The effect of head and neck cancer on the oral food process Deficits in mastication, salivary flow, and swallowing Jorine A. Vermaire

The effect of head and neck cancer on the oral food process PhD Thesis, Utrecht University, the Netherlands, J.A. Vermaire, 2022 Manuscript Cover image: Pixabay Chapter images: Lay-out: J.A. Vermaire Printed by: Ipskamp printing ISBN: 978-94-6421-866-4 All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means without prior permission in writing from the author and the publisher holding the copyright of the published articles. This work was supported by the Dutch Cancer Society (NL45051.029.13) © Jorine Vermaire, Utrecht 2022 The copyright of some of the papers presented in this thesis has been transferred to the respective journals.

The effect of head and neck cancer on the oral food process Deficits in mastication, salivary flow, and swallowing Het effect van hoofd-halskanker op het voedselproces (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op maandag 10 oktober 2022 des ochtends te 10.15 uur door Jorine Ariane Vermaire geboren op 6 augustus 1992 te Goes

Promotor C.H.J. Terhaard Copromotoren C.M. Speksnijder C.P.J. Raaijmakers Beoordelingscommissie Prof. dr. R. de Bree Prof. dr. B.W. Raaymakers Prof. dr. A.J.W.P. Rosenberg Prof. dr. J.H.A.M. Kaanders Dr. H. Jager-Wittenaar

Contents Chapter 1 Introduction 7 Chapter 2 Mastication in health-related quality of life in patients treated for oral cancer: a systematic review 21 Chapter 3 Reliability of the Mixing Ability Test testing masticatory performance in patients with head and neck cancer and healthy controls 43 Chapter 4 Reliability of the 100 mL Water Swallow Test in patients with head and neck cancer and healthy subjects 57 Chapter 5 Mastication, swallowing and salivary flow in patients with head and neck cancer; objective tests versus patientreported outcomes 75 Chapter 6 Factors associated with masticatory function as measured with the Mixing Ability Test in patients with head and neck cancer before and after treatment: a prospective cohort study 105 Chapter 7 Factors associated with swallowing dysfunction in patients with head and neck cancer 121 Chapter 8 The course of swallowing problems in the first two years after diagnosis of head and neck cancer 139 Chapter 9 Summary and Discussion 161 Nederlandse samenvatting 172 List of Acronyms 178 List of Publications 179 Acknowledgements 181 Curriculum vitae 185

7 Chapter 1 Introduction

8 Food processing The main purpose of mastication is to break down food into smaller particles that bind to each other through saliva, forming a food bolus ready for swallowing and digestion.1,2 Mastication is a learned automatic complex process involving the interaction of hard and soft tissues in order to grind a food bolus prior to swallowing.3 In the mouth, food undergoes several steps: First, the food is transported from the front teeth to the molars (stage I transport). Here the food is analyzed through taste, retronasal olfaction and oral receptors of the somatosensory system. In the second step, the food is converted into a food bolus by means of the teeth and with the aid of saliva and lingual and facial muscles. In the third step, the chewed food is transported backwards to the oropharyngeal surface of the tongue (stage II transport). Finally, the upper esophageal sphincter is opened. The chewing movement takes place as food conversion and backward transport occur almost simultaneously, and food moves across the tongue surface.4 Through receptors in the oral cavity and nose, changes in food are sensed during chewing, which also leads to the perception of taste, smell, and texture of the food.5 Chewing also initiates various digestive and metabolic activities, both in the mouth and through reflexes in the cephalic phase (the secretion of gastric juices before food enters the stomach, due to the taste, sight, smell and/or thought of food), which ensure that digestion starts.4 Mastication involves several nerves, muscles, and connective tissue structures.6 The m. masseter, m. temporalis, m. pterygoidus medialis and m. pterygoidus lateralis are considered the main muscles of the masticatory system.7 These muscles work in a coordinated way with other muscle groups of the face during chewing, such as the infrahyoidal, suprahyoidal, palatal and temporomandibular muscles.8 During chewing, food hardness influences the masticatory force, activity and amplitude of mandibular (lower jaw) movements.2 Chewing is characterized by a relatively rhythmic movement of the chewing muscles.9 The cooperation between these jaw-opening and closing muscles is elicited by a central pattern generator in the brainstem.1,2 This pattern generator receives signals from the mouth and motor cortex, which are converted into a rhythmic chewing movement.9 Chewing can be unilateral, bilateral or alternating bilaterally. The preferred side in most cases depends on the number of occlusal units (the surface of a tooth that meets the surface of its opposing tooth in occlusion), and where they are positioned. When occlusion is the same on both sides, there is often a preference for alternating two-sided chewing; changing chewing sides regularly.7 Several factors influence the ability to chew efficiently, such as the maximum bite force, maximum mouth opening, sensory function of the tongue, tongue force, the number of occlusal units, and saliva flow. The maximum bite force depends on the muscle volume, the

