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IN HEAD AND NECK CANCER PATIENTS

Dissertation Submitted to

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY In Partial Fulfilment for the Degree of

MASTER OF DENTAL SURGERY

BRANCH IX ORAL MEDICINE AND RADIOLOGY MAY 2019

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ACKNOWLEDGEMENTS

Words seem fewer to put across my gratitude to my guide, Dr. S. Kailasam B.Sc., MDS, Professor and Head, Department of Oral Medicine and Radiology, Ragas Dental College and Hospital, Chennai, who has been instrumental in shaping my views throughout the completion of my dissertation in all aspects. His enthusiasm and unlimited zeal proved to be a major driving force throughout the dissertation completion. Sir, I solemnly express my deep felt gratitude for your valuable guidance and suggestions, tireless pursuit for perfection, constant support and keen surveillance for the minute details throughout this dissertation.

I take this opportunity to thank, Dr. N.S. Azhagarasan, M.D.S, Principal, Ragas Dental College & Hospital and to Dr. N. R. Krishnaswamy, M.D.S, Vice-principal, Ragas Dental College for their generous support rendered throughout my course.

I thank Dr. N. Santana, M.D.S, Professor, Department of oral medicine and radiology, Ragas Dental College, for helping me throughout my study, shaping up my clinical acumen and giving me constant support and encouragement.

I express my deep sense of gratitude to Dr. F. Massillamani, M.D.S, Reader, for her valuable help and who was there at each step guiding me to prepare this dissertation. I am deeply grateful for her detailed and constructive comments, and for her important support throughout this work.

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I extend my sincere heartfelt thanks to Dr. B .Anand, M.D.S, Dr. K. Sangeetha , M.D.S, Dr. Venkatalakshmi Aparna, M.D.S, Dr. R. Malavika, M.D.S, Readers, Department of oral medicine and radiology, Ragas Dental College, for helping me throughout my study and giving me constant support and encouragement.

I extend my heartfelt thanks to Dr. M. Deivanayagi, M.D.S, Dr.

I. K. Mammootty, M.D.S, Dr. Lalitha, Senior lectures, Department of oral medicine and radiology, Ragas Dental College, for helping me throughout my study and giving me constant support and encouragement.

I am very thankful and indebted to Dr. Balasundaram M.D. R.T, Head of Department of Radiation Oncology, V.S. Hospitals, Chennai for being very helpful and encouraging and kindly permitting me to carrying out my study in the hospital.

I am thankful to Mr. Bharadwaj and Mr. Senthil of Noveau Medicaments, Chennai for providing Convales(L-Glutamine granules) to the patients.

I would like to thank all my Patients for their kind cooperation

I extend my gratitude to my seniors Dr. Lakshmi Nurshinman,

Dr. B. Niveditha, Dr. Priyadarshini, Dr C. K .Vishnu Priya for encouraging me and helping me in completing this dissertation. I also thank my colleagues Dr.Leena Dandu , Dr. Ezhil Pallavi, Dr. Geetha And my juniors for their friendly help, support and cooperation throughout my postgraduate life.

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I would like to especially thank my dear parents Mr. Rama Krishna G and Mrs.Shanthi G, my late grandmother Mrs. Naga Rathnam, my aunt Mrs.

Rathnam for their love, understanding, support encouragement and their prayers throughout these years without which, I would not have reached so far. I would like to express my indebtedness for all the sacrifices they have made to see me succeed in my past, present and all my future endeavours.

Last but not the least I thank the Almighty for giving me the strength and stamina in accomplishing this dream into a reality, without whom this work would have been impossible.

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1 WHO World Health Organisation

2 3DCRT 3 Dimensional Conformal

Radiotherapy

3 IMRT Intensity Modulated

Radiotherapy

4 IGRT Image Guided Radiotherapy

5 FU Fluoro uracil

6 RTOG Radiation Therapy Oncology

Group

7 NCI-CTC National Cancer Institute

Common Toxicity Criteria

8 RT Radiotherapy

9 CA Carcinoma

10 DNA Deoxyribo nucleic acid

11 RNA Ribo Nucleic Acid

12 ICD International Classification of

Diseases

13 IARC International Agency for

Research on Cancer

14 CT Computed Tomography

15 CBCT Cone Beam Computed

Tomography

16 MV Mega Volt

17 IL Interleukin

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20 AP activator protein

21 NF-κB transcription factors nuclear

factor kappa B

22 MMP matrix metalloproteinase

23 TNF tumor necrosis factor-alpha

24 TLR-4 toll-like receptor 4

25 GTV Gross Tumor Volume

26 PTV Planned Tumor Volume

27 CTV Clinical Tumor Volume

28 TPF regimen Docetaxel+cisplatin+5-Fluoro-

uracil

29 NRS Numeric Rating Scale

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S.NO TITLE PAGE NO

1 INTRODUCTION 1

2 AIMS AND OBJECTIVES 5

3 REVIEW OF LITERATURE 6

4 MATERIALS AND METHODS 39

5 FIGURES 46

6 RESULTS 50

7 TABLES AND GRAPHS 55

6 DISCUSSION 62

7 SUMMARY AND CONCLUSION 71

8 BIBLIOGRAPHY 73

9 ANNEXURE --

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mucositis in 1st week of treatment

2 Distribution of subjects based on WHO grading of mucositis in 2nd week of treatment

55

3 Distribution of subjects based on WHO grading of mucositis in 3rd week of treatment

55

4 Distribution of subjects based on WHO grading of mucositis in 4th week of treatment

56

5 Distribution of subjects based on WHO grading of mucositis in 5th week of treatment

56

6 Comparison of time of onset of Grade II and Grade III mucositis between control and glutamine

groups

57

7 Distribution of subjects based on NRS pain scale in 1st week of treatment

57

8 Distribution of subjects based on NRS pain scale in 2nd week of treatment

57

9 Distribution of subjects based on NRS pain scale in 3rd week of treatment

58

10 Distribution of subjects based on NRS pain scale in 4th week of treatment

58

11 Distribution of subjects based on NRS pain scale in 5th week of treatment

59

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2 Distribution of subjects with the presence of cancer at the anatomical sites of head and neck in control

group

60

3 Distribution of subjects with the presence of cancer at the anatomical sites of head and neck in

glutamine group

61

4 Comparison of maximum mucositis score between control and glutamine group

61

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2 Carcinoma of tongue 46

3 Carcinoma of alveolus 47

4 Grade I Mucositis 47

5 Grade II Mucositis 48

6 Grade III Mucositis 48

7 Grade IV mucositis 49

8 L-Glutamine 49

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Introduction

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Neoplasia was defined by the British pathologist Sir Rupert Willis as follows “a neoplasm is an abnormal mass of tissue, the growth of which exceed and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of stimuli that evoke the change”85. Cancer is malignant neoplasm and is the second leading cause of death worldwide with nearly 1 in 6 deaths being due to cancer and the incidence of new case will increase as the population grows along with lifestyle modifications and exposure to carcinogens increases.

