cell transplantation and myelosuppressive chemotherapy for solid tumours. So, OM if not detected or treated adequately, can lead to pain, discomfort and inability to tolerate food or fluids with increased propensity for opportunistic infections in the mouth and worsens the patients quality of life. Poorly managed OM is one of the leading causes for unplanned treatment interruptions and therefore increasing overall treatment time. Prolongation of overall treatment time adversely affects the tumour control probability. It also increases the overall cost of the treatment. The main aim of this module is to provide you with the knowledge and understanding of the risk factors, pathogenesis and development of oral mucositis. It will guide the reader for the early diagnosis and accurate management of oral mucositis in head and cancer patients undergoing treatment. This module should take approximately 4-5 hours to complete, comprising the learning activities and time for reading, thinking and reflection.

Learning objectives
The activities and content of this module are built around the following learning objectives: Understanding the magnitude of the problem; Understanding the risk factors; Understanding the pathogenesis and its development; Developing skills for early and exact diagnosis; Learning the accurate management.

The incidence of oral mucositis

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral cavity usually caused by cancer therapy.


Oral mucositis (OM) is a common complication of treatment in head and neck cancer patients. The nature and degree of mucositis varies according to the treatment regimen applied, whether radiotherapy or chemotherapy as an independent modality or in combination. Trotti (2003) studied more than 6,000 patients with squamous cell carcinoma of the head and neck (SCCHN) who received radiotherapy (RT) with or without chemotherapy (CT). The overall incidence of mucositis in this patient population was 80 to 100%, with 25-45 % of cases being grade 3/4, (Table 1) which limited or prevented alimentation and significantly decreases a patient's quality of life. Table 1: Incidence of oral mucositis among cancer patients (Trotti et al, 2003)
Incidence (%) Radiotherapy for head and neck cancer Stem-cell transplantation Solid tumors with myelosuppression 85100 75100 540 Grade 3/4 (%) 2545 2560 515

Significant proportions (approximately 40%) of patients who receive standard-dose CT also develop mucositis (Sonis, 1993). Degree of OM may vary according to the drugs being used like 5-fluorouracil (5-FU) and cisplatin causes aggressive OM compared to gemcitabine. Higher rates of mucositis, 60%, are seen in the stem cell transplantation (SCT) setting. This is as a result of high dose CT or total-body irradiation (TBI) (Woo, 1993).

Risk factors for oral mucositis

A systematic review of the research literature identified a vast number of patient and treatment related risk factors (Table 2) (Dodd, 1999). Table 2: Risk factors for oral mucositis
Patient-related Gender Age older than 65 years or younger than 20 years Inadequate oral health and hygiene practices Periodontal diseases Microbial flora Chronic low-grade mouth infections Salivary gland secretory dysfunction Herpes simplex virus infection Inborn inability to metabolize chemotherapeutic agents effectively Inadequate nutritional status Treatment-related Radiation therapy: dose, schedule Chemotherapy: agent; dose, schedule Myelosuppression Neutropenia Immunosuppression Reduced secretory immunoglobulin A Inadequate oral care during treatment Infections of bacterial, viral, fungal origin Use of antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives Impairment of renal and/or hepatic function


Exposure to oral stressors including alcohol and smoking Ill-fitting dental prostheses

Protein or calorie malnutrition, and dehydration Xerostomia

The development of OM is predominantly influenced by the type of malignancy and the cytotoxic therapy administered, but patient factors also play a role. Several patient related factors like poor oral health at baseline, existing mucosal damage, impaired immune status, and decreased salivary production are among the risk factors. Younger patients are more susceptible for OM due to more rapid epithelial mitotic rate or the presence of more epidermal growth factor receptors in the epithelium at the early age. On the other hand, the physiologic decline in renal function associated with aging may result in higher incidence of OM in older patients. Any decrease in neutrophil count before therapy may result in an impaired ability to mount an adequate inflammatory response on the oral mucosa thus causing more OM. Factors that are treatment-related include specific chemotherapeutic drug, dose, schedule, and use of radiation therapy (Borowski, 1994). All of these will affect the subsequent development (severity and duration) of mucositis. Certain chemotherapeutic agents such as methotrexate and etoposide may also be secreted in the saliva, thus the patients being treated by these agents have higher chances of developing OM.

Pathogenesis of oral mucositis

Molecular and cell biology and translational research suggest OM a complex, multistep process. Healthy oropharyngeal mucosa has a rapid cell turn over with a renewal period of 7 14 days and it serves as a barrier to infections. It has been analyzed that shortly after CT or RT administration acute inflammatory/vascular changes occur which leads to the development of OM. Sonis (2004) has described a five phase model to characterize the major steps in development and resolution of OM. (Figure 1, Table 3). Figure 1. The 5 phases of mucositis
(Adapted from Sonis (2004) Nature Reviews Cancer. 4:277-284)


Table 3: The phases of the biologic process of mucositis The phases of oral mucositis
Initiation Cell exposure to chemo- and radiotherapy causes DNA damage and generates reactive oxygen species (ROS), which are able to injure cells, tissues and blood vessels ROS cause further DNA damage and stimulate expression of transcription factors that lead to tissue injury and apoptosis Release of pro-inflammatory cytokines result in further tissue damage, which amplifies the signalling cascade Painful ulcers form that provide an entry point for bacteria, viruses and fungi. Bacterial cell wall components can further induce inflammation A signal from submucosal tissue allows renewed cellular proliferation and differentiation restoring the lining of the oral cavity