9 1 muscle activity and the coordination between the different chewing muscles.1 It determines the amount of available force to cut and crush food.10 When the maximum mouth opening is reduced, this can have an adverse effect on food intake and the maintenance of good oral health, due to a lower masticatory efficiency.11 The tongue plays an essential initial role in breaking down food into a food bolus and moving food between the molars. The number of teeth determine the size of the occlusal area where the food is grinded and broken down during each chewing cycle.1,10 Tooth loss, the presence of cavities, inadequate restorations, malocclusion or periodontal disease can therefore adversely affect chewing function.2,5 Finally, the production of sufficient saliva is indispensable for good chewing as it moistens the food and binds the particles into a coherent bolus that can be easily swallowed.1,5 Saliva consists for 99% of water and 1% of ions, enzymes and other proteins. Chemicals in the food are dissolved in saliva and are therefore more easily transported to the taste buds, enabling us to taste food. Furthermore, saliva plays a role in the digestion of starch and lipids and in the clearance of food debris after swallowing.5 After the food is chewed and processed, swallowing takes place. This is a physiological process formed by oral, pharyngeal and esophageal phases.12 Swallowing occurs due to neuromuscular actions involving sensitive cranial, motor and parasympathetic nerves.13 Its purpose is to transport food from the mouth to the stomach, promoting hydration and nutrition. To transport food, a number of rapid, coordinated and accurate events have to occur, such as soft palate elevation, vocal fold closure, pharyngeal muscle contraction, laryngeal elevation and anteriorization and epiglottis lowering.14 These mechanisms occur involuntarily after stimulation of sensory receptors, especially located in the oropharyngeal cavity.13 The initiation of oral swallowing is voluntary, and depends on a threshold for food particle size and particle lubrication.1 The pharyngeal phase is considered a reflex response, and the esophageal phase is mainly under dual control of the somatic and autonomic nervous systems.15 The primary function of the oral phase is movement of the tongue, pressing the bolus against the hard palate, and initiating the movement of the bolus to the posterior part of the tongue and towards the oropharynx. In this stage, the contraction of the lips and cheek muscles are crucial to prevent the escape of solids and liquids from the oral cavity.15 The pharyngeal phase involves not only pharyngeal and laryngeal muscles, but also muscles in the oral cavity such as the tongue and suprahyoid muscles.15 The shape of the pharynx is altered dynamically for breathing, eating and vocalization. The pharynx dilates in order to maintain airway patency for breathing, and is constricted to push the food bolus down the esophagus during swallowing.16 The passage of food is separated from the lower airway and nasal cavity. It is essential that the coordination between respiration and digestion is well coordinated so that food can be efficiently transported to the stomach and intestines,

10 thus preventing aspiration of foreign materials into the trachea before or during swallowing.16 Since there is a brief pause in breathing when swallowing food, food should be chewed well and mixed with saliva to minimize swallowing time and the associated brief cessation of breathing.17 This pause in breathing is caused by the inhibition of respiration in neural control centers in the brainstem, and not simply due to closure of the upper airway.16 The esophageal phase consists of a peristaltic wave of muscle contraction, which propagates to the stomach. Head and neck cancer Head and neck cancer (HNC) is the seventh most common cancer worldwide, and develops in the mucosal surfaces of the upper aero digestive tract.18 HNC can be divided into different sub sites: the oral cavity (including the lips, tongue, floor of the mouth, hard palate, and gum), the pharynx (including the oropharynx, hypopharynx and nasopharynx), the larynx (supraglottic, glottic, and subglottic regions), the nasal cavity and paranasal sinuses, and the salivary glands. Risk factors for developing HNC are alcohol and tobacco (ab)use, or viral infections such as the human papilloma virus (HPV).18 Curative treatment options for HNC include surgery, radiotherapy (RT), chemoradiotherapy (CRT), or a combination of these treatment modalities. The type of treatment depends on the tumor site, tumor stage and patient characteristics. Early-stage cancers are usually treated with either surgery or RT, while locally advanced cancers are treated with surgery followed by adjuvant radiation or chemoradiotherapy.19 In addition, oral cavity tumors are most often treated with surgery, while oropharynx and larynx tumors are primarily treated with RT. Surgery The main goal of surgery is complete tumor resection while maximizing post-operative function. This is often difficult to achieve, and depends on several variables such as tumor size and location, neck involvement, type of surgical reconstruction and dental status of the patient.3 Surgery may require wide resections of one or multiple sub sites, including tongue, floor of mouth, or lower gingiva.20 It may be combined with reconstruction of the tumor site by a tissue transfer and/or neck dissection. A laryngectomy, in which the total larynx is removed, may be needed for advanced stage IV tumors. Radiotherapy RT uses ionizing radiation that damages and/or destroys all cells receiving a radiation dose, including normal tissue cells surrounding the tumor. By increasing the dose, the probability to destroy malignant cells increases as well. However, in order to spare healthy tissue, the dose to these fields has to be limited. It is therefore important to create a balance in which