Head and neck cancer is the 6th most common cancer worldwide whereas cancer of the oral cavity and lip is the most common cancer among men in India.24,52 It accounts for 25-30% of all cancers in India compared to 3-4% in the developed countries22,71. The etiological factors for oral cancer are tobacco, smoking, alcohol and betel nut. Viruses like Human Papilloma Virus, immunosuppression, environmental factors such as sun exposure, previous radiation exposure, dental factors such as poor oral hygiene and poor dental status, infections such as syphilis have also been implicated as an etiological factor for oro-pharyngeal cancer27. Signs and symptoms include red or red and white patches in the oral mucosa, ulcers that do not heal, swelling that persists for long time, dysphagia and difficulty in mouth opening, burning sensation, numbness of jaws and tongue, swelling of tongue. Although screening can help in early detection of cancer, patients generally present in advanced stages

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leading to high mortality. This is due to an alarming lack of general awareness about the signs and symptoms.

Diagnosis and staging of head and neck cancer is made by various imaging modalities such as Computed Tomography, Magnetic Resonance Imaging, nuclear imaging studies and histopathological grading of biopsy sample using WHO classification. A multidisciplinary approach is followed for the management of head and neck cancer based on staging, location extent of the primary tumour. Standard treatment for early stage I and II is single modality using either surgery or radiotherapy. For advanced cases, multimodality treatment is preferred- surgery with radiotherapy and/or chemotherapy.

Radiotherapy is the preferred treatment modality in our country in early stage I and II cases. Radiotherapy techniques have evolved over the years from telecobalt machine to organ sparing techniques such as 3D CRT, IMRT and IGRT. Systemic therapy for head and neck cancer is by chemotherapeutic agent which is given as either neoadjuvant or adjuvant chemotherapy. The most commonly used chemotherapeutic agent in head and neck cancer is cisplatin. Other drugs used are carboplatin, docetaxel, cetuximab, paclitaxel, 5- FU.18, 83

Since radiation and chemotherapy affects normal tissues, both acute and late toxicity occurs. The acute effects occur in rapidly proliferating cells. The oral mucosa has a rapid rate of turnover and hence is at a higher risk of injury from ionizing radiation. Mucositis is the most common acute complication for

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chemoradiotherapy patients. It occurs sue to systemic effects of chemotherapy patients and local effects of radiation on the oral mucosa. Almost 100% of patients undergoing chemoradiotherapy develop mucositis.44

The severity of mucositis is dependent on the type of ionizing radiation, the volume of irradiated tissue, cumulative dose and patient factors. It begins as erythema and develops to desquamative patches and large contiguous lesions covered with pseudomembrane. Symptoms range from discomfort and pain to an inability to tolerate food and fluids. Patients have difficulty in swallowing, speaking and chewing due to pain and have an increased risk of secondary infection as well as reduced compliance to treatment leading to treatment breaks. It worsens the quality of life of patient and has a negative influence on treatment outcome.35, 44 Various classification systems have been proposed for mucositis and the most commonly used are the WHO and RTOG classification system.57

Various studies have been conducted regarding interventions for prevention and management of oral mucositis. Guidelines62 have been formulated based on level of evidence obtained in the studies and is being updated regularly as new interventions are being studied. Current guidelines to prevent oral mucositis include basic oral care, oral cryotherapy, low level laser therapy, palifermin, benzydamine mouthwash and zinc supplementation.

Treatment is by transdermal fentanyl, 0.2% morphine mouthwash, 0.5%

doxepin mouthwash. Current studies under evaluation include granulocyte

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colony stimulating factor, granulocyte macrophage colony stimulating factor, oral glutamine, supersaturated calcium phosphate, prostaglandin E2.

Though various therapeutic agents claim to prevent or reduce, there is no single intervention that is completely successful. L-glutamine is a conditionally essential amino acid and is the most abundant free amino acid. Depletion of glutamine levels occur in cancer which is further reduced by chemoradiotherapy. Glutamine alters inflammatory response and decreases mucous membrane injury and its breakdown product is an antioxidant.

Glutamine was initially used in the management of radiation induced intestinal toxicity. It provides primary oxidative fuel to the gut epithelium and maintains its integrity. These trials led to its use in preventing acute toxicities such as oesophagitis in various cancers such as lung cancer, breast cancer.8 Studies have also been done to assess its effects on reducing chemotherapy induced cardiotoxicity and neurotoxicity. Glutamine has also shown to increase sensitivity of cancer cells to chemotherapeutic agents, thus increasing the therapeutic index of chemoradiotherapy by sensitising cancer cells.42

Very few studies have been done using glutamine and have demonstrated significant effects in prevention of oral mucositis.29,45,16,77,78

In light of this, a prospective randomized trial was carried out to evaluate the therapeutic benefit of L-Glutamine in prevention and management of acute radiation induced mucositis, involving the oral mucosa in head and neck cancer patients undergoing radiotherapy.

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Aim and Objectives

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management of acute radiation induced mucositis in Head and Neck cancer patients undergoing chemoradiotherapy

OBJECTIVES

1. To assess the grades of oral mucositis in patients undergoing chemoradiotherapy in study group (L-Glutamine) and control group.

2. To assess the time of onset of oral mucositis in the glutamine group and control group.

3. To compare the differences in mucositis grading between the glutamine group and control group.

4. To compare the difference in subjective benefit of relief of pain between the glutamine group and control group.

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Review of Literature

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REVIEW OF LITERATURE

Cancers involving the oral cavity include those affecting the lips (ICD-9, site 140), gingival, tongue, gums, floor of mouth, palate and oropharynx(site 141, 143-146). Cancer presents a major public health burden being the second most common cause of mortality globally, causing 8.8 million deaths in 2015.

It is projected that there will be 26 million new cases and 17 million deaths by 2030.30.Nearly 1 in 6 deaths is due to cancer. Tobacco usage accounts for approximately 22% of cancer deaths.23

According to IARC30 and GLOBOCAN24, the incidence rates of lip, oral and pharyngeal cancer will increase from 529500 cases in 2012 to 856000 by 2035.24,30,39 The highest rates of oral cavity cancer are in Pakistan, Brazil, India and France. Cancer of oral cavity and lip accounts for the most common cancer among men in India.72 Squamous cell carcinoma constitutes more than 90% of all oral cavity cancers.

The treatment of oral cancer encompasses a multimodality approach based on the staging of disease, consideration of disease control, cosmetic and functional outcome, resource availability and expertise19. Superficial carcinomas can be managed with surgery or radiation with excellent cure rates.