Signalling Amplification Ulceration Healing


Initiation: reactive oxygen species (ROS) generated by exposure to chemotherapy or radiation therapy result in DNA strand breaks and damage to cells, tissues, and blood vessels, which ultimately cause apoptosis. Message generation: Such damage triggers activation of transcription factors such as nuclear factor kappa B (NF-B), which in turn causes increased production of proinflammatory cytokines like interleukin (IL)-1 and IL-6. These increased levels of cytokines thus trigger the initiation of various pathways that damage epithelial cells and surrounding fibroblasts causing tissue injury and apoptosis. Signaling and amplification: Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-) activates ceramide and caspase pathways and these signals further increase production of TNF- , IL1 and IL-6 and thus causing amplification effect. Ulceration and inflammation: Inflammatory infiltrate composed of polymorphoneuclear and round inflammatory cells are found in the mucosa. As there is a breach in the mucosal barrier, penetration of the epithelium into the submucosa can occur and mucosa gets prone for bacterial infection which further lead to increase in the production of TNF- , IL1 and IL-6. This further enhances the mucosal injury thus causing more severe mucositis in form of ulceration allowing colonization by oral bacteria and increasing the risk of sepsis. It is likely that each of these stages of mucositis pathogenesis occurs in a continuous, overlapping manner. Healing: Healing of oral lesions starts with a signal from the extracellular matrix in the nonmyelosuppressed patient within 2 to 3 weeks following cancer treatment. Mechanisms of healing include renewal of epithelial proliferation and differentiation in parallel with white blood cell recovery, and re-establishment of normal local microbial flora.





This pathogenesis model has suggested a variety of potential therapeutic targets which can act on various steps. Hence it has led to the development of agents that can prevent or ameliorate the process of OM and associated symptoms e.g. some agents down regulate NF-B activation which is a trigger for activation of various pathways leading to the oral mucosal damage.


Activity 1 (allow approximately 60 minutes)

Task 1: Consider the different treatment and patient related risk factors causing oral mucositis in cancer patients. How does the severity of oral mucositis vary with age? Allow 30 minutes Task 2: Follow the five stage of pathogenesis given by Sonis and try to locate the possible sites where intervention can help in the management of oral mucositis. Allow 30 minutes

Resources required to complete this activity

Useful websites Cancer Consultants http://www.cancerconsultants.com/mouth-sores-mucositis/ National Institute of Dental and Craniofacial Research (Oral Complications of Cancer Treatment: What the Oncology Team Can Do) http://www.nidcr.nih.gov/oralhealth/topics/cancertreatment/oralcomplicationscanceroncology.ht m From CancerCare, a downloadable patient guide to mucositis: http://cancercare.org/pdf/booklets/ccc_mouth_pain.pdf Background reading Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP & Hayat M. (1994) Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomized controlled trial comparing two protocols of dental care. European Journal of Cancer. Part B: Oral Oncology. 30B:93-97. Dodd M J, Miaskowski C, Shiba G H, Dibble S L, Greenspan D, MacPhail L, Paul S M & Larson P. (1999) Dodd MJ, Miaskowski C, Shiba GH, et al. Risk factors for CT-induced oral: dental appliances, oral hygiene, previous oral lesion, and a history of smoking. Cancer Investigation. 17:278. Sonis ST. (1993) Oral complications of cancer therapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia: JB Lippincott Co. pp2385. Sonis ST. (2004) The pathobiology of mucositis. Nature Reviews Cancer. 4:277284. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L & Zilberberg MD. (2003) Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiotherapy & Oncology. 66:253262. Woo S-B, Sonis ST, Monopoli MM, & Sonis AL. (1993) A longitudinal study of oral ulcerative in bone marrow transplant recipients. Cancer. 72:1612.


How to diagnose oral mucositis

Diagnosis is based on the clinical appearance, location, timing of oral lesions and use of certain types of therapy known to be associated with OM. It is characterized by erythema, inflammation, pain and ulceration. Symptoms can include: Ulcers or sores on the mouth, gums, or tongue A burning sensation in the mouth Loss of taste Sensitivity to hot or cold foods Dry mouth All assessors should have thorough familiarity with the normal anatomy of oral cavity, clinical signs and symptoms of oral complications. Consistent and frequent oral cavity assessment under intense white light is needed to visualize all soft and hard tissues and dentition before, during, and after the treatment time course. OM, if not diagnosed and managed, may interfere with daily activities such as talking and eating, increases the risk for systemic infections and possibly hospitalization. Systemic effects of OM results in the symptom complex, characterized by fatigue, taste alterations, anaemia, anorexia, cachexia, neurocognitive alterations, and depression which may often be termed as sickness syndrome (Hickok, 2005). Thus a systematic and routine assessment of the oral cavity should be performed in all patients vulnerable to be at risk for developing oral mucositis. This permits early identification of the lesion and makes timely intervention possible. A number of scoring systems have been defined to assess the severity of OM (Table 4), but no one scale is uniformly employed. The major hurdle has been a lack of a definitive technique to appropriately measure OM. Some established guidelines are those proposed by the World Health Organization (WHO) in 1979 and the National Cancer Institutes Common Toxicity Criteria (NCI CTC version 3 and 4). Both objective mucosal changes like redness, ulceration with functional outcomes like ability to eat has been integrated in WHO scale. In contrast, NCI CTC has been developed to classify OM in patients receiving radiation therapy, chemotherapy, and conditioning regimens for bone marrow transplantation. Based upon clinical examination four distinct stages/grades can be identified which have been given 0 to 4 mucositis scores. Oral intake is maintained in grade 1 and 2 however compromised thereafter in higher grades. Sonis et al (1999) have devised an Oral Mucositis Assessment Scale (OMAS). This scale separates objective and subjective findings. Degrees of ulceration and redness measured in specific sites in the mouth were primary indicators of OM while oral pain, difficulty in swallowing, and the ability to eat were taken as secondary indicators. A single score is not produced from this scale, rather a score for ulceration and redness based on different locations in the mouth are used. This scale is more quantitative for clinical research but may be difficult to use in routine clinical care. Other scoring systems by RTOG have been proposed (Cox, 1995), but the lack of standardization has hampered their acceptance.