11 1 the dose to the tumor can be maximized, while keeping the dose to the healthy tissues and organs at risk (OAR) acceptable.21 RT for HNC is usually divided into 35 fractions of 2 Gy spread out over seven weeks. Between each fraction, healthy tissue can recuperate from the radiation dose while malignant cells, who are less able to repair themselves, do not recover. However, damage to normal tissue cells still occurs, also caused by the reduced regenerative potential of irradiated tissue. Chemotherapy Chemotherapy is administered concomitantly with radiotherapy. Frequently used classical chemotherapeutics include cisplatin and carboplatin which are provided 3 times during the course of radiotherapy. Cisplatin acts by binding to DNA, thereby inhibiting the DNA synthesis. It enhances the effect of RT by inhibiting the repair of cells.22 Targeted therapy using the monoclonal antibody cetuximab is administered when patients are not fit enough to receive cisplatin. Cetuximab has fewer oral side effects, although systemic side effects such as acneiform rash, asthenia, and allergic reactions are common. Immunotherapy can be provided for patients with advanced head and neck cancer in a palliative setting, with immunotherapeutic agents such as nivolumab which can increase mean survival rates of patients.23 Toxicity after surgery During the oral phase of food processing, the teeth and tongue need to work together to transport the food to the molars. In addition, the muscles together with nerves and connective tissues need to break down the food to form a bolus, and transport the food backwards to the oropharyngeal surface of the tongue. Chewing and swallowing are interrelated, because chewing plays a fundamental role in the process of swallowing food.24 Surgical resection of the tongue will compromise lingual mobility and strength.3 Tongue dysfunction leads to impaired mastication, bolus formation and bolus transport, as tongue function is key to optimal mastication.3,25 Resection of masticatory and facial musculature will lead to facial deformity and loss of oral competence. A reduced closing pressure of the lips may lead to drooling.25 When nerves are transected, this may lead to sensory dysfunction of, e.g. the tongue, lips, chin, or facial musculature.26 Neck dissection can lead to impaired neck and shoulder mobility.27 Surgery may also result in alteration of the temporomandibular joint anatomy, disarticulation of the temporomandibular joint, loss and alteration of the masticatory muscles or loss of mandibular and maxillary structural integrity together with loss of teeth, leading to radical alteration of the oral anatomy.3 This can result in decreased tooth-to-tooth contact, sensory and soft-tissue deficits, and thus compromising the patients’ ability to form and manipulate a food bolus that is ready to be

12 swallowed. If mastication is compromised, tougher foods are more difficult to process because they require a higher muscle force and more chewing cycles.28 Therefore, some patients switch their diet to softer foods, because the muscle force needed to break down food is too high. This can negatively affect orofacial muscle tonus or even nutritional status.2,8 Malnutrition is defined as a state of nutrition in which a deficiency of energy, protein and other nutrients cause measurable adverse effects on tissue and body form.29 Malnutrition can result in a higher morbidity, mortality, and care costs, because these patients are at a higher risk to develop diseases and infections, caused by the negative impact on the immune response.24,30 Surgical resection of the soft palate, floor of mouth, or base of tongue can cause severe problems by compromising lingual mobility, muscle strength, mastication, swallowing, muscle action, and muscle coordination.31-33 Surgery of the larynx (laryngectomy) is the optimal therapy for advanced stage IV local disease, resulting in severe effects on swallowing and speech. Over 40% of postoperative patients may experience subjective dysphagia in long term follow-up.34 Dysphagia is a significant toxicity resulting in difficulty in swallowing, caused by abnormalities in structure or function of cartilaginous, bony, muscular or neural anatomy involved in normal swallowing.33 Dysfunction of the pharynx can lead to impaired swallow initiation, ineffective bolus propulsion, and retention of a portion of the bolus in the pharynx after swallowing.25 In addition, patients need to re-learn how to speak after a laryngectomy, for example by using esophageal speech, pneumatic speech, tracheoesophageal speech, or an electrolarynx. Similarly to masticatory problems, swallowing problems may also affect nutritional status, because a change in diet is often recommended when swallowing problems occur, by changing the consistency of liquids and/or food in order to prevent dysphagia.24 Toxicity after radiotherapy and chemo radiation Radiotherapy of the oral cavity may result in acute effects such as pain, mucositis, dermatitis, a decrease in saliva production, or edema.3,35,36 RT can also lead to necrosis of irradiated bone, resulting in osteoradionecrosis of the jaw.3 To prevent this, some teeth may need to be extracted pre-treatment.3 Loss of teeth reduces masticatory performance, as chewing can be prolonged, and particle size of the bolus becomes larger due to lower efficiency of mastication.25 Saliva is needed to moisten the food, bind the particles into a bolus and transport the bolus. In addition, it dilutes flavor and alters food consistency during mastication.37 Salivary glands are particularly sensitive to ionizing radiation, with doses to the parotid gland between 28 and 39 Gy leading to a 50% complication probability.38 Doses