The choice of treatment is based on patient’s compliance and preference, cost and quality of life. Surgery has the advantage of complications and shorter duration of treatment. External beam radiotherapy with or without concomitant chemotherapy is used adjuvant to primary surgery in cases where pathological

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feature are unfavourable for enhancement of loco regional control, as a primary treatment in cases unsuitable for surgery and as a salvage treatment in recurrent or persistent cases. Brachytherapy can be used as single modality in early well defined primary tumor or as an adjuvant in cases with positive margins.

Radiotherapy involves the use of ionizing radiation. The biological effectiveness depends on the linear transfer energy of the type of radiation used, the total dose, the number of fractions, the fractionation rate and the radiosensitivity of the target tissue. Ionizing raditation is being used based on the rationale that cancer cells which are rapidly proliferating are more sensitive than normal cells to the effects of radiation. They can act directly by damaging the DNA and causing cell death or it can act indirectly by causing ionization or excitation of water components of the cell which produces free radicals. Thus radiation therapy achieves therapeutic effect by inducing DNA damage leading to cell death. Several studies were performed that found that the DNA repair mechanism in cancer cells is slower than normal cells. Also, the DNA damage mechanism and the proteins involved in cell death decreases the radioresistance of fast doubling cancer cells and conversely slows the radioresistance of normal cells which are slow doubling compared to cancer cells..

Radiation therapy consists of teletherapy or external beam radiotherapy and brachytherapy. Teletherapy techniques have evolved over the years from earlier telecobalt machines using telecobalt machines that produced gamma

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radiation to linear accelerators that generate high energy X rays and photons.

Head and neck radiotherapy is challenging as tumors are often located in close proximity to critical structures and adequate dose has to be delivered to the tumor while protecting the organs at risk.Various techniques are currently being used.

3 Dimensional Conformal Radiation Therapy- 3DCRT involves 2 opposing lateral field to irradiate the primary tumor and the cervical lymph nodes and an anterior field to irradiate the supraclavicular lymph nodes. The 3 fields of 6 MV beams are planned such that there is no overlap.

Intensity Modulated Radiation Therapy- IMRT delivers non uniform beam with varying intensities across the tumors. The beam arrangement for bilateral tumor consists of 9 coplanar 6 MV photon beams that is evenly distributed around the patient whereas unilateral cases consists of 7 coplanar beams that are angled from the tumor side. This technique provides conformal dose distribution to the tumor and sparing of critical structures and is ideal for head and neck cancers .

Volumetric Modulated Arc Therapy- VMAT allows motion of gantry and multileaf collimator as well as simultaneous adjustment of gantry speed, MLC speed and dose rate. Based on unilateral or bilateral tumors, plan consists of 2- 3 partial or full arcs with increased number of beams and thus produces a more conformal dose distribution and horter dose delivery time than traditional IMRT.

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Image Guided Radiation Therapy improves the precision and accuracy of treatment delivery by using imaging techniques immediately before treatment to verify correct patient position. Generally CT on rails which connects a conventional CT scanner with linear accelerator by sharing the same treatment table or CBCT images can be acquired by the treatment portal (MV) or by an orthogonal kV source.

Adaptive Radiation Therapy is advantageous in cases with significant tumor volume reduction during therapy or for patients who experience dramatic weight loss. A second replanning CT is taken in the midcourse of treatment and is registered with the initial planning CT. The initial contours are transferred from initial planning CT to replanning CT and are manually edited.

Brachytherapy or internal radiotherapy uses radiation source that are placed inside the body. It is used either as single modality in early stages or in combination along with external beam radiotherapy. It is of two types, interstitial- when the radiation source is placed within the tissues and intracavitary- when it is placed in a container within a natural body cavity such as maxillary sinus. The commonly used sources of irradiation are radium, radon, tantalum, gold, caesium and iridium68.

Ionizing radiation acts against tumor cells and also normal cells in the field of radiation. It also affects the neighbouring normal cells by inducing DNA damage, causing gap junction, cellular toxicity mediated by cytokines and through activation of various other cellular and micro environmental

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signalling cascades causing bystander effect61. Although various new techniques have been developed in radiation delivery, complications cannot be avoided completely. The radiation related changes can be early involving mucosa, taste, salivary glands, intermediate involving salivary glands and taste and late effects in salivary glands, dentition, periodontium, bone, muscles and joints.

Chemotherapy is used as induction chemotherapy before surgery or radiotherapy, concurrent chemotherapy along with radiotherapy or as adjuvant chemotherapy after definitive treatment. The commonly used chemotherapeutic agents in head and neck cancer are cisplatin, carboplatin and 5-flourouracil. Induction chemotherapy is not yet part of treatment protocol but some studies have shown good results but survival rates have not yet been established. Docetaxel is used in induction chemotherapy51.

Radiotherapy induced mucositis is the reactive inflammation of the oral and oropharyngeal mucosa during radiotherapy. It is the most common acute complication that decreases the quality of life of patients and is the major dose limiting factor in head and neck cancer patients. It is associated with discomfort, pain at rest, difficulty in chewing and swallowing. It also predisposes to local and systemic infection.63

JOHN E ROBINSON32 1964 described the changes after irradiation in the oral mucosa. The first oral change occurs by the end of first week when upto 1250-1500 rads has been administered and manifests as redness of the

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mucosa. This is due to inflammation and edema. This is followed by white patches which occur on mucosa of lips, cheeks, and tongue by the middle of second week when upto 2500 rads has been administered. Some of the white patches are sloughing mucosa and this occurs throughout the treatment period.

These changes occur quite rapidly in debilitated patients and those on high antibiotics due to disruption of normal flora leading to superimposed infection.

The sides of tongue become severely irritated by the middle of third week. By the fourth and fifth week when 4500-5500 rads have been administered, ulceration of corners of mouth and lips occur. All these manifestations resolve within 2 to 3 weeks after completion of radiotherapy.

DREIZEN S67 et al 1978 described chemotherapy induced mucositis as a common complication seen in patients undergoing chemotherapy. The stomatitis presented as excruciatingly painful localised or generalised mucosits of lips, gingiva, tongue, buccal mucosa, floor of mouth and palatal mucosa.

The most common drugs causing mucostis are antimetabolitis, antibiotics and hydroxyurea. These drugs act by interfering with epithelial cell production, maturation and replacement. The antimetabolite drugs act by preventing formation of DNA by inhibiting the formation of its precursor, thymidilic acid.

The antibiotics and hydroxyurea bind to DNA and prevents RNA synthesis.

Mucosits begins shortly after the treatment is started, peaks a week after the drugs are stopped and slowly recedes. The clinical manifestations are decreased mucosal thickness and keratinization, followed by superficial

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sloughing along with intense reddening of involved tissues followed by ulceration. He noted that the oral lesions may be localised or generalized, are reversible and totally repairable after withdrawal of the causative drug. The course of the lesions is altered by trauma, infections and haemorrhage.