Because of large variation among these scales, making comparisons between the scales is difficult. Table 4: Oral mucositis assessment scales Grade 0
WHO None No change over baseline

Grade 1
Soreness with erythema Injection/ may experience mild pain not requiring analgesic

Grade 2
Erythema, ulcers, can eat solids Patchy mucositis which may produce an inflammatory serosanguinitis discharge/ may experience moderate pain requiring analgesia Severe 1 3 sq cm patchy ulcerations or pseudomembranes

Grade 3
Ulcers, liquid diet only Confluent fibrinous mucositis/ may include severe pain requiring narcotic

Grade 4
Alimentation not possible Ulceration, haemorrhage or necrosis


OMAS Ulceration / erythema NCI CTCAE v3.0 Clinical Criteria

Normal Normal None

Not severe < 1 sq cm erythema of the mucosa

NA >3 sq cm confluent ulcerations or pseudomembrane; bleeding with minor trauma

NA NA tissue necrosis: significant spontaneous bleeding: lifethreatening consequences

Functional Criteria


Minimal symptoms, normal diet

Symptomatic but can eat and swallow modified diet;

Symptomatic and unable to adequately aliment or hydrate orally

Symptoms associated with life-threatening consequences



Asymptomatic or mild symptoms; intervention not indicated

Moderate pain; not interfering with oral intake; modified diet indicated

Severe pain; interfering with oral intake

Life-threatening consequences; urgent intervention indicated.

WHO: World Health Organization, RTOG: Radiation therapy oncology group, OMAS: Oral mucositis assessment scale, NCI-CTCAE: National Cancer Institute Common Toxicity Criteria for Adverse Events

Differential diagnosis of OM may include Oral candidiasis (thrush) Herpes simplex virus (HSV) Graft-versus-host disease (GVHD) in transplant patients Candidal overgrowth (candidiasis), which occurs in response to RT or CT, usually responds well to systemic antifungal medication. HSV is frequently seen in immunocompromised cancer patients receiving chemotherapy, with lesions appearing on the lips (cold sores) or intraoral mucosa.

Initiation of antiviral therapy may ameliorate HSV-associated OM and reduce symptoms. OM can also occur in patients receiving myeloablative conditioning regimens for allogeneic hematopoietic SCT and in those with GVHD, affecting the oral mucosa.

Economic impact
Mucositis and its treatment can have a significant economic impact. Patients incur increased costs for treatment, including in some cases hospitalization or emergency room visits for complications or life-threatening situations.

Activity 2 (allow approximately 90 minutes)

Task 1: Select a patient receiving radiotherapy. Observe the changes in oral mucosa develop during the course of radiotherapy. What symptoms does the patient describe? How do these oral problems affect the treatment plan and quality of life of the patient? Allow 45 minutes Task 2: Compare the severity of oral mucositis in different schedules of radiotherapy. What are the differences in grades of oral mucositis in patients receiving concurrent chemo-radiotherapy? Allow 45 minutes

Resources required to complete this activity

Useful websites For a review article published in the Journal of Supportive Oncology, New Strategies for Management of Oral Mucositis in Cancer Patients: www.supportiveoncology.net/journal/0402s1.html For information from the National Cancer Institute: www.cancer.gov/CancerTopics/pdq/supportivecare/oralcomplications/Health Professional/page5 Cancer Therapy Evaluation Program (CTEP) website at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm Updated January 12, 2010. Background reading Cox JD, Stetz J, Pajak TF. (1995) Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). International Journal of Radiation Oncology*Biology*Physics. 31:1341-1346. Hickok JT, Morrow GR, Roscoe JA, Mustian K, Okunieff P. (2005) Occurrence, severity, and longitudinal course of twelve common symptoms in 1129 consecutive patients during radiotherapy for cancer. Journal of Pain Symptom Management. 30: 433442.

National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S. Department of health and human services National Institutes of Health (NIH) Publication No. 09-5410 http://evs.nci.nih.gov/ftp1/CTCAE/About.html Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett WH Jr, Mulagha MT, Peterson DE, Rose AH, Schubert MM, Spijkervet FKL, Wittes JP. (1999) Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer. 85(10): 2103-13. Trotti A, Dimitrios CA, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Norman CC & Rubin P. (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in Radiation Oncology. 13( 3): 176-181 World Health Organization. (1979) WHO Handbook For Reporting Results Of Cancer Treatment. Geneva, Switzerland: World Health Organization. 15-22. Sonis 2003

Management guidelines
Several management protocols have been developed for prevention and treatment of OM but the widely accepted one is given by Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO). These guidelines were first published after the work of Rubenstein in 2004. These were later updated by the Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) (McGuire, 2006). Discussions by the panel resulted in the development of a set of recommendations for the prevention and treatment of OM and guidelines that are relevant to the care of patients with head and neck cancer. In 2007, Keefe et al and the MASCC/ISOO Mucositis Study Group updated clinical practice guidelines for the prevention and treatment of mucositis. These guidelines are most widely employed in our clinical practice [Table 5]. These guidelines suggest a multi-professional intervention for early diagnosis and management of OM. Foundation of care includes oral care, routine assessment of oral cavity, pain management using validated instruments, and regular dental assessment and dental care prior to the start of cancer therapy. It clearly suggests avoidance of any irritants to the oral mucosa (e.g., spicy foods or alcohol). This recommendation also stressed the need for education of staff as well as patients and their families. They should be properly told about the proper oral care and the importance of outcome.