13 1 over 50 Gy cause irreversible hypofunction and permanent xerostomia.39 When salivary glands are in the RT field, this will negatively affect saliva quantity and quality, exacerbating masticatory problems.25 The submandibular glands are responsible for most of the saliva production (60-65%) in the non-stimulated state,39 and are mainly responsible for flow rate during sleep. Most patients with HNC complain of a dry mouth at night caused by irradiation of the submandibular glands, with 65% of patients having severe complaints 1 year after RT.40 Long term RT damage may consist of fibrosis, periodontal disease, ulcers, or vascular toxicity. These effects can be attributed to hypoxic, hypo-vascular, or hypocellular tissue. RT often leads to fibrotic tissue and hyposalivation, which can also lead to trismus, xerostomia, and radiation-induced caries.41-43 Chemotherapy can add to these effects, because it causes immunosuppression and is not tumor specific but acts on all cells in the body. As a result, patients exhibit acute toxicity with oral manifestations, such as oral mucositis, nausea, vomiting, renal insufficiency, loss of hearing and appetite, cytopenia, xerostomia, neurotoxicity, and stomatotoxicity.37 In addition, it can enhance radiationinduced fibrosis of the muscles and cause edema.35 Irradiation of swallowing related normal tissues may lead to dysphagia, fibrosis, edema, ulcers, vascular toxicity, and osteoradionecrosis.44,45 Complications such as malnutrition, aspiration and subsequent pneumonia can occur.33 Irradiation of swallowing tissues may result in a thick, viscid saliva that impairs deglutition, resulting in significantly longer oral transit times and a delayed swallow initiation, a greater pharyngeal residue and decreased pharyngeal transport, a lower swallowing efficiency, a shorter cricopharyngeal opening duration, and ineffective laryngeal protection.25 This also puts the patient at risk for coughing and aspiration.3 Chemotherapy can add to the effects of RT and cause edema, mucositis and fibrosis of the swallowing structures.33 Food processing measurements To measure food processing, objective and subjective measures can be used. Objective measures are based on how well a person can perform a task, irrespective of what they experience while performing the task. Subjective measures depend on individual values and priorities, and thus reflect a patients’ expectation and personal importance of oral functioning on daily life satisfaction. Objective masticatory performance can be measured with, for example, comminution methods, sieving and optical scanning methods, gummy jelly as test food, and mixing ability methods.46 One method using the mixing ability method (the Mixing Ability Test (MAT)) has

14 proven to be highly reliable in patients with HNC.47 Objective swallowing performance can be measured with, for example, Fibreoptic Endoscopic Evaluation of Swallowing (FEES), or in a non-invasive and fast manner with minimal equipment using a 100 mL Water Swallow Test (WST).32,48,49 Measures of objective salivary flow rate from parotid and submandibular glands have been used for years to determine the dose response relationship between RT dose and degree of hyposalivation or sticky saliva.38,39,43,50,51 To obtain high quality measures, it is important to assess measurement properties such as reliability.52 The reliability of a test measures the degree to which a certain test produces stable and consistent results. This can be achieved by, e.g., a test-retest with corresponding intraclass correlation coefficient (ICC) (for continuous data). In addition, inter- or intra- rater differences can be assessed. During each test, a measurement error is thought to occur, either by the measurement instrument itself, the measurement situation, the person taking the test, or the person being tested. The general idea is that, the lower the measurement error, the higher the reliability and thus the quality of the measurement.52 Subjective oral functioning can be measured with several validated questionnaires.53 The European Organization for Research and Treatment of Cancer Quality of Life core Questionnaire, Head and Neck module (EORTC QLQ-H&N35) was especially developed to measure HNC specific problems and addresses different items of oral functioning.54-56 The Dutch version of the Swallow Quality of Life questionnaire (SWAL-QOL) was developed to address swallowing and food processing related problems.57,58 The Groningen RadiationInduced Xerostomia (GRIX) was developed to observe xerostomia and sticky saliva during day and night.59

15 1 Thesis outline As described above, mastication, swallowing and salivary flow are important functions which can deteriorate due to head and neck cancer itself, or because of its treatment. Therefore, the aim of this thesis is to further optimize the understanding of mastication, swallowing, and salivary flow in patients with head and neck cancer and investigate associated factors possibly affecting these functions, up to two years after treatment. Chapter 2 consists of a review that was written about masticatory ability, to provide an overview of the existing literature about oral health related quality of life (QoL) as measured with the University of Washington Quality of Life (UW-QoL) questionnaire. This questionnaire is often used in oral cancer, in which patients have to state whether they can chew normally, can only chew soft food, or cannot chew soft (nor hard) food. In order to predict the burden of masticatory and swallowing dysfunction, the first important step was to determine the reliability of the tests used to measure objective masticatory and swallowing function, and to determine the measurement error of these tests. Chapter 3 was written to assess the reliability of the Mixing Ability Test (MAT), which measures masticatory performance. The reliability of the 100 mL Water Swallow Test (WST) to assess swallowing was described in chapter 4. The next step was to determine the correlation between objective function outcomes and patient-reported outcomes, to investigate whether objective tests measure the same construct as patient-reported outcomes. Chapter 5 therefore assesses this correlation between objective tests and questionnaires. Based on chapter 5, associative models were created to investigate masticatory performance and swallowing function in relation to demographic and clinical factors, and to describe the course in time of these tests. In chapter 6, the associative model for masticatory performance was described, and in chapter 7 the associative model for swallowing function was described. Chapter 8 describes the course in time of the SWALQOL questionnaire, in which the whole food process from eating to swallowing, as well as mental problems caused by food processing difficulties, are taken into account. In addition, an associative model was created which describes patients that are most likely to experience problems after HNC treatment.