SONIS74 et al 1998 explained the pathogenesis of mucositis as a 4 step process-

Inflammatory/vascular phase: The inflammatory phase begins shortly after radiotherapy or chemotherapy has been started. The exposed epithelial tissue releases proinflammatory cytokines, modified proteins and free radicals, including tumor necrosis factor, Interleukin 1, 6. These cytokines cause local tissue damage and initiates mucositis and cause further damage by increasing vascular permeability causing increased uptake of cytotoxic drugs in the mucosa.

Epithelial phase: Radiotherapy and chemotherapeutic drugs, especially those that act on S-phase of cell cycle retards cell division of dividing cells of the oral mucosal basal epithelium. This causes reduced epithelial renewal, atrophy and ulceration which occurs within 4-5 days of initiation of therapy.

Ulceration is exaggerated by functional trauma such as mastigation, swallowing and speech and is amplified by locally produced cytokines.

Ulcerative/Bacterial phase: This is the most symptomatic phase occurring at the end of first week. Localised areas of erosion of epithelium occur which are covered by fibrinous pseudomembrane. Secondary microbial colonization

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occurs, especially gram negative bacteria. These are also a source of endotoxins which further stimulate the production of cytokines from connective tissue surrounding the cells. These cytokines along with nitric oxide intensify the patient’s condition. The ulcerative phase occurs at time of patient’s maximum neutropenia.

Healing phase: It occurs between days 12 and 16. Epithelial proliferation and differentiation is renewed. It depends on many factors including normalisation of peripheral white blood cells count, re-establishment of the local microbial flora along with absence of factors that may interfere with wound healing such as mechanical irritation and infection.

STOKMAN46 et al 2002 did a study on 10 patients being treated for oral, oro-pharyngeal and salivary gland malignancies with post-operative curative conventional fractionated radiotherapy with a minimum cumulative dose of 50Gy to compare the viable cells and mature cells during the treatment course. Tryphan blue stain was used to quantify the viable cells and papanicolaou stain was used to identify the epithelial cell maturity. He noted that the percentage of viable cells increased from baseline 46.2% to 62.9%

during the first three weeks of radiotherapy and gradually increases during the next three weeks. The increase in viable epithelial cells is due to desquamation of the nonvital upper oral epithelial layer. The decrease in viable cells after 3 weeks occurs as the basal membrane develops leakage and disruption causing disruption of the normal architecture of the mucosa is disturbed. The cell

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maturity changes from immature and intermediate to more mature cells during the first 3 weeks. This possible shows basal cell layer changes due to disturbed cell proliferation caused by radiotherapy. During the first 3 weeks, the change in viability of cells preceded the changes in WHO score and hence is more sensitive. He concluded that as the development of severe mucositis is at its peak at three weeks, the viable cell count method can be used during this period to follow the course of treatment.

SONIS76 et al 2004 further described the pathogenesis of mucositis based on messenger signals. He modified his previous pathobiology of mucositis and developed the following theory:

Initiation phase: radiotherapy and chemotherapy cause DNA strand breakage causing clonogenic cell death through generation of reactive oxygen species, enzymatic or transcription factor activation in various cellular elements of mucosa. The reactive oxygen species damages other cells and tissues and it also leads to stimulation of secondary mediators of injury, including transcription factors like nuclear factor-κB. Activation of these transcription factors leads to gene upregulation such as tumor necrosis factor-α, IL-1β, 6.

Other genes are also upregulated, causing production of adhesion molecules, cyclo-oxygenase -2 and subsequent angiogenesis.

Upregulation and generation of messenger signals phase: Enzymes such as sphingomyelinase and ceramide synthase which catalyse ceramide synthesis are activated by radiotherapy and chemotherapy directly or by reactive oxygen

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species and tumor necrosis-α indirectly. This pathway is an alternative pathway for apoptosis of submucosal and basal epithelial cells. Also, breakdown of fibronectin causes macrophage activation and further tissue injury that is mediated by matrix metalloproteinase and additional tumor necrosis factor-α.

Signalling and amplification phase: By positive feedback loop, many inflammatory mediators are released in response to initial insult and through transcription factors and ceramide and caspase pathway, tissue injury is prolonged and amplified. This further leads to gene upregulation resulting in increased cytokine production. As these occur in the submucosa and the basal epithelium, the mucosal surface clinically appears normal.

Ulcerative phase: This phase is clinically associated with mucositis and the patient is most symptomatic. The loss of basal epithelium in the previous phases causes atrophic changes that culminate leading to breakdown of mucosa. The ulcer is the focus of bacterial colonization causing secondary infection. The toxic bacterial products can penetrate the submucosa and can stimulate the macrophages to release additional proinflammatory cytokines. In cases of neutropenic patients, bacteraemia or sepsis can occur if the bacteria invade submucosal vessels.

Healing phase: The healing phase begins with signal from the extracellular matrix. This renews the proliferation and differentiation of epithlium and re- establishment of normal microbial flora. After the healing phase, though the mucosa appears normal clinically, the mucosal environment has altered.

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Residual angiogenesis is present and the patient is at increased risk of mucositis with subsequent therapy.

LINDA S ELTING44 et al 2007 conducted a retrospective study of 204 head and neck cancer patients who received radiotherapy with or without chemotherapy to find the risk, outcome and economic costs of oral mucositis in these patients. Oral mucositis occurred in 91% of patients and 66%

developed severe mucositis of grade 3 and 4. Oral mucositis was higher in those who received chemoradiotherapy 98% compared to radiotherapy alone which was 85%. Patients with diabetes and altered fractionation were more likely to develop severe mucositis. The clinical course of oral mucositis persisted for more than 5 weeks in patients undergoing radiotherapy and upto 7 weeks among those who also had chemotherapy. Grade 3 and 4 mucositis persisted for more than 2 weeks. The severity of oral mucositis peaked during 5th week of treatment. Around 5.5% of patients required treatment breaks of around 5.8 days. 67% of patients with severe mucositis and 38% with grade 1, 2 could not tolerate solid food or soft diet. Severe oral pain was present in 41% among those who received RT and 59% among radiochemotherapy patients. Weight loss of > 5% of baseline body weight was 37% among RT alone and 59% among chemoradiotherapy patients. Inability to eat solid foos was 55% among RT patients compared to 88% among chemoradiotherapy patients. Oral infections occurred in 18% of patients who received RT and 72% among chemoradiotherapy group. Oral mucositis was also associated

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with increased visits to the emergency department, increased visits to the dental oncologist, increased use of opioid analgesics, intravenous antimicrobials and gastrostomy tube which overall increased outpatient costs.