Table 5: Management guidelines for OM Summary of Evidence-based Clinical Practice Guidelines for Care of Patients with Oral and Gastrointestinal Mucositis (2005 Update) Oral Mucositis Foundations of Care
Multidisciplinary development and evaluation of oral care protocols that include frequent use of non-medicated oral rinses (e.g. saline mouth rinses 46 times/day) is recommended. Patient and staff education in the use of such protocols to reduce the severity of oral mucositis from chemotherapy and/or radiation therapy. As part of the protocols, the use of a soft toothbrush that is replaced on a regular basis. Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health. The inclusion of dental professionals is vital throughout the treatment and follow-up phases. Patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Regular oral pain assessment using validated instruments for self-reporting is essential. Use of midline radiation blocks and three-dimensional radiation treatment to reduce mucosal injury. Benzydamine oral rinse for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy. Sucralfate Antimicrobial lozenges Chlorhexidine Oral cryotherapy (30 min) in patients receiving bolus 5-FU Oral cryotherapy (2030 min) is suggested to decrease mucositis in patients treated with bolus doses of edatrexate Acyclovir and its analogues.

Radiation Therapy Prevention Recommended

Not Recommended

Standard-Dose ChemotherapyPrevention Recommended

Not Recommended

Standard-Dose ChemotherapyTreatment Chlorhexidine not to be used to treat established oral mucositis.

Background reading Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST. (2004) Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 100(suppl):20262046.



Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE. (2007) Mucositis Study Section of the Multinational Association of Supportive Care in Cancer, International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. Mar. 1;109(5):820-31.

Treatment options
Given that hundreds of thousands of cancer patients worldwide are affected by OM, a significant need for effective therapy exists. A single efficacious intervention or agent for the prophylaxis or management of RT or CT induced OM has not yet been identified. Many different treatments are used to prevent or treat OM. Few interventions used in clinical practice have never been rigorously evaluated. Furthermore, many combinations of agents are advocated by local experts without evidence to support their use. Several new approaches to OM have been taken, but in the absence of double-blind and placebo controlled clinical trials many of the management recommendations are subjective.

Basic oral care

Poor oral hygiene along with associated dental and periodontal pathology, such as dental caries, ill-fitting prostheses, orthodontic appliances, leads to a greater risk for OM in the course of RT or CT. Hence MASCC/ISOO recommends basic oral care as a standard practice to prevent and alleviate mucosal symptoms. The basic oral care (McGuire, 2006) typically includes: Pretreatment careful inspection of the oral cavity Evaluation by dental specialists Dental work to eliminate caries and existing gum disease before beginning cancer treatment Examination of oral cavity should be repeated in the course of treatment This pre-treatment assessment not only helps in the differentiation of OM from preexisting changes, such as pemphigoid, lichen planus, leukoplakia, and GVHD, but also permits the identification and elimination of pre-existing potential sources of infection which may affect the severity of the OM. Meticulous pretreatment assessment will reduce the incidence and duration of OM thus further reducing the risk for dental complications, including infections, caries, gingivitis, and osteoradionecrosis (Shieh, 1997). The basic oral care protocols during radiation involve: Brushing in a non-traumatic fashion, 2-3 times in a day with a soft-bristle toothbrush. Replacing the toothbrush on a regular basis. Using o ral rinses with regular frequency. Avoiding irritation like hot, spicy, and coarse foods, fruits and beverages with a high acid content, and alcohol (including alcohol-containing elixirs). Abstaining from smoking. Dental fluoride prophylaxis as (brushing) gels, rinses, and vacuum-formed vinyl splints loaded with fluoride gel are frequently used to prevent caries and mucositis in the course of RT or CT. It


has been seen that fluoride incorporates into tooth enamel and dentin and they also reduce oral bacterial load. But their role has not been confirmed in different studies. Oral rinses To maintain oral moistness patients should do frequent rinsing with bland solutions such as normal saline. This saline solution is made by adding tablespoon salt to 1 litre water and the solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse several times as often as necessary to maintain oral comfort. Sodium bicarbonate (baking soda) tablespoons can be added, if viscous saliva is present. Saline solution can increase oral lubrication by acting directly as well as by stimulating salivary glands to increase salivary flow. saline solution is made by adding tablespoon salt to 1 litre water

Oral care protocols not routinely recommended include: Daily use hydrogen peroxide rinses. Chlorhexidine, antiseptic mouthwash. Magic mouthwash or mouthwash cocktail. The daily use hydrogen peroxide rinses is not recommended, especially if mucositis is present because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing (Tombes, 1993). Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 to 2 days since more extended use may impair timely healing of mucosal lesions associated with bleeding. Chlorhexidine is an oral broad spectrum antibiotic rinse, known to reduce the colonization of microorganism in the oral cavity. Randomized controlled trial of Cheng et al (2004) concluded that the use of chlorhexidine, antiseptic mouthwash was associated with increase in oral mucosal inflammation, general mouth discomfort, taste alteration and staining of teeth. Based on these trials and updated recommendations of MASCC/ISOO, use is not recommended. The so called magic mouthwash or mouthwash cocktail is used by different institutions across the world. Such mouthwash usually have a variety of ingredients like lidocaine, diphenhydramine, topical antifungal nystatin and an antacid containing aluminum/magnesium hydroxide in equal parts. These formulae are popular for OM treatment owing to its painrelieving properties and its coating of the mucosa. However diphenhydramine is sedating, may carry unpleasant anticholinergic properties and on the other hand oral ketoconazole and fluconazole are more efficient in controlling oral candidiasis compare to nystatin. MASCC/ISOO guidelines do not recommends use of such cocktail mouth wash for the prevention and treatment of oral mucositis. It is also recommended that patients should be advised to avoid factors that cause irritation like hot, spicy, and coarse foods, fruits and beverages with a high acid content, and alcohol (including alcohol-containing elixirs) and should abstain from smoking (Rugg,1990).