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17 1 22. Bhide SA, Nutting CM. Advances in chemotherapy for head and neck cancer. Oral oncology. 2010;46(6):436-438. 23. Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral oncology. 2018;81:45-51. 24. Mann T, Heuberger R, Wong H. The association between chewing and swallowing difficulties and nutritional status in older adults. Aust Dent J. 2013;58(2):200-206. 25. Matsuo K, Palmer JB. Anatomy and physiology of feeding and swallowing: normal and abnormal. Phys Med Rehabil Clin N Am. 2008;19(4):691-707, vii. 26. Spiegel JH, Deschler DG. Oral Cavity Reconstruction: Anatomy of the Oral Cavity and Related Structures 1st edition ed: Taylor & Francis; 2006. 27. Speksnijder CM, van der Bilt A, Slappendel M, de Wijer A, Merkx MA, Koole R. Neck and shoulder function in patients treated for oral malignancies: a 1-year prospective cohort study. Head & neck. 2013;35(9):1303-1313. 28. van der Bilt A, Abbink JH. The influence of food consistency on chewing rate and muscular work. Archives of oral biology. 2017;83:105-110. 29. O'Keeffe M, Kelly M, O'Herlihy E, et al. Potentially modifiable determinants of malnutrition in older adults: A systematic review. Clinical Nutrition. 2019;38(6):2477-2498. 30. Favaro-Moreira NC, Krausch-Hofmann S, Matthys C, et al. Risk Factors for Malnutrition in Older Adults: A Systematic Review of the Literature Based on Longitudinal Data. Adv Nutr. 2016;7(3):507-522. 31. Kreeft AM, van der Molen L, Hilgers FJ, Balm AJ. Speech and swallowing after surgical treatment of advanced oral and oropharyngeal carcinoma: a systematic review of the literature. Eur Arch OtoRhino-L. 2009;266(11):1687-1698. 32. Russi EG, Corvo R, Merlotti A, et al. Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: Review and recommendations of the supportive task group of the Italian Association of Radiation Oncology. Cancer treatment reviews. 2012;38(8):10331049. 33. Riffat F, Gunaratne DA, Palme CE. Swallowing assessment and management pre and post head and neck cancer treatment. Current opinion in otolaryngology & head and neck surgery. 2015;23(6):440-447. 34. Zenga J, Goldsmith T, Bunting G, Deschler DG. State of the art: Rehabilitation of speech and swallowing after total laryngectomy. Oral oncology. 2018;86:3847. 35. Nemeth D, Zaleczna L, Huremovic A, et al. Importance of chewing, saliva, and swallowing function in patients with advanced oral cancer undergoing preoperative chemoradiotherapy: a prospective study of quality of life. International journal of oral and maxillofacial surgery. 2017;46(10):12291236. 36. Owosho AA, Pedreira Ramalho LM, Rosenberg HI, et al. Objective assessment of trismus in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT). Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2016;44(9):1408-1413. 37. Caputo JB, Campos SS, Pereira SM, et al. Masticatory performance and taste perception in patients submitted to cancer treatment. Journal of oral rehabilitation. 2012;39(12):905-913. 38. Dijkema T, Terhaard CH, Roesink JM, et al. Large cohort dose-volume response analysis of parotid gland function after radiotherapy: intensity-modulated versus conventional radiotherapy. International journal of radiation oncology, biology, physics. 2008;72(4):1101-1109. 39. Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and function relationships in parotid salivary glands following conformal and intensitymodulated irradiation of head and neck cancer. Int J Radiation Oncology Biol Phys. 1999;45(3):577–587. 40. Dijkema T, Raaijmakers CP, Braam PM, Roesink JM, Monninkhof EM, Terhaard CH. Xerostomia: a day and night difference. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2012;104(2):219-223.