J. EILERS35 et al 2007 reviewed the causes of mucositis and summarised patient and cytotoxic therapy related factors. Patient related factors include age where young patients and old patients have an increased risk due to increased cell turnover rate and old patients due to decreased wound healing respectively. Female gender, patients with poor oral health and hygiene, decrease saliva, low body mass index, poor renal function, smoking, previous cancer treatment and genetic factors are more likely to develop mucositis. The cytotoxic therapy related factors are specific chemotherapeutic agents such as antimetabolites, antitumor antibiotics, alkylating agents, and other miscellaneous drugs. Dose of agent as when increased dose is given and administration schedule as when the drug is given as bolus dose instead of continuous infusion influences the severity of oral mucositis. Similarly, the type of transplant such as allogenic transplant, radiation site and fractionation of radiation and combine modality chemoradiotherapy has greater risk of developing mucositis.

PANGHAL49 et al 2012 conducted a prospective study among 186 head and neck cancer patients to identify the prevalent bacterial and fungal in salivary and blood samples. He divided the patient groups based on treatment modality as radiotherapy, chemotherapy and radiochemotherapy groups.

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Pseudomonas aeruginosa and klebsilla pneumonia were isolated from blood of radiotherapy patients and oral cavity of chemotherapy patients. Gram positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis) were observed in blood of chemotherapy, radio chemotherapy cases and oral cavity of radiotherapy, radio chemotherapy treated cases. C.albicans fungi was the most significant pathogen of oral cavity in 48.78% of radiotherapy and 27.72% of radio chemotherapy cases. Candida colonization in influenced by adherence mechanism among fungi and oral epithelial cells. Radiotherapy induced hyposalivation and mucostis encouraged candida colonization.

The grading of mucositis helps us to compare the toxicity of treatment regimens as well as evaluation of various modes of intervention for mucositis.

Many different scales of mucositis have been proposed. They are based on objective findings such as ulceration and erythema, descriptive findings such as pesudomembrane formation, symptomatic interpretation, functional outcomes or by nursing managememt endpoints. A good scoring system should include all patient related factors along with a detailed inspection of the oral cavity. Some of the grading systems commonly used are the World Health Organization (WHO) scale, National Cancer Institute Common Toxicity Criteria (NCI-CTC).

WHO scale scores the anatomical, symptomatic and functional elements.

It is the most widely used scoring system in routine clinical practice.21 Grade 0 = no oral mucositis

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19 Grade 1 = erythema and soreness

Grade 2 = ulcers, able to eat solids

Grade 3 = ulcers, requires liquid diet (due to mucositis) Grade 4 = ulcers, alimentation not possible (due to mucositis)

The National Cancer Institute- Common Toxicity Criteria exists for oral mucositis caused by radiation therapy, chemotherapy and for bone marrow transplantation.. the grading of oral mucositis caused by radiation therapy is as follows:

Clinical exam:

Grade 1: erythema of the mucosa

Grade 2: patchy ulcerations or pseudomembrane

Grade 3: confluent ulcerations or pseudomembranes, bleeding with minor trauma

Grade 4: tissue necrosis; significant spontaneous bleeding; life threatening consequences.

Grade 5: death

Functional/ symptomatic exam:

Grade 1: minimal symptoms; normal diet

Grade 2: symptomatic but can eat and swallow modified diet

Grade 3: symptomatic but unable to adequately aliment or hydrate orally Grade 4:symptoms associated with life threatening consequences Grade 5: death

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The Radiation Therapy Oncology Group (RTOG)79 determined the acute radiation morbidity scoring criteria for mucous membranes. It is as follows:

Grade 1- Irritation, may experience slight pain, not requiring analgesic.

Grade 2- Patient has patchy mucositis that may produce inflammatory serosanguinitis discharge; may experience moderate pain requiring analgesia.

Grade 3- Patient has confluent, fibrinous mucositis, may include severe pain requiring narcotic.

Grade 4- Patient has ulceration, hemorrhage, or necrosis.

Oral Mucositis Assessment Scale is objective assessment of oral mucositis based on the presence and size of the ulceration on the upper and lower lips, right and left cheeks, right and left ventral and lateral tongue, floor of the mouth, soft palate, and hard palate. The grading is as follows73

Grade 0- Indicates no lesion.

Grade 1- Size of the lesion is less than 1cm2. Grade 2- Size of the lesion is between 1 and 2 cm2. Grade 3- Size of the lesion is greater than 3 cm2.

Similarly, depending on the severity of erythema, it is graded as follows:

Grade 0- Indicates no erythema.

Grade 1- Indicates non severe erythema.

Grade 2- Indicates severe erythema.

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Although many scoring systems document the severity of mucositis and helps in evaluating the effect of intervention or prevention, all these scoring systems are subjective and hence intervariability is possible. In vitro assays help in quantization of mucosal injury.

Management of oral mucositis:

Although a variety of approaches have been taken to oral mucositis, a single efficacious intervention has not yet been identified. Treatment methods is basically divided as 1) basic oral care; 2) growth factors and cytokines; 3) anti-inflammatory agents; 4) antimicrobials, coating agents, anesthetics, and analgesics; 5) laser and other light therapy; 6) cryotherapy; and 7) natural and miscellaneous agents.

LOCALLY APPLIED NONPHARMACOLOGICAL METHODS:

a) Cryotherapy:

MAHOOD48 et al 1991 conducted a study to evaluate the efficacy of cryotherapy in the prevention of 5-Fluorouracil induced oral mucositis.

Cryotherapy causes vasoconstriction and temporarily decreases blood flow to oral mucous membrane. 5-Fluorouracil diffuses rapidly into all tissue compartments. The control group patients placed ice chips in their mouth 5 minutes prior to each dose of 5FU and the patients were asked to continuously swish the ice chips and replenish the ice chips before the ice chips have completely melted, for a total of 30 minutes. Grading of mucositis was assessed after 2 to 3 weeks by questionnaries and 1 month after the end of

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chemotherapy cycle by the physician. There was significantly less incidence of mucositis in the cryotherapy group and the grading of mucositis was also significantly less.

b) Soft lasers:

BENSADOUN R.J.5 et al 1999 studied the effects of low energy Helium- neon laser on prevention of radiotherapy induced mucositis among 30 head and neck cancer patients. Patients underwent treatment throughout the course of radiotherapy before each session. 60 mW HeNe laser of wavelength 632.8nm was given at posterior third of the internal surfaces of the cheeks, soft palate and anterior tonsillar pillars. HeNe lasers promote wound healing, modulates nerve conduction by production of endorphins and enkalphins and neutralises free radicals. He found that grade 3 mucositis occurred in 35.2% of patients in control group and 7.6% of patients in study group. Similarly, he found that the severity of severe pain was 23.8% in control group and 1.9% in patients of study group. Thus he concluded by saying that HeNe laser reduced the severity and duration of severe mucositis in radiotherapy patients.

c) Basic oral care:

K.K.F. CHENG40 et al 2000 conducted a study to assess the effect of oral care protocol in prevention of oral mucositis in pediatric cancer patients undergoing chemotherapy. The oral care protocol consists of tooth brushing, 0.9% saline rinse and 0.2% chlorhexidine mouth rinse. Clinical evaluations were performed twice a week for 21 days. He found that there was a 38%

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reduction in the incidence of ulcerative mucositis in children using the oral care protocol when compared to the control group. There was a significant reduction in the severity of oral mucositis and related pain intensity in the intervention group.