Conformal radiotherapy & intensity-modulated radiation therapy (IMRT)

Mucositis is a common complication of radiotherapy to the head and neck region that occurs in up to 100% of patients. Many factors like field size, radiation dose and fractionation schedule determines the severity of mucositis. Combined use of CT and RT has resulted in better tumour control and overall survival in locally advanced head and cancer patients. Now-a-days monoclonal antibody, cetuximab have also been tried as concurrent chemo radiotherapy (Bonner, 2010) with promising results. But this intensification in treatment modalities is at the cost of increased toxicity in the form of OM. Trotti et al (2003), in his literature review article concluded more incidences of grade 3 mucositis in patients treated by concurrent chemotherapy plus radiation in comparison to radiation alone. Course/ pattern of Oral Mucositis (Wong, 2006)
Chemotherapy Usually begins 3 to 5 days after the start of therapy and peaks at 7 to 10 days. Radiotherapy Typically appears toward the end of the second week of treatment, plateaus during the fourth week of radiation, and may persist for 2 to 3 weeks after treatment is over.

Pathogenesis of radiation induced oral mucositis: RT directly damages the basal epithelial cell layer of the oral mucosa leading to the loss of the renewal capacity of the epithelium. Erythema of the involved mucosa in the second week of therapy will result due to subepithelial edema aggravating to an epithelial breakdown. As treatment continues, the epithelial surface cells shed, but their replacement by cells from the basal level does not occur. The mucosa becomes thin and superficially ulcerated, appearing as white patches, commonly mistaken for a yeast infection. As radiation progresses, the patches coalesce, forming large fields of superficial ulceration, referred to as confluent mucositis. Infrequently, radiation-induced mucositis can form deep ulceration with necrosis and hemorrhage. By the end of treatment, diffuse erythema, ulceration, spontaneous bleeding, and white or yellow pseudomembrane formation may be present. Among the various radiotherapy techniques available like IMRT, 3-Dimensional or 2Dimensional Radiotherapy technique only IMRT has the advantage of generating the sharp dose fall off near the targets and thus limiting the radiation dose to critical structures. Although all the radiotherapy techniques results in the varying grades of mucositis but with the help of IMRT we can spare the mucosa and thus limit the acute and long term morbidity associated with grade 3 and 4 mucositis (Sanguineti, 2006). In conventional radiotherapy, midline blocks help to reduce the incidence of mucositis (Perch, 1995). MASCC guidelines suggest use of midline radiation blocks and three dimensional radiation treatments to reduce the mucositis.

In this method, patient is advised to chew popsicles or ice chips during or after cancer treatment. This results in local vasoconstriction thus reducing the blood flow to the oral mucosa. Reduced blood flow will also reduce the amount of drug reaching to the oral mucous membranes, and may therefore will reduce mucositis caused by CT drugs such as 5-fluorouracil (5-FU).


Sucking ice chips for half an hour during intravenous infusion of 5-FU significantly reduces the severity and incidence of OM, successfully studied in the randomized trials (Cascinu, 1994; Mahood, 1991) The use of cryotherapy is a readily available, cheap and effective method of minimizing mucositis induced by bolus 5-FU, but this measure is not effective for continuous infusions (Rocke, 1993). Use of ice chips in patients receiving melphalan and edatrexate based CT regimens as a prophylactic measure also indicate reduced incidence of OM. Current MASCC/ISOO guidelines recommend cryotherapy for the prevention of oral mucositis with standard dose chemotherapy.

Pain management
Pain is the single most important distressing symptom in cancer patient having some degree of OM. If not properly addressed, it can also lead to decreased oral intake leading to malnutrition and the need for total parenteral nutrition (TPN). The inability to control mucositis-related pain can be frustrating for both the patient and the treating physician. Most patients require both systemic and topical analgesics. Recommendation is: Systemic analgesics, including patient-controlled analgesia, should be implemented as needed to reduce the pain associated with severe mucositis. So many local anesthetics agents, such as diphenhydramine, viscous xylocaine, lidocaine as oral solutions, are frequently used for the temporary relief of OM related pain. But all these agents interfere with taste perception, thus possibly contributing to hypo alimentation. Thus these topical anesthetic agents are not recommended. So the frequent and prophylactic use should be discouraged. Few studies suggest combinations of local anesthetics and mouth coating agents like sucralfate can also be used ([Barker, 1991). However the use of sucralfate is controversial as most of the randomized trials (Carter, 1999) failed to demonstrate beneficial effects. MASCC/ISOO guidelines do not support the use of sucralfate. One may have to use systemic analgesics and opioids to control the pain. A randomized trial of morphine versus tricyclic antidepressants for treatment of RT induced OM pain in HNC, showed that morphine produces greater pain relief than do tricyclic antidepressants (Ehrnrooth, 2001) Such patients should be given narcotic analgesics in the form of morphine, transdermal fentanyl patches along with laxatives to avoid constipation. Irritant laxative are preferred compared to bulk forming because of compromised oral intake. The dose of narcotic analgesic, their frequency, and duration should be regularly adjusted to meet the intensity level of pain. Despite the recommendations from MASCC/ISOO a recent symptom review study shows that very few patients are being given adequate narcotic analgesia.