18 41. Wetzels JW, Merkx MA, de Haan AF, Koole R, Speksnijder CM. Maximum mouth opening and trismus in 143 patients treated for oral cancer: a 1-year prospective study. Head & neck. 2014;36(12):1754-1762. 42. Vissink A, Burlage FR, Spijkervet FKL, Jansma J, Coppes R. Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med. 2003;14(3):213-225. 43. Braam PM, Roesink JM, Raaijmakers CP, Busschers WB, Terhaard CH. Quality of life and salivary output in patients with headand-neck cancer five years after radiotherapy. Radiation oncology. 2007;2:3. 44. Hutcheson KA, Lewin JS, Barringer DA, et al. Late dysphagia after radiotherapybased treatment of head and neck cancer. Cancer. 2012;118(23):5793-5799. 45. Alterio D, Gerardi MA, Cella L, et al. Radiation-induced acute dysphagia : Prospective observational study on 42 head and neck cancer patients. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al]. 2017;193(11):971-981. 46. Elgestad Stjernfeldt P, Sjogren P, Wardh I, Bostrom AM. Systematic review of measurement properties of methods for objectively assessing masticatory performance. Clinical and experimental dental research. 2018;5(1):76-104. 47. Vermaire JA, Weinberg FM, Raaijmakers CPJ, Verdonck-de Leeuw IM, Terhaard CHJ, Speksnijder CM. Reliability of the mixing ability test testing masticatory performance in patients with head and neck cancer and healthy controls. Journal of oral rehabilitation. 2020. 48. Patterson JM, Hildreth A, McColl E, Carding PN, Hamilton D, Wilson JA. The clinical application of the 100mL water swallow test in head and neck cancer. Oral oncology. 2011;47(3):180-184. 49. Nathadwarawala KM, Nicklin J, Wiles CM. A timed test of swallowing capacity for neurological patients. J Neurol Neurosurg Psychiatry. 1992;55(9):822-825. 50. Roesink JM, Moerland MA, Battermann JJ, Hordijk GJ, Terhaard CH. Qualitative dosevolume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region. Int J Radiation Oncology Biol Phys. 2001;51(4):938–946. 51. Dijkema T, Raaijmakers CP, Ten Haken RK, et al. Parotid gland function after radiotherapy: the combined michigan and utrecht experience. International journal of radiation oncology, biology, physics. 2010;78(2):449-453. 52. Scholtes VA, Terwee CB, Poolman RW. What makes a measurement instrument valid and reliable? Injury. 2011;42(3):236240. 53. van der Veen J, Nuyts S. Can IntensityModulated-Radiotherapy Reduce Toxicity in Head and Neck Squamous Cell Carcinoma? Cancers. 2017;9(12):135. 54. Singer S, Arraras JI, Chie WC, et al. Performance of the EORTC questionnaire for the assessment of quality of life in head and neck cancer patients EORTC QLQH&N35: a methodological review. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2013;22(8):1927-1941. 55. Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQC30 (version 3.0) and the head and neck cancer specific module (EORTC QLQH&N35) in head and neck patients. EORTC Quality of Life Group. European journal of cancer. 2000;36(14):1796-1807. 56. Singer S, Araujo C, Arraras JI, et al. Measuring quality of life in patients with head and neck cancer: Update of the EORTC QLQ-H&N Module, Phase III. Head & Neck. 2014. 57. Bogaardt HC, Speyer R, Baijens LW, Fokkens WJ. Cross-cultural adaptation and validation of the Dutch version of SWALQoL. Dysphagia. 2009;24(1):66-70. 58. Rinkel RN, Verdonck-de Leeuw IM, Langendijk JA, van Reij EJ, Aaronson NK, Leemans CR. The psychometric and clinical validity of the SWAL-QOL questionnaire in evaluating swallowing problems experienced by patients with oral and oropharyngeal cancer. Oral oncology. 2009;45(8):e67-71. 59. Beetz I, Burlage FR, Bijl HP, et al. The Groningen Radiotherapy-Induced Xerostomia questionnaire: development and validation of a new questionnaire. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2010;97(1):127131.

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21 Chapter 2 Mastication in health-related quality of life in patients treated for oral cancer: a systematic review Jorine A. Vermaire Abbergayle S.K. Partoredjo Reilly J. de Groot Henk S. Brand Caroline M. Speksnijder Submitted

22 Abstract Background Treatment for oral cancer can impair oral functions such as mastication, which may negatively affect Quality of Life (QoL). In this review, an overview is provided of masticatory ability in patients treated for oral cancer. Methods The PubMed (MEDLINE), Embase and Cochrane databases were systematically searched for scientific literature on masticatory ability in relation to QoL in patients treated for oral cancer. Studies were included when oral cancer treatment was given, and the University of Washington Quality of Life questionnaire (UW-QoL) was used. Risk of bias (MINORS) was independently assessed by two authors. Results The PubMed (MEDLINE), Embase and Cochrane search yielded 575 unique records of which 111 were assessed full text, and 27 studies were included. The UW-QoL mastication scores ranged from 31.9 to 97.4. There was a wide variety in methodology, patient groups, tumor site, treatment, and assessment moment, to such a degree that outcome scores are difficult to compare. Conclusion The wide variety in studies exploring Health Related QoL in relation to mastication in oral cancer patients prevents the identification of possible relations between treatment, masticatory ability and QoL. Our findings underline the limitations in currently available literature and indicate the necessity for more comparable research.

23 2 Introduction Oral cancer is currently in the top ten most common cancers worldwide.1 More insight into oral cancer and advancement in procedures have contributed to a more effective treatment. However, tumor eradication is not the only outcome that should be included in the evaluation of treatment success. Quality of life (QoL) of patients after cancer treatment has become more significant in the past decade.2 A patient’s self-reported Health Related QoL (HR-QoL) contributes to a better understanding of the range of health challenges patients with cancer may encounter.3 Those issues may continue long after initial curative treatment, and can be easily overlooked without adequate follow-up and assessment of HR-QoL. Primary curative treatment for oral cancer is mostly surgical ablation of the tumor, which can be followed by (chemo)radiotherapy, depending on affected regional lymph nodes (Nstage), extent of radical resection, and tumor specific growth factors.4,5 The sequelae of curative treatment can temporarily or permanently impair oral functions, because treatment may affect vital structures for mastication, such as dentition, musculature, and nerves.3,6 This is one of the considerations for the multidisciplinary team regarding cancer treatment.7,8 Masticatory performance depends on maximum bite force, tongue function, maximum mouth opening and dental status.9,10 Ideally, to prevent loss of masticatory function, early identification of a lesion and referral to a head and neck cancer (HNC) specialist for further examination is preferred. Early-stage oral cancers with a relatively small affected area are less likely to drastically impact oral function after treatment. However, treatment of advanced tumors will include a larger area and more likely involve multiple structures, thus having a higher risk of impacting speech, mastication and swallowing.11,12 Post-surgery deformities may occur, depending on resection procedure. Aesthetics can be (partially) restored by reconstructing the affected site. Unfortunately, reconstruction has its limitations. For example, soft tissue reconstruction following a glossectomy can replace the missing part of the tongue with a free flap such as the radial forearm flap.13 Although the result can be aesthetically acceptable, this is not necessarily equivalent to adequate oral function. Tongue function will mostly depend on the remaining tongue structures after resection.13,14 After segmental mandibulectomy, loss of vital structures is linked to the location and extent of the resection.11 Nonetheless, fibula reconstruction in combination with implant rehabilitation in larger resections can give adequate oral function, provided that there is no tongue impairment, resulting in less impact on masticatory functioning.15 In addition, (chemo)radiotherapy may be indicated during treatment with concomitant oral complications such as trismus, xerostomia, mucositis, dyspepsia and increased risk of infectious disease.16-18