LOCALLY APPLIED PHARMACOTHERAPEUTICS:

a) Antiseptic and antibiotic agents:

Selective decontamination:

SPIJKERVET FKL75 et al 1990 conducted a prospective study to study the efficacy of antimicrobial lozenges of 1 g containing an antimicrobial combination of polytnyxin E (colistin) 2 mg, tobramycin 1.8 mg and amphotericin B 10mg. The lozenges were given 4 times daily throughout radiotherapy treatment. He found that the study group developed only erythema as clinical sign and did not develop pseudomembrane or ulcerations.

He concluded that selective decontamination of gram negative flora significantly decreased the severity of mucositis in head and neck radiotherapy PVP-Iodine:

RAHN R60 et al 1997 conducted a randomized, controlled prospective study on the efficacy of povidone iodine in the management of oral mucositis in 40 head and neck cancer patients. All the 40 patients received nystatin suspension, dexapanthenol tablets, rutoside tablet, weekly immunoglobulin intramuscular injections throughout radiotherapy and were asked to rinse with 100mL povidone iodine diluted 10:8 for 3 minutes 4 times daily. Oral

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mucositis was observed in 70% of patients in study group and in all patients of control group. He observed that the mean onset of mucostis was 2.25 weeks in treatment group and 1.5 weeks in control group. Grade 3 mucositis was seen in 4 patients of study group and in 13 patients of control group. Total duration of mucositis was 1-9 weeks in study group and 6-14 weeks in control group.

b) Mouth Coating agents:

Sucralfate:

ALLISON RR2 et al 1995 studied the effects of sucralfate for prevention and management of oral mucositis in 40 head and neck patients. Half of the patients were prophylactically initiated and were given 1gm suspended in 5cc of water, swished, swirled and swallowed every 6 hours from the start to completion of treatment along with 100mg fluconazole once daily for 14 days during the 4th and 5th week of treatment. The other half of patients was treated after the development of mucositis. None of the patients in the prophylactic group developed ulcerations. Patients in the therapeutic group became symptomatic in the 3rd week of treatment. Once treatment was started with sucralfate and fluconazole, they were able to return to normal diet within 10 days.

c) Cytoprotectants:

Vitamin E:

WADLEIGH RG84 et al 1992 evaluated the efficacy of vitamin E supplementation in the treatment of chemotherapy induced mucositis in a

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randomized, double blind, placebo controlled trial. Vitamin E has a stabilising action on many membranes due to its anti-oxidant properties. Since studies have shown that patients with malignancy have decreased serum vitamin E levels, this study was conducted to determine the usefulness of its supplementation. 18 patients who were undergoing chemotherapy were given either vitamin E oil or placebo as soon as mucositis developed. One mL of vitamin E oil, 400 mg/mL, was applied topically twice daily for 5 days. He found that 66% of patients treated with vitamin E oil showed complete resolution within 4 days whereas those given placebo didn’t show relief of symptoms during the same period.

d) Anti-inflammatory agents:

Corticosteroids:

J.H. LEBORGNE33 et al 1997 did a randomized, double blind study to study the effectiveness of corticosteroids in the management of oral mucositis.

32 patients were given 40 mg/ day prednisone and 34 patients were given placebo. Prednisone was given from day 8 to day 28. From day 29 through 33, dose was tapered to 20mg daily and from day 34 through 43 to 20mg every other day. Analysis of results showed that the total treatment duration was 29.9 days in treatment group and 34.4 days in placebo group. There was less treatment interruption in prednisone group. But there was no difference in the maximum mucositis, median duration of mucositis in both the groups.

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26 Benzydamine:

A.KAZEMIAN38 et al 2009 performed a prospective trial on head and neck cancer patients to evaluate the efficacy of benzydamine oral rinse in the prevention of oral mucositis. Benzydamine hydrochloride is a non steroidal agent which has analgesic, anti-inflammatory, anaesthetic and antimicrobial properties and reduced pro-inflammatory cytokines. Patients were given 0.15% benzydamine oral rinse and placebo and were asked to rinse with 15mL for 2 minutes, 4 times a day throughout radiotherapy. There was a statistically significant reduction in mucositis in the benzydamine group. There was statistically significant difference in the incidence of grade 3 mucositis between benzydamine group (43.6%) and placebo group (78.6%). The study also concluded that grade 3 mucositis was 2.6 times more frequent in placebo group. But few other studies have shown no significant results.

e) Multiagent mouthrinse:

BRUCE R ROTHWELL64 et al 1990 studied the effectiveness of multiagent mouthrinse. The solution contained tetracycline, 500 mg; nystatin, 1,200,000 U; hydrocortisone, 100 mg; and diphenhydramine elixir, 10 mL to make a solution of 250 mL. 12 patients were included in the study and were divided into experimental group who were given multiagent mouthrinse and control group who were given cherry syrup containing sorbitol, magnesia and alumina suspension, and vitamins. Patients were asked to rinse with 10ml of solution 4 times daily and mucositis was evaluated weekly. He noted that the

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patients in experimental group had lesser incidence of mucositis and was of less severity and did not increase in severity beyond the 3rd week. Though the study showed a decrease in mucositis, the population group was small.

f) Agents influencing mucosal proliferation:

Silver nitrate:

Maciejewski B47 et al 1991 evaluated the effects of silver nitrate which is an astringent that stimulates cell proliferation. 16 patients were painted with 2% silver nitrate 3 times a day covering the entire left buccal mucosa.

Conditioning of the mucosa was done from 5 days before radiotherapy to 3 days after the start of radiotherapy. The acute mucosal reactions on both the cheeks were evaluated every other day. He noted that the development of erythema started later than the contralateral mucosa. Similarly, in the conditioned mucosa, he noted that mucosa did not develop any worse reaction than severe erythema while in unconditioned mucosa, confluent mucositis was present.

g) Local Anaesthetics:

STINE MOGENSEN53 et al 2017 studied the efficacy of bupivacaine lozenge of 25mg in the management of oral mucositis pain in 50 head and neck radiotherapy patients who were randomized to treatment with bupivacaine taken up to every 2 hours plus standard pain treatment and standard pain treatment plus topical lidocaine in control group. He found that mean pain reduced significantly 60 minutes after taking the lozenge when

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compared with control group. Pain in the oral cavity also significantly reduced in the lozenge group when compared with study group. He concluded that bupivacaine can be used as add on strategy for pain management in mucositis patients.