Activity 3 (allow approximately 80 minutes)

Task 1: Select a patient who is receiving cancer treatment either by radiotherapy or chemotherapy and consider the following: How can you help the patient maintain oral hygiene and proper oral care? How can the patient make an ideal oral rinse from salt and water? How many times should the patient use an oral rinse? Allow 40 minutes


Task 2: Select a patient who has got oral mucositis with uncontrolled pain not relieved by conventional analgesics. Consider how you would describe a morphine schedule to the patient and manage any other resulting side effects. Allow 20 minutes Task 3: Select a patient who is receiving the chemotherapy and explain to them the benefits of chewing ice popsicles during and after the treatment. Allow 20 minutes

Useful resources
Useful websites For clinical practice guidelines from the Multinational Association of Supportive Care, click on Mucositis at www.mascc.org Background reading Barker G, Loftus L, Cuddy P, Barker B. (1991) The effects of sucralfate suspension and diphenhydramine syrup plus kaolin-pectin on radiotherapy- induced mucositis. Oral Surgery, Oral Medicine, and Oral Pathology. 71: 288-293. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncology. 11(1): 21-28. Carter DL, Hebert ME, Smink K, Leopold KA, Clough RL, Brizel DM. (1999) Double-blind randomized trial of sucralfate vs placebo during radical radiotherapy for head and neck cancers. Head Neck. 21: 760-766. Cascinu S, Fedeli A, Fedeli SL, Catalano G. (1994) Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. European Journal of Cancer. B Oral Oncology. 30B: 234-236. Cheng KK, Chang AM, Yuen MP. (2004) Prevention of oral mucositis in paediatric patients treated with chemotherapy; a randomized crossover trial comparing two protocols of oral care. European Journal of Cancer. 40: 1208-1216. Ehrnrooth E, Grau C, Zachariae R, Andersen J: (2001) Randomized trial of opioids versus tricyclic antidepressants for radiation-induced mucositis pain in head and neck cancer. Acta Oncologica.40: 745-750. Mahood DJ, Dose AM, Loprinzi CL, Veeder MH, Athmann LM, Therneau TM, Sorensen JM, Gainey DK, Mailliard JA, Gusa NL. (1991) Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. Journal of Clinical Oncology. 9: 449-452.



McGuire DB, Correa ME, Johnson J, Wienandts P. (2006) The role of basic oral care and good clinical practice principles in the management of oral mucositis. Support Care Cancer. 14:541 547. Perch SJ, Machtay M, Markiewicz DA, Kligerman MM. (1995) Decreased acute toxicity by using midline mucosa-sparing blocks during radiation therapy for carcinoma of the oral cavity, oropharynx, and nasopharynx. Radiology;197:863-866. Rocke LK, Loprinzi CL, Lee JK, Kunselman SJ, Iverson RK, Finck G, Lifsey D, Glaw KC, Stevens BA, Hatfield AK, Vaught NL, Bartel J, Pierson N (1993) A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil- related stomatitis. Cancer. 72(7): 2234- 2238. Rugg T, Saunders MI, Dische S. (1990) Smoking and mucosal reactions to radiotherapy. British Journal of Radiology. 63: 554-556. Sanguineti G, Endres EJ, Gunn BG, Parker B. (2006) Is there a mucosa-sparing benefit of IMRT for head-and-neck cancer? International Journal of Radiation Oncology*Biology*Physics. 66: 931938. Shieh SH, Wang ST, Tsai ST, Tseng CC. (1997) Mouth care for nasopharyngeal cancer patients undergoing radiotherapy. Oral Oncology. 33: 36-41. Tombes MB & Gallucci B. (1993) The effects of hydrogen peroxide rinses on the normal oral mucosa. Nursing Research. 42(6): 332-337. Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L, Zilberberg MD. (2003) Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiotherapy Oncology. 66: 253262. Wong PC, Dodd MJ, Miaskowski C, Paul SM, Bank KA, Shiba GH, Facione N. (2006) Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors. Journal of Pain Symptom Management. 32: 2737.

Targeting infection
It is well known that oral cavity of normal individual harbours a variety of potentially pathogenic microorganisms. But due to maintained mucosal integrity and normal immunity, healthy individual are not susceptible to infection in oral cavity. But due to decreased immunity, cancer patients are more vulnerable to get infections from viral, fungal, and bacterial sources. Normally, the mucous membranes are a barrier to these agents, but the loss of mucosal integrity can permit systemic entry of organisms that leads to infection (Costa, 2004). It is important that patients be monitored closely for any acute exacerbation of sign and symptoms which will suggest oral/pharyngeal infection that may commonly include candidiasis, bacterial, or herpes simplex. Keeping a high index of suspicion, culture and sensitivity should be done. A number of systemic and topical antimicrobial agents have been evaluated for OM. Many authors have emphasized the necessity of a variety of disinfectant, antibacterial, antiviral, and antifungal agents for the prophylaxis and treatment of OM (Makkonen, 1989), but due to variable results there are no uniform consensus and therefore, routine use is not recommended (Symonds, 1996).


Targeting inflammation
Various preclinical and clinical researches have evaluated the role of anti inflammatory agents, steroidal and nonsteroidal like betamethasone, prednisolone, and prostaglandins E1 (PGE1). None have shown positive impact on OM prevention (Lalla, 2006). The prophylactic use of the prostaglandin E2 (PGE2) derivate, misoprostol have produced controversial results (Labar, 1993). Benzydamine hydrochloride is a nonsteroidal agent, frequently used in Canada and the European Union exhibits, antimicrobial, anti-inflammatory, anesthetic, and analgesic effects (Kim, 1986). Its action may be mediated by the prostaglandin system. It has been evaluated in phase III trials and found to be effective in low doses of radiation up to 50 Gy (Epstein, 1989). Thus this study provided preliminary evidence that benzydamine might be beneficial in patients undergoing radiation therapy to the oral cavity. Patients were instructed to rinse with benzydamine hydrochloride for 2 minutes, four to eight times daily, before and during radiation therapy and for 2 weeks after completion of radiation therapy. Benzydamine hydrochloride Associated with significantly reduced erythema and ulceration and delayed use of systemic analgesics. Effective in patients receiving low dose radiotherapy Not effective for patients receiving accelerated or high dose radiation therapy.