24 Although the importance and value of HR-QoL studies is widely acknowledged, there is little standardization in these studies.2 Use of different HR-QoL questionnaires makes it difficult to compare obtained data. One of the most frequently used questionnaires that specifically focuses on mastication is the university of Washington quality of life (UW-QoL) questionnaire.3 The UW-QoL is a brief and self-administered multi-factorial questionnaire, with questions specific to head and neck cancer (HNC), and reflects the QoL as indicated by the patient.19 To our knowledge, no overview is available regarding QoL based on UW-QoL outcomes in patients treated for oral cancer with an emphasis on masticatory ability. Therefore, this systematic review was conducted, to provide an overview of the available scientific literature on masticatory ability in relation to QoL in patients treated for oral cancer. This will provide insight into the effect of masticatory ability on HR-QoL in oral cancer patients after primary curative treatment. Methods This systematic review was conducted according to the preferred reporting item for systematic reviews and meta-analyses (PRISMA) guidelines.20 Eligibility criteria Studies that were eligible were full text articles focusing on HR-QoL and masticatory ability in oral cancer patients after primary curative treatment using the validated UW-QoL.3,19,21 There were no restrictions in year of publication or use of a translated version of the UWQoL. Exclusion criteria were: (1) studies that did not differentiate between different types of HNC; (2) inclusion of the oropharynx; (3) inclusion of the base of the tongue; (4) ameloblastoma or other benign tumors; (5) case reports, reviews, comments or ongoing trials; (6) and studies written in a language other than English. Information sources Studies were retrieved by searching the following electronic databases: PubMed, Embase and Cochrane. No limits were applied in the search. The final search was conducted on 2 November 2021. Search The search strategies terms were synonyms, variations and associated terms with regard to the following keywords: “head and neck neoplasms”, “mastication” and “quality of life”.

25 2 In PubMed, combinations of MeSH Terms and title/abstract were used. Embase and Cochrane had adapted search strategies based on the PubMed search strategy. Grey literature was not included. The full strategies for each database are presented in Appendix A. Study selection All records were imported in reference manager Endnote X9 (Clarivate Analytics 2013). After manual removal of duplicates, the eligibility assessment based on title and abstract was independently conducted by two authors (JV and AP). Afterwards, disagreements between reviewers were resolved by discussion. Full-text articles were obtained and independently assessed on inclusion and exclusion criteria. Conflicts between reviewers were resolved in all cases. If needed, a third author (CS) was available to resolve any disagreements. Data collection process, data items and summary measures A data extraction sheet was used, which included clinical and demographic characteristics of patients as well as study related details relevant to our review. One author (AP) extracted the data from included studies and the other author (JV) verified the extracted data. Any seemingly incorrect data were discussed. If needed, a third author (CS) was available to resolve any disagreements. The following information was extracted from each included study: (1) study characteristics (study design, number of included patients); (2) patients characteristics (sex, age, tumor site, tumor stage); (3) type of cancer treatment; (4) assessment (evaluation frequency, assessment moment, follow-up); and (5) UW-QoL outcome regarding masticatory ability (mean with standard deviation (SD) or standard error (SE)). When authors clearly defined different subgroups in their study, composed data as well as specified data were extracted. Risk of bias in individual studies The risk of bias was evaluated with the validated methodological index for non-randomized studies (MINORS).22 This instrument contains eight items for non-comparative studies and four additional items for comparative studies. The grading of each item is done by appointing one of three grades: not reported (0); reported but inaccurate (1); reported and adequate (2). The studies were independently assessed by two authors (JV and AP). Criteria for scoring each item were discussed by the two reviewers before as well as during the assessment of the publications. Any disagreements were resolved by discussion. A third