SYSTEMICALLY APPLIED PHARMACOTHERAPEUTICS:

a) Agents influencing mucosal proliferation:

Beta Carotene:

MILLS14 et al 1988 studied the effects of beta carotene supplementation in management of oral mucosal reaction in synchronous radiochemotherapy treatment in 20 head and neck cancer patients. 10 patients assigned to treatment group were given 250 mg daily up to day 21 and thereafter 75 mg daily for the duration of the treatment. Beta carotene has protective effects on the mucosa and also has been found to have anti tumor effects. The author noted that the treatment group experienced less severe mucositis when compared to control group. Similarly, the time to develop severe mucositis was significantly delayed in treatment group. Although the results showed decrease in mucositis severity, the small group prevents statistical validity.

b) Immunomodulatory drugs:

Indomethacin:

PILLSBURY59 et al 1986 did a controlled, randomized, double blind study in 19 head and neck cancer patients. They were divided into 2 groups and were given either 25mg or placebo 4 times a day. He found that the onset of grade 3 mucositis delayed in the intervention group when compared to

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control group and there was no significant difference in the extent of tumor at the end of study in both the group. Inhibition of prostaglandin synthesis is the mechanism of action of indomethacin, which is an inflammatory mediator.

Since the therapeutic index of indomethacin for management of mucositis is less, further large scale studies are required to prove the hypothesis.

c) Cytoprotectants:

Amifostine:

BOURHIS J7 et al 2000 assessed the usefulness of amifostine in the management of oral mucositis in 26 head and neck cancer patients undergoing accelerated radiotherapy. Amifostine was given intravenously 150mg/m2 as rapid i.v. infusion(3 mins) in 20cc normal saline twice daily, 15 to 30 mins prior to each radiation therapy session. He found that grade 4 mucositis developed in less number of patients in amifostine group. Similarly, the duration of grade 3 mucositis was 25.1 days in amifostine group and 49.2 days in control group. The study showed that amifostine decreased the severity and duration of severe mucostis. But interruption was required in 38% of patients due to adverse effects.

d) Anti-inflammatory agents:

Placental extract:

KAUSHAL37 et al 2001 evaluated the efficacy of human placental extract in the treatment of oral mucositis in head and neck cancer patients. a randomized controlled trial was done in 120 patients divided into study and

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control group. When the study group developed grade 2 mucositis, placental extract 2 mL was given deep intramuscularly 5 days a week for 15 days. He observed that there was subjective decrease in pain in 80% of placental group patients when compared to 36.7% of control group. Progression to grade 3 mucositis is 40% in study group when compared to 86.7% in study group.

Subjective improvement in difficulty in swallowing was 93% in study group and 15% in control group.

e) Cytokines Palifermin:

MICHAEL HENKE28 et al 2011 conducted a prospective, double randomized, placebo controlled study on the efficacy of palifermin in the management of oral mucositis in head and neck cancer patients. Palifermin, a N terminal, truncated version of keratinocyte growth factor, is a fibroblast growth factor exerts cytoprotective effects on epithelial cells. Palifermin was given weekly 120µg/kg from 3 days and continued throughout radiochemotherapy. He noted that in patients taking palifermin, the percentage of patients with severe mucositis was less (51%) when compared with study group (67%). The duration of severe mucositis was less (4.5 days) in palifermin group when compared with control group (22 days). Similarly, the time to develop severe mucositis was prolonged in study group (45days) when compared with study group (32 days). He concluded that palifermin decreased

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the incidence, the duration of severe mucositis and prolonged the time to develop severe mucositis.

f) Haematopoietic growth factor:

Granulocyte- Macrophage Colony Stimulating Factor(GM-CSF):

KANNAN36 et al 1997 studied the efficacy and safety of GM-CSF in patients undergoing conventional fractionated radiotherapy. GM-CSF was given subcutaneously 1µg/kg body weight from 20Gy to end of radiotherapy.

The author noted that all patients developed grade I mucositis by the time they were administered 20Gy. In 4 patients, mucositis remained at grade I till the end of treatment. In 6 patients, it progressed to grade II after 40Gy was administered. All the lesions were less than 1 cm. none of the patients in the group developed grade III mucositis. The lesions healed 3-8 days after completion of radiotherapy.

g) Anti-Oxidants:

Zinc Sulphate:

ERTEKEIN20 et al 2004 studied the effects of zinc sulphate supplementation in the prevention and management of oral mucositis in head and neck cancer patients. He conducted a prospective randomized study on 30 head and neck cancer patients. 15 patients were given zinc sulphate 50 mg supplementation was given thrice daily at 8 hourly interval from the beginning till end of radiotherapy. He observed that none of the patients in study group developed grade 3 and grade 4 mucositis. He also observed that confluent

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mucositis developed earlier in control group than in zinc sulphate group and started to improve sooner in zinc sulphate group when compared to control group.

STUDIES RELATED TO THE PRESENT STUDY:

ZIEGLER80 et al 1990 conducted dose response study on clinical safety, pharmacokinetics and metabolic effects of glutamine supplementation in humans. Glutamine was given as oral dose at 0.1g/kg(low dose) and 0.3g/kg(high dose). Glutamine levels peaked 30 mins after oral ingestion.

Glutamine levels peaked at a mean concentration of 1028 ± 97 µM and 1328 ± 99 µM from baseline level of 721±25 µM. whole blood levels of its metabolites glutamate and ammonia also increased but could not be distinguished from its baseline values. When intravenous infusion of 0.0125 g/kg/hr was given, the peak levels rose after 30 mins to 725±36 µM. The initial half life is 12±2 minutes and terminal half life is 67±11minutes. No adverse effects were seen in any of the patients.

SANCHEZ50 et al 1999 reviewed the effects of glutamine which is a precursor in the formation of glutathione, an anti-oxidant. Glutathione is the most important anti-oxidant molecule quantitatively and qualitatively. It is tripeptide g-glutamyl-cysteinyl-glycine. Metabolism of glutamine forms glutamate, which is transported back to cytosol to form glutathione.

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Extracellular glutathione pretreatment protects cultured rat gastric cells from hydrogen peroxide damage by accelerating intracellular glutathione synthesis.

ANDERSON3 et al 2000 did a randomized, placebo, double blind, crossover study to evaluate the effects of mucositis in patients undergoing chemotherapy with predominantly doxorubicin containing regimens. Other agents were carboplatin, 5-Fluorouracil, leucovorin and methotrexate. 2g/m2 of either glutamine (intervention) or glycine(control) were given twice daily from the beginning of chemotherapy and was continued upto 14 days after chemotherapy. The author noted that the duration of mucositis was 4.5 days less in glutamine group when compared to glycine group. The severity of oral pain was also reduced in the glutamine group. He also noted that the number of days affected by ≥grade 2 was 4 days less in glutamine group.