MASCC guidelines do recommend the use of benzydamine for the prevention of radiation induced mucositis in patients with HN cancer receiving moderate-dose radiation therapy.

Useful resources
Background reading Costa SF, Miceli MH, Anaissie EJ. (2004) Mucosa or skin as a source of coagulase-negative staphylococcal bacteraemia? Lancet Infectious Diseases. 4: 278286. Epstein JB, Stevenson-Moore P, Jackson S, Mohamed JH, Spinelli JJ. (1989) Prevention of oral mucositis in radiation therapy: a controlled study with benzydamine hydrochloride rinse. International Journal of Radiation Oncology*Biology*Physics. 16(6): 1571-1575 Kim JH, Chu FC, Lakshmi V, Houde R. Benzydamine HCl. (1986) A new agent for the treatment of radiation mucositis of the oropharynx. American Journal of Clinical Oncology. 9: 132-134. Labar B, Mrsic M, Pavletic Z, Bogdani V, Nemet D, Aurer I, Radman I, Filipovi-Grci N, Serti D, Kaleni S. (1993) Prostaglandin E2 for prophylaxis of oral mucositis following BMT. Bone Marrow Transplant. 11(5): 379-382. Lalla RV, Schubert MM, Bensadoun RJ, Keefe D. (2006) Anti-inflammatory agents in the management of alimentary mucositis. Support Care Cancer. 14(6): 558-565.



Makkonen TA, Borthen L, Heimdahl A, Joensuu H, Lehtonen OP, Nord CE . (1989) Oropharyngeal colonisation with fungi and gram-negative rods in patients treated with radiotherapy of the head and neck. British Journal of Oral and Maxillofacial Surgery. 27: 334340. Symonds RP, McIlroy P, Khorrami J, Paul J, Pyper E, Alcock SR, McCallum I, Speekenbrink AB, McMurray A, Lindemann E,Thomas M. (1996) The reduction of radiation mucositis by selective decontamination antibiotic pastilles: A placebo controlled double-blind trial. British Journal of Cancer. 74(2): 312-317.

Future directions
A number of targeted therapies have recently been evaluated for prevention and/or treatment of oral mucositis, including amifostine and other antioxidants, growth factors, cytokines, and glutamine Amifostine Amifostine is a cytoprotective pro-drug which is selectively taken up by non malignant cells and gets activated to the free thiol metabolite at the tissue site. These thiol metabolites are responsible for most of the cytoprotective and radioprotective properties of amifostine. It is preferentially taken up by healthy cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. It has unique antioxidant property acting against ROS produced by RT and responsible for mucositis (Grdina, 2000). Its role for prevention of oral mucositis induced by CT or RT has been widely studied. A metaanalysis (Sasse, 2006) of 1,451 has demonstrated statistically significant role in reducing the severity of oral mucositis in patients receiving RT with amifostine. However this reduction was at the cost of increased adverse effects associated with amifostine like nausea, vomiting, hypotension, and allergic reactions. Because of inconsistent results it has not been approved for OM. Till now amifostine has been approved for reducing the incidence of severe xerostomia in patients with head and neck cancer associated with radiation therapy. Palifermin Palifermin is a human recombinant keratinocyte growth factor (KGF) produced in Escherichia coli. It reduces the OM due to RT and CT by stimulating the growth of the cells that line the surface of the oral cavity. Palifermin selectively binds to the epithelial cell-surface receptors and stimulates epithelial cell proliferation, differentiation, and upregulation of cytoprotective mechanisms (Blijlevens, 2007). It reduces the incidence and duration of severe oral mucositis (Spielberger, 2004) by protecting those cells and stimulating the growth of new epithelial cells to build up the mucosal barrier. Clinical trials have demonstrated that palifermin can exert a mucoprotective effect in patients who were treated with chemotherapy or radiation therapy (Rosen, 2006). Further studies are ongoing to further evaluate and confirm the ability of epithelial growth factor reduce oral mucositis in patients receiving chemoradiotherapy for head and neck cancer. Glutamine Glutamine is a nonessential amino acid which reduces mucosal injury by reducing the production of pro-inflammatory cytokines and cytokines related apoptosis (Klimberg, 1990).