26 author (CS) was consulted in case of doubt. The ideal score for non-comparative studies is 16 and 24 for comparative studies. Synthesis of results and additional analyses The ability of MINORS to differentiate between poor or excellent quality studies has not been validated.22 Thus, rating the methodological quality as ‘poor’ or ‘excellent’ based on MINOR scores cannot be done. However, the scores can be displayed as a fraction of the ideal score and corresponding percentage. Results The search of PubMed (n=336), Embase (n=474) and Cochrane (n=53) provided a total of 863 records. After duplicate deletion, 575 unique records remained. After title and abstract were screened and consensus was reached between authors on all records, 464 studies were discarded. Of the 111 records that were read full text, a total of 27 studies were identified for inclusion in the review. No meta-analysis was performed in this study. An overview of the study selection process is shown in Figure 1. Study characteristics The studies selected for this review were 20 cross-sectional studies and 7 longitudinal studies, of which 11 were prospective, 10 were retrospective and 6 did not report prospective or retrospective data collection. The included studies involved a total of 1849 oral cancer patients of which at least 1308 were male, as one study did not report sex of patients.23 Eleven studies only reported mean or median age with SD and did not mention range.24-34 One study did not mention age of patients,23 and 3 studies categorized patients in age groups without further details about mean and SD.31,34,35 Studies were mainly conducted in China,28,33-44 followed by India,24,45-47 the United Kingdom,25,27,31,48 Brazil,26,32 the United States,30,49 Germany,29 and Pakistan.23 Tumor sites included: tongue, buccal mucosa, gingiva, floor of mouth (FOM), palate, retromolar region, lip, alveolar process, and gum. Tumor stage was reported in all studies, except one.48 All studies included patients with curative intended treatment, as mentioned in the inclusion criteria. However, the type of primary treatment differed: besides primary surgery (tumor resection), a (selective/functional) neck dissection was performed in some studies.24,25,32,33,35-37,39,42,45,48,49 Most surgical treatments included reconstruction.26-31,33-35,3740,42-48 Only two studies did not apply or mention adjuvant therapy.42,49 One study did not report any treatment details.23

27 2 Figure 1. PRISMA flowchart of the literature search and study selection Summarized literature search methodology, in accordance to the PRISMA Statement20 As stated in the inclusion criteria, HR-QoL outcomes were assessed in all studies by using the UW-QoL questionnaire. In addition, some studies also used the Oral Health Impact Profile (OHIP-14 or OHIP-49) questionnaire,34,38,40,42,43 and one study used the European Organization for Research and Treatment of Cancer Head and Neck Cancer module (EORTC QLQ-H&N35).43 Evaluation of HR-QoL outcomes was performed at different moments in time. In some studies, patients administered the questionnaire at least once pre- and posttreatment.24,41 Patients in other studies administered the questionnaire only once posttreatment.23,25,26,28,30,32-38,40,42,44-49 The questionnaire was administered twice post-treatment in two studies.31,43 The follow-up time between treatment and assessment of HR-QoL varied from less than 3 months46 to 10 years.31 Characteristics and assessment details are presented in Table 1. Risk of bias within studies The methodological quality of all studies was assessed and is presented in Table 2. The MINORS quality scores of non-comparative studies ranged from 44%23 to 69%,34,36,46 with an average of 60%. The MINORS quality scores of comparative studies ranged from 54%45,49 to 75%,28,33,34,41,44,47 with an average of 67%.

28 Results of individual studies Detailed outcome scores of each study are presented in Table 1. HR-QoL masticatory ability scores clustered by time are presented in Figure 2. Vakil et al. did not report any specific data to compare with other studies included in the present review.23 Agarwal et al. showed that the ability to chew solid food at baseline reduced to only semisolids and liquids post-treatment.24 Li et al. followed 47 hemiglossectomy patients and reported that only 7 patients complained about a negative effect on chewing ability.39 Rogers et al. stated that chewing scores were maintained over time.27 An 8-year longitudinal study by Yan et al. showed the worst QoL-scores for mastication 3 months post-treatment.41 The scores improved at the 1-year assessment and remained the same at the 8-year assessment. Nonetheless, overall, the problems with chewing significantly worsened between time of diagnosis and 8 years after treatment. Rogers et al. showed an improvement from 2 years to 10 years post treatment.31 Bekiroglu et al. reported a mean decline in chewing of 25 points after 1 year for patients treated with a combination of surgery and RT, and a mean decline of 7 points for those treated with surgery without RT.25 The percentage of patients considering chewing as one of the 3 most important domains of the UW-QoL differed between 33.3% (2nd rank)36 and 94.1% (1st rank).38 Other studies only reported the rank of the chewing domain: 1st rank,35,40,46 2nd rank,45 and 3rd rank.45 Soares et al. used an alternative way to present outcomes. At 41.5 months, patients scored as follows: cannot chew anything (n=26), chews light food (n=20) and chews light food and solids (n=1). There were no significant associations between chewing scores and demographic or clinical variables.26 Ochoa et al. reported patients scores as follows: I cannot even chew soft solids (n=0), I can eat soft solids but cannot chew some foods (n=2), I can chew as well as ever (n=37). Chewing was one of the worst scoring domains in this study.49 Vakil et al. also presented their findings in a slightly different manner. A score from 1 to 3 was used, where 1 indicated no change in chewing function and 3 indicated that patients could not chew soft food. In this study, the most frequently occurring value was 2 with a standard deviation of 0.7.23