AMARA70 et al 2008 reviewed the role of glutamine in the prevention of chemotherapy induced peripheral neuropathy. Peripheral neuropathy is seen in neurotoxic chemotherapy, especially with taxanes, platinum compounds, and vinca alkaloids. Glutamine is thought to have a neuroprotective role. 2 studies were reviewed in which patients under paclitaxel chemotherapy were given glutamine supplementation. Intervention group showed reduced numbness, dysesthesias, and motor weakness, as well as a smaller loss of vibratory sensation when compared with control group. Another study was reviewed where patients with colorectal cancer treated with oxalipaten were given glutamine. Patients showed reduced peripheral neuropathy. As these

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studies have smaller sample size, large placebo controlled, randomized studies have to be taken to assess the efficacy of glutamine.

SHARMA SM69 et al 2008 studied the levels of antioxidant glutathione in the serum of patients with oral cancer and compared with healthy controls.

Glutathione is an antioxidant and is made of the aminoacids glycine, glutamate and cysteine. When exposed to high levels of xenobiotics, more glutathione is utilised in the conjugation step of metabolism, making it less available for its anti-oxidant role. Antioxidants decrease oxidative damage to DNA and decrease abnormal increase in cell division. He compared the glutathione levels in 30 newly diagnosed squamous cell carcinoma of oral cavity patients preoperatively and 1 and 6 months post operatively and 15 healthy controls.

The mean glutathione level was significantly lower in oral squamous cell carcinoma patients when compared to healthy controls. He also noted that the glutathione levels gradually increased post operatively.

JODY E NOÉ31 2009 reviewed extensively the use of glutamine in the prevention of mucositis and cachexia. Oral glutamine supplementation enhances the selectivity of antitumor drugs by sensitizing tumor cells to chemotherapy treatment–related tissue injury and at the same time protects normal tissues from them. tumor growth is also counterbalanced by restoring host glutamine levels, glutathione production, and increased immune function through natural killer (NK) cell activity. Immune system is upregulated through increased production, would lead to decreased PGE2 synthesis and

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upregulation of NK cytotoxic activity. In normal tissues, toxicity secondary to radiation and chemotherapy occurs when glutathione levels are depleted which can be reversed by glutamine supplementation. The therapeutic dose range for GLN is 20 g/d via total parenteral nutrition, from 4 g orally twice daily to up to 30 g orally per day in divided doses. no clinical evidence of toxicity at doses up to 0.3 g/kg. If the liver enzyme levels are higher than 3 times the normal ranges, GLN should be used as a swish and spit, and not as a swish and swallow.

UYANGAA17 et al 2012 studied the immunomodulatory effects of glutamine and leucine against mucosal infection of Herpes Simplex Virus-1 in mice. 4% solution of glutamine and leucine were administered intraperitoneally either once or twice daily separately. The author noted that the mice administered with twice daily administration of glutamine and leucine has less viral load with significantly less levels of shedding virus, increased interferon-γ, increased Natural Killer cell activity by increased secretion of antiviral cytokines interferon-γ and Tumor Necrosis Factor-α.

CD4+ T cells which confer efficient protective immunity against mucosal HSV-1 also increased which was determined by increased IFN-γ+TNF- α+CD4+ T cells.

OLIVER CHOW55 et al 2014 reviewed the role of immunonutrition in wound healing. Immunonutrition is the use of specific nutritional elements to modulate the immune system during disease or trauma. Research on

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immunonutrition has led to the recognition of conditionally essential nutrients which are basically nonessential and become essential in certain clinical conditions. He briefly reviewed about glutamine which is the most abundant amino acid. Glutamine supplementation has found to decrease infectious complications. It protects from inflammatory injury through the expression of heat shock proteins that protect the cell during inflammation, injury and stress.

Glutamine is also considered as a nutritional mediator of inflammation.

GUL26 et al 2015 studied the beneficial role of oral glutamine supplementation in the management of esophagitis in lung cancer patients.

glutamine was given at a dose of 30g/day (10g/8h orally, dissolved in water or fruit juices) starting one week before radiotherapy and was continued for two weeks post radiotherapy to 16 patients and the rest 16 patients did not get glutamine supplementation. The author noted that 53.4% of glutamine group developed esophagitis whereas all patients in non-supplemented group developed esophagitis. Esophageal scintigraphy was done to evaluate the esophageal motility. Total transit time was prolonged in non- supplemented patients. cytokine levels significantly decreased in glutamine group especially IL-6 and IL-8. Total duration of esophagitis was less and the initial occurrence of esophagitis was delayed in glutamine group.

DE URBINA34 et al 2017 studied the effects of oral glutamine in inflammatory and autophagy response in 43 patients treated with abdominal radiotherapy in a double blind, randomized, controlled pilot study. Patients

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received 30g glutamine in intervention group or 30g casein in placebo group.

Both group showed increase in whole blood mRNA levels of inflammatory and autophagic markers, but patients of intervention group showed significantly lower expression of toll-like receptor 4 (TLR4), CD36, interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), cyclooxygenase- 2 (COX-2), and matrix metalloproteinase-9 (MMP-9), transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). Autophagy response was inhibited which increases cancer cell sensitivity to radiotherapy and chemotherapy.

PETERSON12 et al 2017 studied the effects of oral glutamine in management of oral mucositis in breast cancer patients receiving anthracycline based chemotherapy. This was a double blind, placebo controlled, crossover phase III trial where 163 patients were allocated each in intervention and control group. Patients who developed ≥grade 2 mucositis in chemotherapy where selected and were given either glutamine 2.5 mg per 5mL 3 times a day or placebo during the next chemotherapy cycle. 37.4% of patients in glutamine group developed grade 2 mucositis whereas it was seen in 42.9% of patients in control group. Grade 3 mucositis was seen in 1.2% of patients in glutamine group and 6.7% of patients in control group. Worst ulceration score was significantly less in glutamine group.

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CHATTOPADHYAY77 et al 2014 conducted a randomized, single institutional study to determine the efficacy of glutamine. 70 head and neck cancer patients were randomized to study or control group. Patients were given either oral glutamine suspension 10g in 1000mL 2 hours before radiation or nothing. 91.4% of patients in glutamine arm developed mucositis whereas 97.15% of patients in control group developed mucositis. Grade 3 mucositis was seen in 14.29% of patients in glutamine arm and 2.86%

developed grade 4. 37.14% of patients developed grade 3 mucositis and 17.14% of patients developed grade 4 mucositis in study arm.

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Materials and Methods

References

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