Many malignancies are characterized by decreased glutamine levels, which can be further exacerbated by cell damage caused by cancer therapy. Glutamine supplementation can reverse this effect and may help to protect mucosal tissues from damage by RT or CT and thus accelerate recovery (Savarese, 2003). Glutamine has been used in different trials as oral, systemic and as mouth washes. Data suggest that this agent may be useful in preventing or reducing the incidence and severity of oral mucositis in patients undergoing cancer therapy (Anderson, 1998). However due to inconsistent results, MASCC/ISOO do not recommends its routine use in present guidelines. Further studies on this approach are warranted. G-CSF and GM-CSF These granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colonystimulating factor (GM-CSF) are used extensively with high dose chemotherapy as systemic administration. Research data have clearly shown the local accumulation of activated neutrophils following to systemic administration of G-CSF and GM-CSF. This local accumulation thus enhances the defense mechanisms of the oral mucosa (Lieschke, 1992). Both the systemic (Schneider, 1999) and local use as topical mouth wash of G-CSF and GM-CSF, respectively, has been evaluated in different trials for the prevention and treatment of oral mucositis. But the results of these trials favor the systemic intervention group however no preventive effect was found for the topical administration group. In view of inconsistent results MASCC/ISOO guidelines do not recommend the routine use of GM-CSF and G-CSF in any form for the prevention or treatment of oral mucositis. Low-level laser therapy (LLLT) LLLT or soft laser has been thought to have analgesic, anti-inflammatory, and wound healing effects by speeding up the oral re-epithelialization. Different trials have evaluated LLLT during RT for head and neck cancer and in the transplant setting (Bensadoun, 1999). There is no known clinical toxicity or side effects of the application of low-energy helium-neon lasers (soft lasers) and it favorably influence the outcome of oral mucositis. However there is no specific guideline regarding type of light source, wavelength, and dose schedule which has to be used and it requires special training and necessary technology. MASCC guidelines suggest LLLT use in the transplant setting but do not offer any specific recommendation during RT for HNC for which there are less available data. Alternative therapy Many supportive drugs have been suggested like: Vitamin A Vitamin E Vitamin B12 Folic acid Aloe Vera PV701 Milk-Derived Protein Extract Conflicting and insufficient evidence are available hence no guidelines are possible.

Useful resources
Background reading Anderson PM, Schroeder G, Skubitz KM. (1998) Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer. 83:1433-1439.



Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM, Viot M, Dejou J, Tardieu C, Benezery K, Nguyen TD, Laudoyer Y, Dassonville O, Poissonnet G, Vallicioni J, Thyss A, Hamdi M, Chauvel P, Demard F. (1999) Low-energy He/Ne laser in the prevention of radiation induced mucositis. A multicenter phase III randomized study in patients with head and neck cancer. Support Care Cancer. 7: 244-252 Blijlevens N, Sonis S. (2007) Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapyinduced mucositis. Annals of Oncology. 18(5): 817-826. http://annonc.oxfordjournals.org/content/18/5/817.full.pdf Grdina DJ, Kataoka Y, Murley JS. (2000) Amifostine: mechanisms of action underlying cytoprotection and chemoprevention. Drug Metabolism and Drug Interactions. 16: 237279. Klimberg VS, Souba WW, Dolson DJ, Salloum RM, Hautamaki RD, Plumley DA, Mendenhall WM, Bova FJ, Khan SR, Hackett RL. (1990) Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer. 66:62-68. Lieschke GJ, Ramenghi U, OConnor MP, Sheridan W, Szer J, Morstyn G. (1992) Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation. British Journal of Haematology. 82: 589-595. Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J, Cesano A, Gayko U, Chen MG, Clarke S. (2006) Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. Journal of Clinical Oncology. 24: 51945200. Sasse AD, Clark LG, Sasse EC, Clark OA. (2006) Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. International Journal of Radiation Oncology*Biology*Physics. 64: 784791. Savarese DM, Savy G, Vahdat L, Wischmeyer PE, Corey B. (2003) Prevention of chemotherapy and radiation toxicity with glutamine. Cancer Treatment Reviews. 29: 501513. Schneider SB, Nishimura RD, Zimmerman RP, Tran L, Shiplacoff J, Tormey M, Contreras R, Juillard GF. (1999). Filgrastim (r-metHuG-CSF) and its potential use in the reduction of radiation-induced oropharyngeal mucositis: an interim look at a randomized, double-blind, placebo-controlled trial. Cytokines, Cellular & Molecular Therapy. 5: 175-180. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre CF, Sung EC, Blazar BR, Elhardt D, Chen MG, Emmanouilides C. (2004) Palifermin for oral mucositis after intensive therapy for hematologic cancers. New England Journal of Medicine. 351:25902598.

Discussion Board
The discussion board is a forum in which you can exchange ideas with other participants. This activity relates to the work you will have completed in earlier tasks and provides an opportunity for you to explore the difference in perspectives between the participants.



Discussion Board
When will it take place For a 3 month period from date of publication of this article. Which discussion thread Oral mucositis in head and neck cancer What is expected of you as a participant This module has only touched on some of the issues oral mucositis in head and neck cancer. By sharing your experiences of the issues that affect your practice, we can build on the current body of knowledge.

Summary of this module

By completing this module you should have a broad overview of oral mucositis and its diagnosis as well as management.

On completion of this module you will have had the opportunity to:
Consider oral mucositis is a serious side effect of cancer therapy. Consider how accurate diagnosis of oral mucositis is critical to ensure selection and timely initiation of optimal therapy. Gain a knowledge of the scales in order to accurately diagnose the grade of OM. Understand the guidelines that are most widely employed in our clinical practice. Understand how basic oral care and good oral hygiene remains the cornerstone of care for these patients. Consider that despite the availability of variety of bland and/ or medicated oral rinses in the market, no rinse appears to be more effective and well tolerated than normal saline solution. Understand how mucositis-related pain should be carefully managed through the use of topical analgesics and nonsteroidal agents and patient controlled analgesia (opioids) for severe pain when necessary.
Dr Raghav C Dwivedi Clinical Fellow Head and Neck Unit Royal Marsden Hospital Fulham Road, London SW3 6JJ, UK. email: raghav_dwivedi@rediffmail.com

Dr Madhup Rastogi Assistant Professor Department of Radiotherapy & Oncology Indira Gandhi Medical College Shimla 171001 India email: drmadhup1@rediffmail.com Dr Rehan A Kazi Honorary Lecturer and Research Team Leader Head and Neck Unit Royal Marsden Hospital Fulham Road, London SW3 6JJ, UK. E-mail: drrehankazi@gmail.com